EARLY THERAPEUTICS AND RARE CANCERS COMMITTEE 2017/RoS Spring 2017 with... · APRIL 26 - 29, 2017 SWOG EARLY THERAPEUTICS AND RARE CANCERS 5 Non-SWOG Studies with SWOG-Credited Registrations

APRIL 26 - 29, 2017 SWOG EARLY THERAPEUTICS AND RARE CANCERS 1

EARLY THERAPEUTICS AND RARE

CANCERS COMMITTEE


CONTENTS

S1609 Phase II ............................................................................................................................................................... 6

EAY131 Master Protocol / Phase II .............................................................................................................................. 8


Patient Registrations to Studies

By 12 Month Intervals

EARLY THERAPEUTICS AND RARE CANCERS COMMITTEE

Screening registrations and registrations to Biologic only studies are excluded

SWOG LAPS MEMBER NCORP

6

1214

3

13

76

0

10

20

30

40

50

60

70

80

Time of Registration

Jan 2011Dec 2011

Jan 2012Dec 2012

Jan 2013Dec 2013

Jan 2014Dec 2014

Jan 2015Dec 2015

Jan 2016Dec 2016

4

11

4

10

7

6

22

41

13


Patient Registrations by Study and Arm EARLY THERAPEUTICS AND RARE CANCERS COMMITTEE

Jul 2016

Dec 2016

Jan 2016

Jun 2016

Jul 2015

Dec 2015

All

Patients

A071102 GBM, adj TMZ +/- Veliparib*

Total Registrations 15 10 8 37

A071401 Prog Meningiomas, SMO/AKT/NF2 Inhib*


ARST1321 NonRhabdo STS,Pazopanib (PAZNTIS)*


EAY131 MATCH*


* For non-SWOG coordinated studies only SWOG registrations are shown.


Non-SWOG Studies with SWOG-Credited Registrations EARLY THERAPEUTICS AND RARE CANCERS COMMITTEE

Studies with Accrual from July 2015 – December 2016

SWOG

Champion

Date

Activated

Date

Closed

Total

Accrual

A071102 GBM, adj TMZ +/- Veliparib D Piccioni 09/19/14 Temp

closed 310

Most Recent Progress Report

A071401 Prog Meningiomas,SMO/AKT/NF2 Inhib D Piccioni 08/06/15 26


ARST1321 NonRhabdo STS,Pazopanib (PAZNTIS) V Villalobos 05/16/14 76


EAY131 MATCH V Villalobos 08/12/15 4121



S1609/II

S1609 Phase II

Coordinating Group: SWOG

DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors

Participants:

SWOG, CTSU

Study Chairs:

S Patel, Y Chae

Statisticians:

M Othus, M Plets, C Ebnesajjad

Data Coordinator:

C McLeod

Date Activated:

01/13/2017

Objectives To evaluate the RECIST 1.1 overall response rate

(ORR) in subsets of patients with advanced rare

cancers treated with ipilimumab plus nivolumab

combination immunotherapy.

To evaluate toxicities in each cohort.

To estimate overall survival (OS), progression-free

survival (PFS), clinical benefit rate; and to estimate

immune-related ORR (irORR), and immune-related

PFS (irPFS) by unidimensional immune-related

response criteria.

To collect specimens for banking for use in future

correlative biomarker research studies.

Patient Population Patients must have enrolled in EAY131, NCI-

MATCH, and were either not matched to a

molecularly-guided therapy or progressed on

molecularly-matched therapy and have no further

molecularly-matched treatment recommendations per

EAY131. Patients must have measurable disease and

histologically confirmed rare cancer and/or cancer of

unknown primary specified on the list of eligible rare

cancer histologic cohorts in the S1609 protocol.

Patients who do not qualify for one of the histologic

cohorts may be considered for registration in the "Not

Otherwise Categorized" Rare Tumors cohort with

confirmation of the study chairs.

Patients must not have received prior anti-PD-1 or

anti-PD-L1 therapy. Other immunotherapy is

permitted, provided that it is completed at least seven

days prior to registration. Patients who had prior

immune-related adverse event with prior

immunotherapy are not eligible. Patients with brain

metastases or primary brain tumors must have

completed treatment, surgery or radiation therapy ≥

28 days prior to registration and have stable disease

at time of registration. Patients with metastatic brain

parenchymal disease must have been treated and

patients must be off steroids for seven days prior to

registration. Patients must have been off all other

systemic anti-cancer therapy at least seven days prior

to registration and any therapy-induced toxicity must

have recovered to ≤ Grade 1.

Patients must have a Zubrod performance status of 0-

2 and have adequate hematologic, hepatic, renal,

thyroid, and adrenal axis function. Patients must not

have active autoimmune disease that has required

systemic treatment in past two years or any

uncontrolled intercurrent illness. Patients must not

have known active Hepatitis B Virus (HBV) or

Hepatitis C Virus (HCV) infection at time of

registration. Patients with HBV or HCV that have an

undetectable viral load, or in the opinion of the


S1609/II

treating investigator is well controlled, are eligible.

Patients who are known to be HIV-positive at

registration are eligible if they meet the conditions

outlined in the protocol.

Stratification/Descriptive Factors Patients will be described by histologic cohorts.

Accrual Goals The accrual goal for this study is 334 patients to

achieve 300 eligible patients. A two-stage design will

be used. Initially, six eligible patients will be

registered to each histologic cohort. If at least one

response is observed within a cohort, an additional 10

eligible patients will be registered to that cohort.


EAY131

EAY131 Master Protocol / Phase II

Coordinating Group: ECOG-ACRIN

NCI-MATCH: Molecular Analysis for Therapy Choice

Participants:

ECOG-ACRIN, CTSU

Study Chairs:

K Flaherty (ECOG-ACRIN), B Conley (NCI),

P O'Dwyer (ECOG-ACRIN), A Chen (NCI),

V Villalobos

Date Activated:

08/12/2015

SCHEMA

Objectives To evaluate the proportion of patients with objective

response (OR) to targeted study agent(s) in patients

with advanced refractory

cancers/lymphomas/multiple myeloma.

To evaluate the proportion of patients alive and

progression free at six months of treatment with

targeted study agent in patients with advanced

refractory cancers/lymphomas/multiple myeloma.

To evaluate the time until death or disease

progression.

To identify potential predictive biomarkers beyond

the genomic alteration by which treatment is assigned

or resistance mechanisms using additional genomic,

RNA protein and imaging-based assessment

platforms.

To assess whether radiomic phenotypes obtained

from pre-treatment imaging and changes from pre-

through post-therapy imaging can predict objective

response and progression-free survival and to

evaluate the association between pre-treatment

radiomic phenotypes and targeted gene mutation

patterns of tumor biopsy specimens.

Patient Population Patients must have histologically documented solid

tumors or histologically confirmed diagnosis of

lymphoma or multiple myeloma that has progressed

following at least one line of standard systemic

Screening

Registration

Tissue Submission for

Molecular Profiling

No Molecular Profile

of Interest

Treatment for

Molecular Profile of

Interest

*Upon progression or inability to tolerate protocol treatment, patients may be re-screened for additional molecular profiles

of interest and corresponding protocol treatment.

Off Study

Toxicity or

Progression*


EAY131

therapy and/or for whose disease no standard

treatment exists that has been shown to prolong

survival. Patients must have measurable disease and

meet one of the criteria in the protocol regarding

tissue procurement.

Patients must not currently be receiving any other

investigational agents. Any prior therapy,

radiotherapy (except palliative radiation therapy of

30 Gy or less), or major surgery must have been

completed at least four weeks prior to treatment on

NCI-MATCH and patient must be recovered from

adverse events due to prior therapy (except alopecia

and lymphopenia). Palliative radiation therapy must

have been completed at least two weeks prior to

enrollment on a NCI-MATCH treatment subprotocol,

and patient must have recovered from any adverse

events of this therapy. Patients with brain metastases

or primary brain tumors must have completed

treatment , surgery, or radiation therapy at least four

weeks prior to start of treatment. Patients must not

require the use of full dose coumarin-derivative

anticoagulants. Factor X inhibitors are permitted.

Patients may receive non-protocol treatment after

biopsy (if clinically indicated) until they receive

notification of results, but patients may not enroll in

another investigational study during this time and the

therapy cannot be an arm in this trial.

Patients must be at least 18 years of age, have an

ECOG performance status of 0 or 1 and must be able

to swallow tablets. Patients must have adequate

hematologic, hepatic, renal, cardiac and marrow

function. Patients must not have any uncontrolled

intercurrent illness. HIV-positive patients are eligible

provided they meet protocol criteria. Each

subprotocol will have additional eligibility criteria

that will be outlined in Section 2.0 of the agent-

specific subprotocol.

Accrual Goals The target screening accrual for this study is

approximately 3,000 patients, with the goal of

accruing 35 patients in each treatment subprotocol. If

after screening 500 patients, the total number of

patients with actionable tumor alteration (therefore

qualifying for treatment) is below 50, results will be

presented to the steering committee for consideration

of terminating the trial. Within any given

subprotocol, if rate of enrollment is such that it is

unlikely accrual can reach 25 patients by the time the

overall study screening accrual goal is met, and if 13

patients have been treated and no responses have

been observed, then the steering committee may

consider terminating accrual in that subgroup due to

lack of feasibility. After 500 patients are screened,

the study design will be reassessed to assure its

appropriateness. An interim analysis of the assay

results will be performed after biopsies from

approximately the first 200 patients are processed.

Summary Statement This study activated on January 26, 2015, with 10

subprotocols included in the activation. Only sites

utilizing the CIRB as their IRB of record are able to

participate in the trial. The study was temporarily

closed to accrual on November 11, 2015, after rapid

accrual of 795 patients to the screening step in only

three months, including 119 SWOG registrations.

This pause in patient enrollment for assessment of

study design appropriateness was lifted on May 31,

2016, when this study reopened to enrollment with an

additional 14 new subprotocols. As of November 16,

2016, accrual to subprotocol N has been suspended

due to drug supply shortage.

ECOG-ACRIN reported a total of 4,121 registered

patients and 368 molecularly matched patients as of

December 31, 2016. This includes 512 screened and

46 molecularly matched SWOG registrations. The

complete Spring 2016 summary of this study from

ECOG-ACRIN is available on the SWOG web site.


EAY131

Registration by Institution

Screening

Registrations ending December 31, 2016

Institutions

Total

Reg Institutions

Total

Reg

Henry Ford Hosp 54 San Antonio, U of TX 7

Cleveland Clinic OH 47 Dayton NCORP 6

Southeast COR NCORP 37 Providence Hosp 6

Kaiser Perm NCORP 28 Arkansas, U of 5

Colorado, U of 27 KaiserPermanenteSCAL/Kaiser Perm NCORP 5

Michigan, U of 27 Kansas City NCORP 5

Sutter Cancer RC 23 Mem Hosp, Co Springs/Colorado, U of 5

Yale University 23 Ozarks NCORP 5

KaiserPermanenteCOL/Kaiser Perm NCORP 20 Beaumont NCORP 4

Kentucky, U of 20 Kadlec Clinic Hem/Fred Hutchinson CRC 4

Fred Hutchinson CRC 18 S Georgia Med Ctr/Brooke Army Med Ctr 4

Wayne State Univ 17 City of Hope Med Ctr 3

Intermountain MC/Northwest NCORP 16 St Jude Medical Ctr/Irvine, U of CA 3

Kansas, U of 16 Cookeville Reg MC 2

Cedars-Sinai Med Ctr 12 Baptist MU-NCORP 1

Poudre Valley Hosp/Colorado, U of 12 CORA NCORP 1

Sutter General Hosp/Sutter Cancer RC 10 Irvine, U of CA 1

Tulane University 10 San Diego, U of CA 1

Davis, U of CA 9 Sinai Hospital/San Antonio, U of TX 1

Hawaii MU-NCORP 8 St Charles Hlth Sys/PCRC NCORP 1

Methodist Hospital 8 Total (41 Institutions) 512

Registration by Institution

Molecularly Matched

Registrations ending December 31, 2016

Institutions

Total

Reg Institutions

Total

Reg

Colorado, U of 5 CORA NCORP 1

Henry Ford Hosp 5 Dayton NCORP 1

Kentucky, U of 5 Hawaii MU-NCORP 1

Cleveland Clinic OH 4 Kansas City NCORP 1

Michigan, U of 4 Methodist Hospital 1

KaiserPermanenteCOL/Kaiser Perm NCORP 3 Providence Hosp 1

Yale University 3 Sutter Cancer RC 1

Arkansas, U of 2 Sutter General Hosp/Sutter Cancer RC 1

Cedars-Sinai Med Ctr 2 Tulane University 1

Davis, U of CA 2 Total (20 Institutions) 46

Southeast COR NCORP 2

A071102 November 2016

Template Version Date: September 24, 2013

Alliance Study A071102 – A Phase II/III Randomized trial of Veliparib or Placebo in Combination with Adjuvant Temozolomide in Newly Diagnosed GBM with MGMT Promoter Hypermethylation

Committee: Neuro-oncology Study Statisticians: Karla Ballman, Ph.D. Study Chair: Jann N. Sarkaria, M.D. S. Keith Anderson, M.S. 1.0 OBJECTIVES Primary

Test whether the experimental combination of ABT-888 (veliparib) combined with TMZ, compared to the control of placebo combined with TMZ, significantly extends overall survival in newly diagnosed GBM patients with tumor MGMT promoter hypermethylation.

Secondary 1. Test whether the experimental treatment significantly extends progression-free

survival. 2. Test whether the experimental treatment improves objective tumor response. 3. Test whether the experimental treatment is associated with significantly greater rates

of grade 3 or higher adverse events.

2.0 CURRENT SCHEMA

3.0 ELIGIBILITY CRITERIA Inclusion Criteria

• Newly diagnosed Grade IV intracranial glioblastoma or gliosarcoma. GBM with oligodendroglial features are NOT PERMITTED in this study if they are 1p19q codeleted.

• Sufficient tissue available for central pathology review and MGMT methylation status evaluation.

• Age ≥ 18 years of age.



• Patients who have had a local MGMT testing that is unmethylated are not allowed to participate.

• Tumor MGMT promoter hypermethylation determined by central testing at MD Anderson.

• Confirmation by central pathology review of WHO Grade IV glioblastoma or gliosarcoma.

• Required initial laboratory values within 14 days prior to study registration: Absolute neutrophil count ≥ 1500 cells/mm3, Platelets ≥ 100,000 cells/mm3, Creatinine ≤ 1.5x ULN, Bilirubin ≤ 1.5x ULN unless patient has Gilbert’s disease, ALT ≤ 3 x ULN, AST ≤ 3 x ULN.

• ECOG Performance Status ≤ 2. • Measurable disease and/or non-measureable disease as defined in section 11.0 of the

protocol. • Patient with complete resection, partial resection, or biopsy are eligible. • Patients deemed to have progressive disease based on clinical deterioration after

chemo-radiation or radiographic progression outside of the radiation field are not eligible. Patients deemed to have pseudo-progression are eligible.

• Not pregnant and not nursing. • Patients receiving anticoagulation should be on stable dose 2 weeks prior to

registration. • Cannot have a seizure disorder that is uncontrolled at the time of registration. The

definition of controlled seizures is patients must be without seizures for at least 10 days prior to registration.

• Cannot have grade 3 or 4 thromboembolic disease within 6 months of registration. • Cannot have a known history of prolonged QT syndrome. • No history of major surgery ≤ 14 days prior to registration.

4.0 TREATMENT SCHEDULE

The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report). 5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors This study is a randomized phase II/III trial in patients with newly diagnosed GBM. A dynamic allocation procedure with a 1:1 randomization will be used to allocate an equal number of patients to two arms. This procedure will balance the marginal distributions of the stratification factors among arms. The stratification factors that will be used are: age (≤ 70 vs. >70), performance score (ECOG 0-1 vs. 2), and extent of resection (gross total resection vs. subtotal resection or biopsy).

5.2 Primary Endpoint The phase II trial has PFS as the primary endpoint and will have one interim analysis for futility using a Lans-DeMets boundary. A total sample size of 293 for the phase II trial will yield 90% power to detect a HR of 0.67 (equivalent to the median PFS of 8.7 vs. 13.0 months) using a one-sided log-rank test with a type I error rate of 0.2 and one interim analysis for futility. The interim analysis for the phase II will occur after 79 PFS events have been observed. We will recommend the trial be stopped for futility if the observed HR (comparing control to experimental arm) is greater than 0.97 at the interim analysis. At the end of the phase II trial we will perform an analysis when 121 PFS events have been observed. We will recommend not proceeding with the phase III trial if the observed HR is 0.86 or greater. The phase III portion of the study has OS as the primary endpoint with one interim analysis (to be done at the completion of the Phase II portion). Based on the RTOG 0525 study, the median overall



survival (OS) for patients with MGMT promoter methylation assessed by the standard qMSPCR assay planned in this study is about 21.2 months with standard therapy of RT/TMZ followed by adjuvant TMZ. In the phase II portion of the study, we plan to enroll a total of 293 patients (73% of total patients needed for phase III comparison) in 4.1 years (49 months) and will do an interim futility analysis for OS (to be done by an independent statistician) if the phase II study was positive (based on PFS). The interim futility analysis will be based on the number of deaths observed at the time the phase II PFS data are mature. We will compare the OS curves and resume the accrual and move on to phase III portion using a futility boundary that accounts for the amount of study information (portion of total deaths) on hand at the time of the phase II final analysis. The table below contains example boundaries as a function of the proportion of deaths (amount of information) observed. The independent statistician will determine the proportion of deaths (amount of information) and use the appropriate futility boundary that spends a beta amount of no more than 0.001. These are Lan-DeMets futility boundaries with OF parameter.

Amount of information

Number of deaths

Do not continue if p-value ≥

Do not continue if HR ≥

10% 30 1.00 4.59 15% 45 1.00 2.43 20% 60 0.99 1.77 25% 76 0.95 1.45 30% 91 0.88 1.28 35% 106 0.82 1.17 40% 121 0.69 1.09 45% 136 0.59 1.04 50% 151 0.48 0.99

Once the study moves on to the phase III portion, we plan to accrue another 107 patients (for a total sample size of 293+107=400 in phase III) in 1.5 years (18 months) with a minimum follow up of 2 years to get a total of 302 death events. This design with one interim analysis for futility will yield 90% power to detect a hazard ratio of 0.71 (median OS of 21.2 vs. 29.7 months) using a one-sided log-rank test with a type I error rate of 0.05. The final analysis of the phase III trial will occur when 302 deaths have been observed (expected approximately 3.5 years after phase III portion opens) and we will conclude the combination therapy TMZ/ABT888 extends the OS significantly if the observed OS HR is 0.82 or smaller (an observed increase in median OS from 21.2 to 25.6 months). 5.3 Target Accrual The target accrual for this study is 440 patients using a 1:1 randomization. We anticipate 338 GBM patients per year will be registered for pathology central review and central MGMT testing. In the RTOG 0525 experience, 71% of patients registered for screening were ultimately randomized to therapy, and 30% of patients with MGMT testing were found to have MGMT promoter hypermethylation. Therefore we anticipate an accrual yield of 21.3% (71%*30%) of pre-registered patients will be enrolled in this study. Thus we expect the accrual rate will be about 72 evaluable methylated (338*21.3%) patients per year from screening, so the target accrual rate is 6 patients per month.

6.0 CURRENT ACCRUAL

Study Activation Date 12/15/2014 Target Accrual (n) 440 Patients screened or pre-registered (n) 980 Current Accrual (n) 229 Expected Accrual Rate 6/month Accrual Rate – Since activation 10.9/month Accrual Rate – Past 6 months 18.2/month



Accrual Rate – Past 12 months 15.4/month

0 0 0 5 3 1 6 9 714 5

1012

1718

2518

1414

17212

Expected Accrual 440 Patients

7.0 CURRENT STUDY STATUS

As of 09/07/2016 a total of 980 patients have been preregistered for this study. Of these 980 patients, 163 of them are still in the pre-registration phase. Of the 817 patients who have completed pre-registration, there have been 588 patients deemed screen failures that will not move forward with registration, and 229 patients have been registered for the study. This means that 28.03% of patients who are being pre-registered are continuing on to treatment. This is greater than the 21.3% projected in section 5.3 of this report. The Statistician team is closely monitoring (via weekly reports) the pre-registration, accrual, and the conversion rate of patient pre-registration to patient accrual. In light of the up to 16-week lag-time from patient pre-registration to registration, the statistician team has developed forecasting tools and graphs to help monitor and determine the appropriate point in time to close pre-registration to prevent over accrual.

8.0 PATIENT CHARACTERISTICS

Per protocol, all ineligible (N=8) and canceled (N=3) patients are removed from the tables below.

Table 8a. Demographics



Total

(N=218) Age N 218 Mean (SD) 59.4 (12.3) Median 61.0 Q1, Q3 53.0, 68.0 Range (20.0-85.0) Race White 197 (90.4%) Black or African American 8 (3.7%) Asian 3 (1.4%) American Indian or Alaska Native 1 (0.5%) Not reported: patient refused or not available 5 (2.3%) Unknown: Patient unsure 4 (1.8%) Gender Female 91 (41.7%) Male 127 (58.3%)

Table 8b. Stratification Factors

Total

(N=218) Age Group Missing 11 < 70 years 164 (79.2%) >= 70 years 43 (20.8%) ECOG Performance Status 0 or 1 203 (93.1%) 2 15 (6.9%) Extent of Surgical Resection Gross Total 130 (59.6%) Subtotal or Biopsy 88 (40.4%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary Adverse events are reported using CTCAE version 4, regardless of attribution. Adverse Events reported as regardless of attribution, are included in the tables below. Two hundred and three patients are evaluable for adverse events (AE) analysis. There have been 2 deaths on treatment. One patient experienced grade 5 aspiration (unlikely related to treatment; during cycle 2). This patient also experienced grade 4 cerebral edema (unlikely related to treatment; during cycle 1) as well as grade 4 adult respiratory distress syndrome (possibly related



to treatment; during cycle 2). Another patient experienced a grade 5 thromboembolic event (possibly related to treatment; during cycle 3). There were also forty-seven grade 4 events experienced by twenty-eight patients (including the two events listed above); however, only forty of these events experienced by twenty-five patients were at least possibly related to treatment. Eighteen patients experienced thrombocytopenia, thirteen patients experienced neutropenia, two patients experienced seizure, two patients experienced leukopenia, one patient experienced adult respiratory distress syndrome, one patient experienced an unspecified blood or lymphatic system disorder, one patient experienced lymphocytopenia, one patient experienced psychosis, and one patient experienced a thromboembolic event.

Summary of Grade 3+ Adverse Events

Regardless of Attribution Number of Evaluable Patients: 203

Patients with a maximum: n (%)

Total

Grade 3 Event 60 (29.6%)



Hematologic Adverse Events




Non-Hematologic Adverse Events




Note: Summaries are based on available patient data

Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event


Grade of Adverse Event 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)

Hematologic Adverse Events Blood/Bone Marrow

Anemia 1 ( 1%) 0 ( 0%) 0 ( 0%) Blood and lymphat sys disord - Oth spec

0 ( 0%) 1 ( 1%) 0 ( 0%)

Bronchial infection 1 ( 1%) 0 ( 0%) 0 ( 0%) CD4 count 1 ( 1%) 0 ( 0%) 0 ( 0%) Leukocytosis 1 ( 1%) 0 ( 0%) 0 ( 0%)






Lymphopenia 23 ( 13%) 1 ( 1%) 0 ( 0%) Meningitis 1 ( 1%) 0 ( 0%) 0 ( 0%) Neutrophils/granulocytes (ANC/AGC)

14 ( 8%) 15 ( 8%) 0 ( 0%)

Platelets 20 ( 11%) 15 ( 8%) 0 ( 0%) Portal vein thrombosis 1 ( 1%) 0 ( 0%) 0 ( 0%) White blood cell decreased 8 ( 4%) 3 ( 2%) 0 ( 0%)

Non-Hematologic Adverse Events Auditory/Hearing

Hearing loss 1 ( 1%) 0 ( 0%) 0 ( 0%) Hip fracture 1 ( 1%) 0 ( 0%) 0 ( 0%)

Cardiovascular Hypertension 3 ( 2%) 0 ( 0%) 0 ( 0%)

Constitutional Symptoms Fatigue (asthenia, lethargy, malaise)

11 ( 6%) 0 ( 0%) 0 ( 0%)

Generalized muscle weakness 3 ( 2%) 0 ( 0%) 0 ( 0%) Gastrointestinal

Colitis 1 ( 1%) 0 ( 0%) 0 ( 0%) Constipation 2 ( 1%) 0 ( 0%) 0 ( 0%) Dehydration 1 ( 1%) 0 ( 0%) 0 ( 0%) Diarrhea 1 ( 1%) 0 ( 0%) 0 ( 0%) Dysarthria 1 ( 1%) 0 ( 0%) 0 ( 0%) Dysphagia (difficulty swallowing) 1 ( 1%) 0 ( 0%) 0 ( 0%) Edema cerebral 0 ( 0%) 1 ( 1%) 0 ( 0%) Nausea 1 ( 1%) 0 ( 0%) 0 ( 0%) Nervous system disorders - Oth spec

1 ( 1%) 0 ( 0%) 0 ( 0%)

Vomiting 4 ( 2%) 0 ( 0%) 0 ( 0%) Infection/Febrile Neutropenia

Infection with unknown ANC 1 ( 1%) 0 ( 0%) 0 ( 0%) Metabolic/Laboratory

Glucose, serum-high (hyperglycemia)

2 ( 1%) 1 ( 1%) 0 ( 0%)

Sodium, serum-low (hyponatremia) 1 ( 1%) 0 ( 0%) 0 ( 0%) Musculoskeletal






Muscle weakness (not due to neuropathy)

3 ( 2%) 0 ( 0%) 0 ( 0%)

Neurology Cognitive disturbance 1 ( 1%) 0 ( 0%) 0 ( 0%) Confusion 4 ( 2%) 0 ( 0%) 0 ( 0%) Encephalopathy 1 ( 1%) 0 ( 0%) 0 ( 0%) Hydrocephalus 1 ( 1%) 0 ( 0%) 0 ( 0%) Psychosis (hallucinations/delusions)

0 ( 0%) 1 ( 1%) 0 ( 0%)

Rash maculo-papular 4 ( 2%) 0 ( 0%) 0 ( 0%) Seizure 0 ( 0%) 2 ( 1%) 0 ( 0%) Skin and subcut tissue disord - Oth spec

1 ( 1%) 0 ( 0%) 0 ( 0%)

Syncope (fainting) 5 ( 3%) 0 ( 0%) 0 ( 0%) Thromboembolic event 3 ( 2%) 3 ( 2%) 1 ( 1%)

Pain Pain 4 ( 2%) 0 ( 0%) 0 ( 0%)

Pulmonary Adult Respiratory Distress Syndrome

0 ( 0%) 1 ( 1%) 0 ( 0%)

Aspiration 0 ( 0%) 0 ( 0%) 1 ( 1%) 10.0 IMBEDDED CORRELATIVES

DNA Extraction from Tissue (A071102-ST1): This is an optional correlative study where the DNA extracted from the tumor block in excess of that required for MGMT analysis will be used for future biomarker predictions for response in comparing veliparib and TMZ. DNA Extraction from Blood (A071102-ST2): This is an optional correlative study where the DNA extracted from blood samples received in the Biospecimen Accessioning and Processing (BAP) core laboratory at Mayo Clinic will be used to isolate and archive germ-line DNA from all patients to support functional analysis of somatic mutations in tumor DNA. Analysis of Advanced MR Imaging (A071102-IM): This is an optional correlative study where the imaging for all patients enrolled will be performed with dynamic susceptibility contrast (DSC) and diffusion weighted imaging (DWI) at each imaging timepoint and submitted to the IROC along with the standard imaging studies for analysis.

ECOG-ACRIN Cancer Research Group EAY131

Study Progress and Safety Report Spring 2016

Page 1

EAY131 MOLECULAR ANALYSIS FOR THERAPY CHOICE (MATCH)

Sponsor(s)

Coordinating Group ECOG-ACRIN

Chairperson(s) Dr. Keith Flaherty

Statistician Shuli Li

Data Specialist Julianne Burns

Phase of Study II

Type of Study Therapeutic

Committee Developmental Therapeutics

Accrual Objective 3000 Patients

Participating Groups ECOG-ACRIN, CTSU

DCP Treatment Credit 0.0

Clinicaltrials.gov Study ID NCT02465060

Study Status Suspended

Date Activated August 12, 2015

Date Suspended November 11, 2015



Page 2

Schema



Page 3

Purpose of the Study

The primary objective is to evaluate the proportion of patients with objective response (OR) to targeted

study agent(s) in patients with advanced refractory cancers/lymphomas. Secondary objectives include: 1)

To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted

study agent in patients with advanced refractory cancers/lymphomas; 2) To evaluate time until death or

disease progression; 3) To identify potential predictive biomarkers beyond the genomic alteration by which

treatment is assigned or resistance mechanisms using additional genomic, RNA and protein-based

assessment platforms.

Study Population

Patients must have histologically documented solid tumors or histologically confirmed diagnosis of

lymphoma that has progressed following at least one line of standard systemic therapy and/or for whose

disease no standard treatment exists that has been shown to prolong survival. Patients must have tumor

amenable to percutaneous biopsy for collection of tissue for determination of the presence of actionable

mutations/ amplifications. Patient must have ECOG performance status </= 2. Women must not be

pregnant or breast-feeding. Patient must have predefined mutation/amplification in tumor biopsy in order to

be assigned to a treatment arm with targeted therapy (Step 1). Any prior therapy, radiotherapy, or major

surgery must have been completed >/= 4 weeks prior to Step 1 registration. If the targeted therapy

associated with the actionable mutation is an oral targeted agent, the patient must not have any significant

gastrointestinal disorder that could interfere with the absorption of the treatment.

Summary of Study Design

The primary endpoint is objective response rate (ORR), defined as a complete or partial response, which is

defined consistent with RECIST version 1.1 criteria for solid tumors, the Cheson (2014) criteria for

lymphoma patients, and the RANO criteria for GBM patients. After completing participation in a given

treatment sub-study, patients may enroll on additional sub-studies if they have another actionable mutation

and meet the eligibility requirements. Such patients will be counted toward the accrual, and their data will

be included in the primary analysis, for any sub-studies in which they participated and were confirmed

eligible. Patients who are determined to be ineligible for an arm on which they are enrolled, or who do not

start treatment on that arm, will be excluded from the primary analysis for the arm. The OR rate will be

compared against a null benchmark value of 5%. If the observed objective response rate is = 5/31 (16%), it

will then be concluded that the agent is promising and worthy of further testing. Allowing for 10%

ineligibility rate, 35 patients will need to be accrued to each treatment arm in order to obtain 31 evaluable

patients. The proposed design has the following operating characteristics: power is 91.8% to conclude an

agent is promising if its true OR rate is 0.25; type 1 error rate (one-sided) is 1.8% (this is the probability to

conclude that a given agent is promising if its true OR rate is 0.05).

Progress to Date

The study was activated on August 12, 2015. Accrual to the initial screening step was temporarily paused

on November 11, 2015 for a scheduled interim analysis, after 795 patients had been enrolled. As of

February 25, 2016, 16 patients with actionable tumor alterations have been enrolled on treatment arms.

Accrual from ECOG-ACRIN and by Group is shown in Tables 1a and 1b, respectively. Table 2 summarizes

patient status as of February 25, 2016. Table 3 shows patient demographic information by step and by

treatment arm. Record status by various forms is presented in Table 4. The distribution of the reasons for

discontinuation of step 1 protocol treatment is given in Table 5.



Page 4

Treatment-related toxicities reported from Case Report Forms (CRFs) are shown in Table 6. Adverse

events at least possibly related to the biopsy have been reported for 17 cases (Table 6a), and grade 3

treatment-related toxicities have been reported for 4 patients on treatment arms (Table 6b). Grade 5 adverse

events via CTEP AERS have been reported for 13 patients (12 on step 0 and 1 on step 1, Table 7).

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 0 Step 1 Step 2

Aultman Health Foundation 1 0 0

Baptist Health System/Mid South MU NCORP 2 0 0

Cancer Research Consortium of West Michigan NCORP 4 0 0

Cancer Research for the Ozarks NCORP 10 0 0

Carle Cancer Center NCORP 2 0 0

Case Western Reserve University 27 2 0

Catholic Health Initiatives NCORP 3 0 0

Colorado Cancer Research Program NCORP 10 0 0

Columbus NCORP 17 0 0

Dartmouth Hitchcock Medical Center 3 0 0

Delaware/Christiana Care NCORP 12 0 0

Emory University/Winship Cancer Institute 3 0 0

Essentia Health NCORP 12 1 0

Fox Chase Cancer Center 1 0 0

Georgia NCORP 24 0 0

Gulf South MU NCORP 2 0 0

Heartland Cancer Research NCORP 39 0 0

Indiana Univ/Melvin and Bren Simon Cancer Center 15 2 0

Iowa-Wide Oncology Research Coalition NCORP 4 0 0

Johns Hopkins Univ/Sidney Kimmel Cancer Center 4 0 0

M D Anderson Cancer Center 38 0 0

Main Line Health NCORP 1 0 0

Mercy Medical Center 1 0 0

Metro Minnesota Community Oncology Res Consortium 40 2 1

Michigan Ca Res Consortium NCORP 23 1 0

Missouri Valley Cancer Consortium 1 0 0

Montana Cancer Consortium NCORP 6 0 0

Nevada Cancer Research Foundation NCORP 7 0 0

Northwest NCORP 9 0 0

Northwestern University 8 2 0

Ochsner NCORP 12 0 0

Pacific Cancer Research Consortium NCORP 3 0 0

Penn State Milton S Hershey Medical Center 1 0 0

Sanford NCORP of the North Central Plains 6 0 0

Stony Brook University Medical Center 1 0 0

Stroger Hospital of Cook County MU NCORP 3 0 0

University of Massachusetts Medical School 4 0 0

University of Pennsylvania/Abramson Cancer Center 3 0 0

University of Pittsburgh Cancer Institute (UPCI) 14 0 0

University of Wisconsin Hospital and Clinics 2 0 0

Wisconsin NCORP 27 0 0

Total 405 10 1



Page 5

Table 1b. Accrual by Group

Step 0 Step 1 Step 2

ECOG-ACRIN 405 10 1

SWOG 119 1 0

ALLIANCE 67 3 0

NRG 204 2 0

Total 795 16 1

Table 2. Patient Status as of February 25, 2016

Step 1 Step 2

Cases Entered 16 1

Ineligible 0 0

Never Started Assigned Therapy 0 0

Table 3. Demographics

Step 0

Variable Level Total (n=795)

Sex Male 305 (38.4)

Female 490 (61.6)

Race White 646 (84.3)

African-American 88 (11.5)

Asian 27 (3.5)

Native American 4 (0.5)

Native Hawaiian 1 (0.1)

Multirace 0 (0.5)

Unknown/Unreported 29

Ethnicity Hispanic 36 (5.7)

Non-Hispanic 738 (94.3)

Unknown/Missing 21

Age Median 63

Minimum 24

Maximum 93



Page 6

Table 3. Demographics

Step 1

Variable Level Arm EAY131-B

(n=3)

Arm EAY131-E

(n=1)

Arm EAY131-F

(n=1)

Arm EAY131-H

(n=2)

Sex Male 1 (33.3) 1 (100.0) 0 (0.0) 1 (50.0)

Female 2 (66.7) 0 (0.0) 1 (100.0) 1 (50.0)

Race White 3 (100.0) 1 (100.0) 1 (100.0) 1 (100.0)

Unknown/Unreported 0 0 0 1

Ethnicity Non-Hispanic 3 (100.0) 0 (0.0) 1 (100.0) 1 (100.0)

Unknown/Missing 0 1 0 1

Age Median 52 77 69 66

Minimum 48 77 69 65

Maximum 71 77 69 66

Step 1 (cont.)

Variable Level Arm EAY131-Q

(n=6)

Arm EAY131-R

(n=1)

Arm EAY131-U

(n=2) Total (n=16)

Sex Male 2 (33.3) 0 (0.0) 1 (50.0) 6 (37.5)

Female 4 (66.7) 1 (100.0) 1 (50.0) 10 (62.5)

Race White 6 (100.0) 1 (100.0) 2 (100.0) 15 (100.0)

Unknown/Unreported 0 0 0 1

Ethnicity Non-Hispanic 5 (100.0) 1 (100.0) 2 (100.0) 13 (100.0)

Unknown/Missing 1 0 0 3

Age Median 69 45 74 67

Minimum 52 45 66 45

Maximum 79 45 82 82

*To maintain patient confidentiality, demographics data for Step 2 is not included in this report.

Table 4. Record Status

Form Name Forms Due Forms Received %

Demography 795 794 99.9

Patient Characteristics 16 15 93.8

Treatment Agent: Pill 10 8 80.0

Treatment Agent: IV 9 8 88.9

Treatment Agent: Pill Drug #2 2 1 50.0

Adverse Event Form 14 13 92.9

Disease Follow-Up Status Form 23 17 73.9

Off-Treatment with Intent to Reg Next Step 7 6 85.7



Page 7

Table 5. Reasons Off Treatment

Step 1

For Patients Not Registered To Subsequent Steps

(Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N %

Disease progression, relapse during active treatment 4 66.7

Physician decision 1 16.7

Patient off-treatment for other complicating disease 1 16.7

Total off treatment 6 100.0

Table 6a. Treatment Related Toxicity Incidence

Step 0

Toxicity Type

n=659

Grade

1 2 3

(n) (n) (n)

Abdominal pain 2 0 1

Anemia 0 0 1

Bleeding, post biopsy 1 0 0

Bloating 1 0 0

Duodenal obstruction 0 0 1

Dyspnea 0 0 1

Hematoma 1 0 0

Hepatic pain 0 1 0

Hypertension 0 0 1

Pain of skin 1 0 0

Pneumothorax 4 2 1

Postoperative hemorrhage 1 0 0

Supraventricular tachycardia 0 0 1

Worst Degree 9 3 5



Page 8

Table 6b. Treatment Related Toxicity Incidence

Step 1

Toxicity Type

Treatment Arm

EAY131-Q

(n=5)

EAY131-B

(n=3)

EAY131-H

(n=2)

EAY131-U

(n=2)

EAY131-R

(n=1)

Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Anemia 1 - - - - - - - - - - - - - -

Diarrhea - - - 1 - - - - - - - - - - -

Ejection fraction

decreased - - - - - - 1 - - - - - - - -

Back pain - - - - - - - - - 1 - - - - -

WORST DEGREE 1 - - 1 - - 1 - - 1 - - - - -

Table 7. Lethal Adverse Events

Step 0

Case Description of Event

10160 Neoplasms - Other


10422 Lung infection

10468 Respiratory failure

10492 Death NOS

10518 Cardiac arrest


10522 Death NOS

10656 Multi-organ failure

10688 Cardiac arrest



Step 1

Case Arm Description of Event

10065 B Neoplasms - Other

ARST1321 Fall 2016 Study Progress Report - Page 1 of 23

Study Progress Report

Study Number and Title: ARST1321, Pazopanib Neoadjuvant Trial in Non-

Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of

Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NSC#

737754, IND# 118613)

Study Chair: Aaron Weiss, MD

NRG Co-Chairs: Yen-Lin Chen, MD and Thomas Scharschmidt, MD

Study Statistician: Yueh-Yun Chi, PhD

Data Cut Off Date: June 30, 2016

I. Study Purpose and Objectives

1.1 Primary Objectives

1.1.1 To identify the dose of pazopanib that is feasible when given in combination with

radiation or chemoradiation in pediatric and adult patients newly diagnosed with

unresected intermediate- and high-risk NRSTS.

1.1.2 To compare the rates of near complete pathologic response (> 90% necrosis) with the

addition of pazopanib to preoperative chemoradiation versus preoperative chemoradiation

alone for potentially resectable > 5 cm, Grade 3 intermediate to high risk chemotherapy-

sensitive NRSTS in the Phase II portion of the study for this cohort.

1.1.3 To compare the rates of near complete pathologic response (> 90% necrosis) with the

addition of pazopanib to preoperative radiotherapy versus preoperative radiotherapy

alone for potentially resectable intermediate to high risk adult and pediatric NRSTS in the

Phase II portion of the study for this cohort (using a Phase II decision rule to go onto the

Phase III portion of the study).

1.1.4 To compare the rates of event-free survival (EFS) with the addition of pazopanib to

preoperative radiotherapy versus preoperative radiotherapy alone for localized

intermediate to high risk adult and pediatric NRSTS in the Phase III portion of the study

for this cohort if the Phase II decision rule is passed.

1.2 Secondary Objectives

1.2.1 To estimate the rates of local failure, regional failure, distant metastasis free survival,

disease-free survival, and overall survival with the addition of pazopanib to preoperative

chemoradiation or preoperative radiation in intermediate to high risk adult and pediatric

NRSTS.


1.2.2 To compare the pattern of recurrence (local, regional and distant) between preoperative

chemoradiation or radiation with the addition of pazopanib for adult and pediatric

NRSTS.

1.2.3 To define the toxicities of ifosfamide and doxorubicin chemotherapy and radiation

when used in combination with pazopanib in intermediate to high risk adult and pediatric

NRSTS.

1.2.4 To define the toxicities of preoperative radiotherapy when used in combination with

pazopanib in intermediate to high risk adult and pediatric NRSTS.

1.3 Exploratory Aims

1.3.1 To gain insight into the disease biology of childhood and adult NRSTS through analysis

of actionable mutations and whole genome sequencing.

1.3.2 To determine if microvessel density and circulating tumor DNA predict response to

pazopanib and outcome.

1.3.3 To determine the effect of pazopanib on doxorubicin exposure in children and adults with

NRSTS.

1.3.4 To evaluate change in FDG PET maximum standard uptake value (SUVmax) from

baseline to Week 10 or 13 in patients with unresected tumors and to correlate this change

with pathologic response and EFS.

1.3.5 To compare the rate of response by standard imaging and pathologic assessment to

determine which correlates better with local tumor control, distant tumor control, EFS,

and overall survival.

II. Study Progress to Date

This study was opened for enrollment on July 7, 2014. The target accrual is up to 100 patients

for the chemotherapy cohort (Stratum 1) and up to 150 patients on the non-chemotherapy cohort

(Stratum 2). Sixty (60) patients were enrolled through 06/30/2016. The expected annual accrual

rate was about 30 for the chemotherapy cohort and 44 for the non-chemotherapy cohort. The

accrual rate was 28 per year for the chemotherapy cohort (based on the accrual from 07/01/2015

to 06/30/2016) and 15 per year for the non-chemotherapy cohort (based on the accrual from

09/01/2015 to 04/30/2016).


A. Patient Status

Total number of patients enrolled: 60.

Thirty-nine (39) patients (65%) were enrolled onto Stratum 1 (chemotherapy cohort), and

21 (35%) were enrolled onto Stratum 2 (non-chemotherapy cohort). Twenty-nine (29) of

the Stratum 1 patients were enrolled in the Efficacy phase, with 14 assigned to Regimen

A (Pazopanib+chemoradiation) and 15 assigned to Regimen B (chemoradiation alone).

All 21 Stratum 2 patients were enrolled in the Dose-Finding phase, with 11 treated at

Dose Level 1 (350 mg/m2; 600 mg) and 10 treated at Dose Level 2 (450 mg/m2; 800 mg).

Total number of ineligible patients: 2.

Both were on Stratum 1, Efficacy phase, with one assigned to Regimen A

(Pazopanib+chemoradiation) and the other assigned to Regimen B (chemoradiation

alone). Reasons for ineligibility included organ function requirements/prior therapy and

inadequate tissue to satisfy study requirements.

B. Study Chair Commentary on Study Conduct and Progress

Study recruitment is progressing as intended for the chemotherapy arm. Enrollment onto

the non-chemotherapy arm remains lower than anticipated. This is partly due to two

temporary closures of the cohort (5/22/15 to 8/24/15 and 4/8/16 to present) for

predetermined protocol-defined toxicity evaluations and partly a result of slower than

expected accrual of adult patients. Strategies to better understand and address this

enrollment gap are actively being developed.

C. Accrual Chart

All Enrollments


Stratum 1 Enrollments

Stratum 2 Enrollments

D. As of 06/30/2016, the number of COG institutions with active IRB approval for

ARST1321 is 184 out of 223 COG member institutions. In addition, 2 institutions have IRB

approval not current.

E. Are there patients still on protocol therapy? Yes.


III. Toxicity and Adverse Events (ineligible cases excluded)

The adverse events and AdEERs tables are included in the end of the document. There were no

deaths on treatment or within one month of the end of treatment which are or can possibly be

attributed to the study treatment.

Study Chair commentary on toxicity:

No unexpected toxicity data has been reported thus far. Four confirmed protocol-defined

targeted toxicities have occurred to date, two on the chemotherapy arm and two on the non-

chemotherapy arm. On the chemotherapy arm, one involved a Grade 3 ALT elevation and one

involved a patient withdrawing from protocol therapy secondary to “intolerable toxicity”. On the

non-chemotherapy arm, one patient experienced a Grade 3 dermatitis radiation and one patient

withdrew from protocol therapy secondary to “intolerable toxicity”. During the dose-finding

phase, 80% of patients on the chemotherapy arm and 95% of patients on the non-chemotherapy

arm received greater than 75% of the prescribed full pazopanib dosing. As of the 6/30/16 data

cut-off, 22 patients have been removed from protocol therapy. Reasons include: physician

determines it is in patient’s best interest (7), refusal of further protocol therapy by

patient/parent/guardian (6), unacceptable toxicity due to protocol therapy (8), and repeat

eligibility studies are outside the parameters required for eligibility (1). Eight patients (13%)

have been removed from protocol therapy due to Grade 3 wound complications. Six patients

(two from the chemotherapy cohort and four from the non-chemotherapy cohort) developed this

complication 3-11 weeks following primary tumor resection and two patients (one from each

treatment cohort) developed this complication at the primary tumor site following radiation

therapy and just prior to primary tumor resection. While direct attribution is likely multi-

factorial, this is a known adverse effect of pazopanib. No changes to protocol therapy are

currently being recommended due to the small sample size and rates are consistent with those

reported in similar patient populations (~30%) but the study team continues to carefully monitor

this toxicity.

IV. Currency of follow-up:

Months since

enrollment Months since last follow-up1 Total

0-5 6-11 12-17 18-24 24+

0-5 15 0 0 15

6-11 18 4 0 22

12-17 6 4 2 12

18-24 4 4 1 9

24+

Total 43 12 3 582 1 Patients who have experienced death or relapse are to be counted as current. 2 Ineligible patients were excluded.


V. History of Study Amendments/Notifications

February 6, 2015: ARST1321 reached Stratum 1 accrual goals for the first pazopanib dose in

the dose finding phase and was partially closed to further patient entry.

March 24, 2015: Action letter from NCI new and/or modified risk information associated with

pazopanib.

May 11, 2015: Part 2 of the study for the chemotherapy cohort, the randomized phase II study

of chemo radiotherapy with or without pazopanib, opened to accrual on Monday, May 11th 2015

using dose level 1 of pazopanib.

May 22, 2105: ARST1321 reached Stratum 2 accrual goals for pazopanib dose level 1 in study

Part 1 (dose-finding phase) for the non-chemotherapy cohort and was partially closed to further

patient entry.

August 24, 2015: Part 1 of the study for the non-chemotherapy cohort, RT with pazopanib, re-

opened to accrual on August 24, 2015 using dose level 2 of pazopanib.

January 25, 2016: The main purpose of this amendment is to insert the dose level found in Part

1 of the Chemotherapy Cohort. In addition, this amendment provides administrative updates.

March 4, 2016: Enclosed please find the no objection letter dated October 31, 2014 from Health

Canada for the original Clinical Trials Application submitted by the Children's Oncology Group

to ARST1321, Pazopanib Neoadjuvant Trial In Non-Rhabdomyosarcoma Soft Tissue Sarcomas

(PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative

Radiation Plus or Minus Pazopanib (NSC# 737754, IND# 118613).

April 13, 2016: ARST1321 has reached accrual goals for pazopanib dose level 2 in study Part 1

(dosefinding phase) for the non-chemotherapy cohort and is partially closed to further patient

entry as of Friday, April 8, 2016. ARST1321 includes a dose-finding and an efficacy phase for

therapy with pazopanib. The dose finding phase of the study will assess for dose-limiting

toxicities and define the maximum tolerated dose (MTD) of pazopanib. The second phase will

determine efficacy. The decision as to how to proceed is expected after information on the

adverse event experience during induction therapy (protocol Weeks 1-6) has been reviewed. Part

2 (efficacy phase) for the chemotherapy cohort remains open to enrollment at this time.

VI. Major Findings: Too early.

VII. Study Conclusions: (if any)

Too early.

VIII. Summary – Recommendations and Future Plans: Too early.


IX. Relevant Publications

van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schöffski P,

Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M,

Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP,

Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group.

Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-

controlled phase 3 trial. Lancet. 2012 May 19;379(9829):1879-86.

This randomized, double-blind, placebo-controlled phase III study demonstrated

significantly improved progression-free survival (PFS) in adult patients with metastatic

soft tissue sarcoma taking single agent pazopanib (median: 20 weeks vs 7 weeks;

p<0.0001). Based on these results, the FDA approved pazopanib for the treatment of

advanced soft tissue sarcoma. The improvement in PFS demonstrated in a variety of

non-rhabdomyosarcoma histologic subtypes and manageable adverse event profile was a

significant factor in the selection of pazopanib over other similar multi-targeted tyrosine

kinase inhibitors to add to the standard chemotherapy backbone of ifosfamide and

doxorubicin along with radiation in ARST1321.

Glade Bender JL, Lee A, Reid JM, Baruchel S, Roberts T, Voss SD, Wu B, Ahern CH, Ingle

AM, Harris P, Weigel BJ, Blaney SM. Phase I pharmacokinetic and pharmacodynamic study of

pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children's

oncology group phase I consortium report. J Clin Oncol. 2013 Aug 20;31(24):3034-43.

This study evaluated the toxicities and maximum tolerated dose (MTD) of pazopanib in

children with advanced soft tissue sarcoma. The MTD for pazopanib in tablet form was

established at 450 mg/m2 (comparable to the adult dose of 800 mg). The MTD in

suspension form was 160 mg/m2. Due to concerns that the defined suspension MTD may

result in suboptimal exposure to demonstrate efficacy, the suspension form of pazopanib

is not available on ARST1321 but a follow-up phase II study (ADVL1322) is currently

underway re-evaluating the suspension MTD. Pazopanib was generally well-tolerated in

children with expected adverse effects. Prolonged stable disease (≥ 6 months) was

demonstrated in some non-rhabdomyosarcoma soft tissue sarcoma histologic subtypes.

These findings further support the use of pazopanib in this patient population and helped

formulate the dosing strategy for adding pazopanib to the chemotherapy backbone of

ifosfamide and doxorubicin along with radiation being used in ARST1321.

Eilber FC, Rosen G, Eckardt J, Forscher C, Nelson SD, Selch M, Dorey F, Eilber FR. Treatment-

induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving

neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol. 2001 Jul

1;19(13):3203-9.

In the largest study evaluating the association of pathologic response and prognosis in

soft tissue sarcomas, 496 patients with intermediate to high-grade extremity soft tissue

sarcomas underwent surgical resection following protocol neoadjuvant

chemoradiotherapy. The 5 and 10 year local recurrence rates for patients with ≥ 95%


pathologic necrosis were significantly lower (6% and 11%, respectively) compared to

those patients with < 95% pathologic necrosis (17% and 23%, respectively, p=0.002).

The 5- and 10-year survival rates were also significantly higher for patients with ≥ 95%

pathologic necrosis (80% and 71%, respectively) than those with < 95% pathologic

necrosis (62% and 55%, respectively, p=0.0001). When analyzed in a multivariate

manner, pathologic necrosis was an independent predictor of survival. These findings

helped form the basis for selecting pathologic response as an early marker of response in

ARST1321.

X. Study Publications

None

Prepared by

Jing Tian, MS

Yueh-Yun Chi, PhD

Aaron Weiss, DO


Adverse Events Table (Chemotherapy Cohort)

Chemotherapy Cohort

CTCAEv4 Adverse Event

Induction

Weeks 1-6

Induction

Weeks 7-12

Surgery

Weeks 13-15

Continuation

Weeks 16-21

Continuation

Weeks 22-25

N = 32 N = 26 N = 21 N = 13 N = 11

% % % % %

None None 65.6 76.9 85.7 61.5 72.7

Blood and lymphatic

system disorders

Anemia 7.7

Blood and lymphatic

system disorders -

Other, specify 3.1

Febrile neutropenia 9.4 4.8

Cardiac disorders Atrial fibrillation 4.8

Atrial flutter 4.8

Cardiac disorders -

Other, specify 3.1

Gastrointestinal

disorders

Diarrhea

Ileus 4.8

Mucositis oral 3.1 3.8

Nausea 6.3

Vomiting 6.3 3.8 9.1

General disorders

and administration

site conditions

Fatigue 6.3

Gait disturbance

Non-cardiac chest pain 3.8

Pain 3.8

Hepatobiliary

disorders

Perforation bile duct

4.8

Infections and

infestations

Device related

infection 3.1

Sepsis 6.3

Skin infection 3.1 4.8 7.7

Soft tissue infection

Urinary tract infection 3.1

Wound infection 15.4

Injury, poisoning and

procedural

complications

Dermatitis radiation

Wound dehiscence 3.8 7.7 9.1


Chemotherapy Cohort


Induction

Weeks 1-6

Induction

Weeks 7-12

Surgery

Weeks 13-15

Continuation

Weeks 16-21

Continuation

Weeks 22-25

N = 32 N = 26 N = 21 N = 13 N = 11

% % % % %

Investigations Alanine

aminotransferase

increased 3.1

Creatinine increased

Ejection fraction

decreased

Lymphocyte count

decreased 6.3 7.7

Neutrophil count

decreased 12.5 7.7 15.4 9.1

Platelet count

decreased 6.3 7.7

White blood cell

decreased 15.6 7.7 23.1

Metabolism and

nutrition disorders

Anorexia 3.1

Dehydration 3.1 3.8 4.8

Hypercalcemia

Hypokalemia 3.1

Musculoskeletal and

connective tissue

disorders

Pain in extremity

Nervous system

disorders

Cognitive disturbance 3.1

Headache

Syncope 3.1

Psychiatric disorders Delirium 6.3

Depression

Renal and urinary

disorders

Acute kidney injury

Respiratory, thoracic

and mediastinal

disorders


and mediastinal

disorders - Other,

specify 3.1

Vascular disorders Hypertension 3.1

Hypotension 3.1

Thromboembolic

event 3.8

Vascular disorders -

Other, specify 3.1


Adverse Events Table (Non-Chemotherapy Cohort)

Non-Chemotherapy Cohort


Induction

Weeks 1-6

Induction

Weeks 7-9

Surgery

Weeks 10-12

Continuation

Weeks 13-18

Continuation

Weeks 19-25

N = 19 N = 16 N = 14 N = 7 N = 3

% % % % %

None None 63.2 87.5 71.4 71.4 100.0

Blood and

lymphatic system

disorders

Anemia 7.1

Blood and lymphatic

system disorders -

Other, specify

Febrile neutropenia

Cardiac disorders Atrial fibrillation

Atrial flutter

Cardiac disorders -

Other, specify

Gastrointestinal

disorders

Diarrhea 10.5

Ileus

Mucositis oral

Nausea

Vomiting 5.3

General disorders

and administration

site conditions

Fatigue 5.3

Gait disturbance 7.1

Non-cardiac chest

pain

Pain

Hepatobiliary

disorders

Perforation bile duct

Infections and

infestations

Device related

infection

Sepsis

Skin infection

Soft tissue infection 7.1

Urinary tract infection

Wound infection 6.3 14.3

Injury, poisoning

and procedural

complications

Dermatitis radiation 5.3

Wound dehiscence 28.6


Non-Chemotherapy Cohort


Induction

Weeks 1-6

Induction

Weeks 7-9

Surgery

Weeks 10-12

Continuation

Weeks 13-18

Continuation

Weeks 19-25

N = 19 N = 16 N = 14 N = 7 N = 3

% % % % %

Investigations Alanine

aminotransferase

increased 5.3

Creatinine increased 5.3

Ejection fraction

decreased 7.1

Lymphocyte count

decreased 5.3

Neutrophil count

decreased

Platelet count

decreased

White blood cell

decreased

Metabolism and

nutrition disorders

Anorexia

Dehydration 5.3

Hypercalcemia 7.1

Hypokalemia 7.1

Musculoskeletal

and connective

tissue disorders

Pain in extremity

5.3

Nervous system

disorders

Cognitive disturbance

Headache 5.3

Syncope

Psychiatric

disorders

Delirium

Depression 5.3

Renal and urinary

disorders

Acute kidney injury

5.3

Respiratory,

thoracic and

mediastinal

disorders


and mediastinal

disorders - Other,

specify

Vascular disorders Hypertension 5.3 6.3

Hypotension

Thromboembolic

event 7.1

Vascular disorders -

Other, specify


AdEERs Table (highlighted are events occurred since last SPR on Jan 1, 2016)

Pt ID AdEERS

ticket Date event Course Event Grade Cause type: Cause name: Attribution

844055 2211691 10/02/2014 1 Febrile neutropenia 3 Agent: Pazopanib: Unlikely Agent: Ifosfamide: Definite Agent: Doxorubicin hydrochloride: Unlikely Disease: Non-Rhabdomyosarcoma soft tissue sarcoma, NOS: Unlikely

846055 2148040 12/12/2014 1 Thromboembolic event

3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Unlikely Agent: Ifosfamide: Unlikely Disease: Synovial sarcoma: Probable

846608 2309899 03/29/2015 5 Wound dehiscence 3 Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Agent: Pazopanib: Possible Disease: Synovial sarcoma: Unrelated

846608 2309899 03/29/2015 5 Wound infection 3 Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Agent: Pazopanib: Possible Disease: Synovial sarcoma: Unrelated

846620 2056920 12/24/2014 1 Acute kidney injury 4 Agent: Pazopanib: Unrelated Concomitant Medication: ciprofloxacin: Probable Disease: Malignant peripheral nerve sheath tumor: Unrelated

846620 2056920 12/24/2014 1 Creatinine increased 4 Agent: Pazopanib: Unrelated Concomitant Medication: ciprofloxacin: Probable Disease: Malignant peripheral nerve sheath tumor: Unrelated

846620 2222862 03/17/2015 3 Wound dehiscence 3 Agent: Pazopanib: Possible Disease: Malignant peripheral nerve sheath tumor: Definite Other Contributing Cause: Morbid obesity: Probable


2 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Disease: Synovial sarcoma: Possible Other Contributing Cause: Central Line infection - Staph Epi + on 12/25/2014: Possible Other Contributing Cause: central line placement: Probable

848134 2448978 01/15/2015 1 Febrile neutropenia 3 Agent: Pazopanib: Unlikely Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Probable Disease: Soft tissue neoplasm, NOS: Unrelated

848134 2467560 01/30/2015 2 Dehydration 3 Agent: Doxorubicin hydrochloride: Possible Agent: Pazopanib: Possible Agent: Ifosfamide: Possible Disease: Soft tissue neoplasm, NOS: Possible

848134 2467560 01/30/2015 2 Nausea 3 Agent: Doxorubicin hydrochloride: Probable Agent: Pazopanib: Possible Agent: Ifosfamide: Probable Disease: Soft tissue neoplasm, NOS: Possible

848134 2467560 01/30/2015 2 Syncope 3 Agent: Doxorubicin hydrochloride: Possible Agent: Pazopanib: Possible Agent: Ifosfamide: Possible Disease: Soft tissue neoplasm, NOS: Possible


Pt ID AdEERS


848134 2467560 01/30/2015 2 Vomiting 3 Agent: Doxorubicin hydrochloride: Probable Agent: Pazopanib: Possible Agent: Ifosfamide: Probable Disease: Soft tissue neoplasm, NOS: Possible

848716 2415376 07/25/2015 7 Wound dehiscence 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Unlikely Agent: Ifosfamide: Unlikely Disease: Synovial sarcoma: Definite

849916 2633318 08/04/2015 4 Wound infection 3 Agent: Pazopanib: Possible Disease: Malignant peripheral nerve sheath tumor: Unrelated

850323 2414617 04/12/2015 1 Pain in extremity 3 Agent: Pazopanib: Unrelated Disease: Soft tissue neoplasm, NOS: Definite

850323 2782528 06/24/2015 3 Anemia 3 Agent: Pazopanib: Unlikely Disease: Malignant fibrous histiocytoma: Possible Other Contributing Cause: resection surgery on 6/22/15: Definite

850323 2782528 06/24/2015 3 Gait disturbance 3 Agent: Pazopanib: Unlikely Disease: Malignant fibrous histiocytoma: Probable Other Contributing Cause: resection surgery on 6/22/15: Definite

850323 2782528 06/24/2015 3 Hyperglycemia 3 Agent: Pazopanib: Unlikely Disease: Malignant fibrous histiocytoma: Unrelated Other Contributing Cause: resection surgery on 6/22/15: Probable

850323 2782528 06/24/2015 3 Hypokalemia 3 Agent: Pazopanib: Unlikely Disease: Malignant fibrous histiocytoma: Unrelated Other Contributing Cause: resection surgery on 6/22/15: Probable

850323 2782528 06/24/2015 3 Soft tissue infection 3 Agent: Pazopanib: Unlikely Disease: Malignant fibrous histiocytoma: Unlikely Other Contributing Cause: resection surgery on 6/22/15: Definite


3 Agent: Pazopanib: Unlikely Disease: Malignant fibrous histiocytoma: Unlikely Other Contributing Cause: resection surgery on 6/22/15: Definite


2 Agent: Pazopanib: Unlikely Disease: Malignant fibrous histiocytoma: Unrelated

851054 2973143 06/20/2015 3 Ejection fraction decreased

3 Agent: Pazopanib: Possible Disease: Soft tissue neoplasm, NOS: Unrelated

851054 2973143 06/20/2015 3 Wound infection 3 Agent: Pazopanib: Possible Disease: Soft tissue neoplasm, NOS: Probable


Pt ID AdEERS


851428 2049449 08/27/2015 3 Wound infection 3 Agent: Pazopanib: Possible Concomitant Medication: cholecalciferol: Unrelated Concomitant Medication: flaxseed oil: Unrelated Concomitant Medication: ibuprofen: Unrelated Concomitant Medication: cialis: Unrelated Concomitant Medication: levocetirizine dihydrochloride: Unrelated Concomitant Medication: losartan-hydrochlorothiazide: Unrelated Concomitant Medication: mometasone: Unrelated Concomitant Medication: multivitamin: Unrelated Concomitant Medication: prochlorperazine: Unrelated Concomitant Medication: docusate: Unrelated Concomitant Medication: oxycodone-acetaminophen: Unrelated Concomitant Medication: trimethoprim-sulfamethoxazole: Unrelated Disease: Fibrosarcoma: Probable Other Contributing Cause: None: Unrelated

851455 2933785 09/17/2015 1 Wound infection 3 Agent: Pazopanib: Unlikely Disease: Leiomyosarcoma: Unlikely

852128 2021027 07/10/2015 2 Febrile neutropenia 3 Agent: Pazopanib: Possible Agent: Ifosfamide: Probable Agent: Doxorubicin hydrochloride: Probable Disease: Synovial sarcoma: Unlikely

852128 2021027 07/10/2015 2 Gastrointestinal disorders - Other, specify diverticulitis

3 Agent: Pazopanib: Possible Agent: Ifosfamide: Probable Agent: Doxorubicin hydrochloride: Probable Disease: Synovial sarcoma: Unlikely

853707 2203006 08/20/2015 1 Sepsis 4 Agent: Ifosfamide: Definite Agent: Pazopanib: Definite Agent: Doxorubicin hydrochloride: Definite Disease: Leiomyosarcoma: Unlikely

853707 2325523 10/23/2015 4 Non-cardiac chest pain

3 Agent: Pazopanib: Possible Agent: Ifosfamide: Possible Agent: Doxorubicin hydrochloride: Unrelated Disease: Leiomyosarcoma: Unlikely

854294 2134325 09/26/2015 1 Mucositis oral 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Possible Disease: Synovial sarcoma: Unrelated

854294 2182040 11/18/2015 1 Wound dehiscence 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Unrelated Disease: Synovial sarcoma: Probable

854294 2329230 10/16/2015 1 Dehydration 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Unrelated Agent: Ifosfamide: Possible Disease: Synovial sarcoma: Unrelated

854294 2329230 10/16/2015 1 Mucositis oral 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Disease: Synovial sarcoma: Unrelated

854294 2329230 10/16/2015 1 Pain 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Disease: Synovial sarcoma: Unrelated


Pt ID AdEERS


854294 2329230 10/16/2015 1 Vomiting 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Probable Disease: Synovial sarcoma: Unrelated

854294 2732534 12/03/2015 1 Skin infection 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Probable Disease: Synovial sarcoma: Probable Other Contributing Cause: febrile neutropenia: Probable

854461 2310543 10/10/2015 2 Diarrhea 3 Agent: Pazopanib: Probable Disease: Non-Rhabdomyosarcoma soft tissue sarcoma, NOS: Unlikely

854461 2515587 12/29/2015 4 Hyperkalemia 3 Agent: Pazopanib: Possible Disease: Non-Rhabdomyosarcoma soft tissue sarcoma, NOS: Unlikely

855185 2137188 01/11/2016 4 Skin infection 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Unlikely Agent: Ifosfamide: Unlikely Disease: Synovial sarcoma: Unlikely

855185 2348521 10/11/2015 1 Hypoxia 2 Agent: Pazopanib: Unlikely Agent: Doxorubicin hydrochloride: Unlikely Agent: Ifosfamide: Unlikely Concomitant Medication: ibuprofen: Unrelated Concomitant Medication: calcium carbonate: Unrelated Concomitant Medication: dapsone: Definite Concomitant Medication: diphenhydramine: Unrelated Concomitant Medication: lidocaine: Unrelated Concomitant Medication: ondansetron: Unrelated Concomitant Medication: miralax: Unrelated Concomitant Medication: ranitidine: Unrelated Disease: Synovial sarcoma: Unrelated

855185 2348521 10/11/2015 1 Skin infection 2 Agent: Pazopanib: Unlikely Agent: Doxorubicin hydrochloride: Unlikely Agent: Ifosfamide: Unlikely Concomitant Medication: ibuprofen: Unrelated Concomitant Medication: calcium carbonate: Unrelated Concomitant Medication: dapsone: Unrelated Concomitant Medication: diphenhydramine: Unrelated Concomitant Medication: lidocaine: Unrelated Concomitant Medication: ondansetron: Unrelated Concomitant Medication: miralax: Unrelated Concomitant Medication: ranitidine: Unrelated Disease: Synovial sarcoma: Possible

855185 2698988 02/17/2016 6 Skin infection 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Disease: Synovial sarcoma: Unlikely

855185 2854372 10/29/2015 2 Febrile neutropenia 3 Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Agent: Pazopanib: Possible Disease: Synovial sarcoma: Unrelated

855185 2959951 02/01/2016 5 Skin infection 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Disease: Synovial sarcoma: Unlikely


Pt ID AdEERS



2 Agent: Pazopanib: Unlikely Agent: Ifosfamide: Unlikely Agent: Doxorubicin hydrochloride: Unlikely Disease: Liposarcoma: Unrelated Other Contributing Cause: Patient had a PICC line which was placed during his last neutropenic fever episode. The clot was found to be at the tip of the PICC line.: Definite

855969 2159695 04/27/2016 5 Atrial fibrillation 4 Agent: Pazopanib: Unlikely Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Probable Concomitant Medication: cytoxan: Definite Disease: Liposarcoma: Unrelated Other Contributing Cause: cyclophosphamide: Definite

855969 2159695 04/27/2016 5 Atrial flutter 4 Agent: Pazopanib: Unlikely Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Probable Concomitant Medication: cytoxan: Definite Disease: Liposarcoma: Unrelated Other Contributing Cause: cyclophosphamide: Definite

855969 2159695 04/27/2016 5 Febrile neutropenia 4 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Definite Concomitant Medication: cytoxan: Definite Disease: Liposarcoma: Unlikely Other Contributing Cause: cyclophosphamide: Definite

855969 2159695 04/27/2016 5 Neutrophil count decreased

4 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Definite Concomitant Medication: cytoxan: Definite Disease: Liposarcoma: Unlikely Other Contributing Cause: cyclophosphamide: Definite

855969 2159695 04/27/2016 5 Sepsis 4 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Definite Concomitant Medication: cytoxan: Definite Disease: Liposarcoma: Unlikely Other Contributing Cause: cyclophosphamide: Definite

855969 2159695 04/27/2016 5 Stroke 4 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Possible Concomitant Medication: cytoxan: Definite Disease: Liposarcoma: Unrelated Other Contributing Cause: cyclophosphamide: Definite

855969 2274090 12/02/2015 1 Atrial flutter 4 Agent: Pazopanib: Unlikely Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Probable Disease: Liposarcoma: Unrelated

855969 2274090 12/02/2015 1 Device related infection

3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Definite Disease: Liposarcoma: Unrelated

855969 2370833 12/30/2015 2 Fever 2 Agent: Pazopanib: Possible Agent: Ifosfamide: Possible Agent: Doxorubicin hydrochloride: Possible Disease: Liposarcoma: Unrelated


Pt ID AdEERS


855969 2375165 02/17/2016 3 Febrile neutropenia 3 Agent: Pazopanib: Unrelated Disease: Soft tissue neoplasm, NOS: Unrelated Other Contributing Cause: PIC Line: Definite

855969 2757468 03/09/2016 4 Atrial fibrillation 3 Agent: Pazopanib: Unlikely Disease: Solid tumor, NOS:Spindle Cell with Rhabdomyosarcomatous Differentiation: Unrelated

855969 2757468 03/09/2016 4 Atrial flutter 3 Agent: Pazopanib: Unlikely Disease: Solid tumor, NOS:Spindle Cell with Rhabdomyosarcomatous Differentiation: Unrelated

856096 2385278 11/04/2015 1 Delirium 3 Agent: Pazopanib: Unlikely Agent: Doxorubicin hydrochloride: Unlikely Agent: Ifosfamide: Probable Disease: Non-Rhabdomyosarcoma soft tissue sarcoma, NOS: Unlikely

856096 2385278 11/04/2015 1 Nausea 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Disease: Non-Rhabdomyosarcoma soft tissue sarcoma, NOS: Unrelated

856096 2385278 11/04/2015 1 Vomiting 1 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Disease: Non-Rhabdomyosarcoma soft tissue sarcoma, NOS: Unrelated

856096 2599790 04/04/2016 6 Nausea 2 Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Probable Agent: Pazopanib: Possible Disease: Soft tissue neoplasm, NOS: Unrelated

856096 2599790 04/04/2016 6 Vomiting 3 Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Probable Agent: Pazopanib: Possible Disease: Soft tissue neoplasm, NOS: Unrelated

856626 2487313 12/28/2015 1 Blood and lymphatic system disorders - Other, specify Methemoglobinemia

3 Agent: Pazopanib: Unrelated Concomitant Medication: Dapsone: Probable Disease: Malignant fibrous histiocytoma: Unrelated

856626 2487313 12/28/2015 1 Hypoxia 3 Agent: Pazopanib: Unrelated Concomitant Medication: Dapsone: Unlikely Disease: Malignant fibrous histiocytoma: Probable


3 Agent: Pazopanib: Unrelated Concomitant Medication: Dapsone: Unlikely Disease: Malignant fibrous histiocytoma: Probable

856689 2644232 12/17/2015 1 Anorexia 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Possible Disease: Solid tumor, NOS:Undifferentiated embryonal sarcoma of the liver: Unrelated

856689 2644232 12/17/2015 1 Vomiting 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Possible Disease: Solid tumor, NOS:Undifferentiated embryonal sarcoma of the liver: Unrelated


Pt ID AdEERS


856689 2980547 03/10/2016 2 Dehydration 3 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Unrelated Agent: Ifosfamide: Unrelated Concomitant Medication: morphine: Unrelated Disease: Solid tumor, NOS:Emryonal Sarcoma of the Liver: Unrelated

856689 2980547 03/10/2016 2 Ileus 4 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Unrelated Agent: Ifosfamide: Unrelated Concomitant Medication: morphine: Possible Disease: Solid tumor, NOS:Emryonal Sarcoma of the Liver: Unrelated

856689 2980547 03/10/2016 2 Perforation bile duct 4 Agent: Pazopanib: Unrelated Agent: Doxorubicin hydrochloride: Unrelated Agent: Ifosfamide: Unrelated Concomitant Medication: morphine: Unrelated Disease: Solid tumor, NOS:Emryonal Sarcoma of the Liver: Unrelated

860130 2168301 04/19/2016 1 Electrocardiogram QT corrected interval prolonged

1 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Unrelated Agent: Ifosfamide: Unrelated Concomitant Medication: Cipro: Possible Disease: Soft tissue neoplasm, NOS: Unrelated Other Contributing Cause: Chemotherapy causing grade 4 decreased WBC's.: Unrelated Other Contributing Cause: Nausea and vomiting causing dehydration resulting in hypokalemia: Possible

860130 2168301 04/19/2016 1 Hypokalemia 3 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Definite Concomitant Medication: Cipro: Unrelated Disease: Soft tissue neoplasm, NOS: Unrelated Other Contributing Cause: Chemotherapy causing grade 4 decreased WBC's.: Definite Other Contributing Cause: Nausea and vomiting causing dehydration resulting in hypokalemia: Unrelated

860130 2168301 04/19/2016 1 White blood cell decreased

4 Agent: Pazopanib: Possible Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Definite Concomitant Medication: Cipro: Unrelated Disease: Soft tissue neoplasm, NOS: Unrelated Other Contributing Cause: Chemotherapy causing grade 4 decreased WBC's.: Definite Other Contributing Cause: Nausea and vomiting causing dehydration resulting in hypokalemia: Unrelated

860130 2214770 05/04/2016 2 Cognitive disturbance

3 Agent: Doxorubicin hydrochloride: Unrelated Agent: Ifosfamide: Definite Agent: Pazopanib: Unrelated Disease: Soft tissue neoplasm, NOS: Unrelated

860130 2214770 05/04/2016 2 Delirium 3 Agent: Doxorubicin hydrochloride: Unrelated Agent: Ifosfamide: Definite Agent: Pazopanib: Unrelated Disease: Soft tissue neoplasm, NOS: Unrelated


Pt ID AdEERS


860130 2739398 05/11/2016 2 Abdominal soft tissue necrosis

3 Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Agent: Pazopanib: Probable Disease: Soft tissue neoplasm, NOS: Unrelated

860130 2739398 05/11/2016 2 Fatigue 3 Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Probable Agent: Pazopanib: Probable Disease: Soft tissue neoplasm, NOS: Unrelated

860130 2739398 05/11/2016 2 Sepsis 4 Agent: Doxorubicin hydrochloride: Definite Agent: Ifosfamide: Definite Agent: Pazopanib: Possible Disease: Soft tissue neoplasm, NOS: Unrelated

860130 2739398 05/11/2016 2 Skin infection 3 Agent: Doxorubicin hydrochloride: Probable Agent: Ifosfamide: Probable Agent: Pazopanib: Probable Disease: Soft tissue neoplasm, NOS: Unrelated

860276 2245679 05/01/2016 1 Dehydration 3 Agent: Pazopanib: Possible Concomitant Medication: oxycodone: Possible Disease: Alveolar soft part sarcoma: Unrelated Other Contributing Cause: Depression: Unlikely

860276 2245679 05/01/2016 1 Headache 3 Agent: Pazopanib: Possible Concomitant Medication: oxycodone: Possible Disease: Alveolar soft part sarcoma: Unrelated Other Contributing Cause: Depression: Unlikely

860276 2245679 05/01/2016 1 Photophobia 2 Agent: Pazopanib: Possible Concomitant Medication: oxycodone: Possible Disease: Alveolar soft part sarcoma: Unrelated Other Contributing Cause: Depression: Unlikely

860276 2245679 05/01/2016 1 Vomiting 3 Agent: Pazopanib: Possible Concomitant Medication: oxycodone: Possible Disease: Alveolar soft part sarcoma: Unrelated Other Contributing Cause: Depression: Unlikely

860276 2993940 05/24/2016 2 Depression 3 Agent: Pazopanib: Unlikely Concomitant Medication: oxycodone: Possible Disease: Alveolar soft part sarcoma: Unrelated

860276 2993940 05/24/2016 2 Dermatitis radiation 3 Agent: Pazopanib: Possible Concomitant Medication: oxycodone: Unrelated Disease: Alveolar soft part sarcoma: Unrelated

860276 2993940 05/24/2016 2 Diarrhea 3 Agent: Pazopanib: Possible Concomitant Medication: oxycodone: Possible Disease: Alveolar soft part sarcoma: Unrelated

860276 2993940 05/24/2016 2 Skin hypopigmentation

2 Agent: Pazopanib: Definite Concomitant Medication: oxycodone: Unrelated Disease: Alveolar soft part sarcoma: Unrelated

860660 2681436 06/08/2016 2 Neutrophil count decreased

4 Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Agent: Pazopanib: Possible Disease: Synovial sarcoma: Unrelated

860660 2681436 06/08/2016 2 White blood cell decreased

4 Agent: Doxorubicin hydrochloride: Possible Agent: Ifosfamide: Possible Agent: Pazopanib: Possible Disease: Synovial sarcoma: Unrelated


EXPERIMENTAL DESIGN SCHEMA





Study A071401 – Phase II Trial of SMO/AKT Inhibitors in Progressive Meningiomas with SMO/AKT Mutations

Committee: Neuro Study Statisticians: Qian Shi, Ph.D. Study Chairs: Priscilla Brastianos, M.D. Eva Galanis, M.D. 1.0 OBJECTIVES Primary

1. To determine the activity of a SMO inhibitor in patients with meningiomas harboring SMO mutations as measured by 6-month PFS and response rate.

2. To determine the activity of a FAK inhibitor in patients with meningiomas harboring NF2 mutations as measured by 6-month PFS and response rate.

Secondary

1. To determine the overall survival and progression-free survival of SMO and FAK inhibitors in patients with meningioma.

2. To determine adverse event rates of SMO and FAK inhibitors in patients with meningioma.

3. To determine the activity of SMO and FAK inhibitors as measured by response rate by central radiology review.

2.0 CURRENT SCHEMA

1 Cycle = 28 Days Note: Pregnancy prevention must start 4 weeks prior to study drug.

P R E - R E G I S T E R

Central, SMO and NF2 Testing AND Central

Pathology Review

SMO R E G I S T E R

Vismodegib 150 mg PO

Daily

NF2

GSK2256098 750 mg PO Twice/Daily

If negative SMO or NF2

Off study

Treatment is to continue until disease progression or unacceptable adverse event. Patients discontinuing treatment for reasons other than progressive disease, will continue following the Study Calendar for disease assessment until progressive disease is documented, for a maximum of 2 years. Patients will be followed for survival up to a maximum of 5 years from registration.

3.0 ELIGIBILITY CRITERIA Pre-registration Inclusion criteria

Local diagnosis of meningioma (any grade) and have FFPE tumor block OR meningioma tissue slides available for submission to central pathology review and SMO and NF2 testing by a CLIA-certified lab.



Registration Inclusion Criteria

1) Histologically proven intracranial meningioma as documented by central pathology review. 2) Molecular documentation: Presence of SMO or NF2 mutation in tumor sample as documented

by central laboratory. 3) Progressive or residual disease, as defined by the following:

• Residual measurable disease immediately after surgery without requirement for progression. For Grade I disease, progression pre-operatively needs to be documented, with an increase in size of the measurable primary lesion on imaging by 25% or more (bidirectional area). The change must occur between scans separated by no more than 12 months.

• Progressive measurable disease: progression defined as an increase in size of the measurable primary lesion on imaging by 25% or more (bidirectional area). The change must occur between scans separated by no more than 12 months.

• Post radiation patients: patients with measurable and progressive meningioma who have received radiation are potentially eligible, but need to show evidence of progressive disease after completion of radiation. At least 24 weeks must have elapsed from the completion of radiation to registration.

4) Measurable disease: measurable disease is defined by a bidimensionally measurable main lesion on MRI or CT images with clearly defined margins. Multifocal disease is allowed.

5) Prior treatment: • Prior therapy is allowed but not required. • No limit on number of prior therapies. • No chemotherapy, other investigational agents within 28 days of study treatment • No other concurrent investigational agents or other meningioma-directed therapy while

on study. • For patients treated with external beam radiation, interstitial brachytherapy or

radiosurgery, an interval of > 24 weeks must have elapsed from completion of XRT to study drug administration.

• Steroid dosing stable for at least 4 days. • Recovered to CTCAE grade 1 or less toxicity from other agents with exception of

alopecia and fatigue. • No craniotomy within 28 days of registration.

6) Non pregnant and non nursing. 7) Age ≥ 18 years. For SMO mutations, patients must be at least 30 years old. (as of Protocol

Update #04, 06/15/2016). 8) ECOG Performance Status ≤ 2 9) Patient history:

• Patients with history of NF may have other stable CNS tumors schwannoma, acoustic neuroma or ependymoma) if lesions have been stable for 6 months.

• No metastatic meningiomas (as defined by extracranial meningiomas) allowed. • No history of allergic reactions attributed to compounds of similar or biologic

composition to assigned study drug. • Known active hepatitis B or C • Current Child Pugh Class B or C liver disease • Uncontrolled gastric ulcer disease • Uncontrolled diabetes defined as a known diabetic with HBA1C >7.5 OR fasting

glucose > 140. • Uncontrolled hypertension defined as BP > 140/90 • Abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days prior to

registration 10) Concomitant Medications



• Chronic concomitant treatment with strong CYP3A4 inhibitors is not allowed. Patients must discontinue the drug for 14 days prior to registration on the study for patients with NF2 mutation enrolled to GSK2256098.

• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment for patients with NF2 mutation enrolled to GSK2256098.

11) Required Initial Laboratory Values: Absolute Neutrophil Count (ANC) ≥ 1,500/mm3

Platelet Count ≥ 100,000/mm3 Creatinine OR ≤ 1.5 mg/dl x upper limit of normal (ULN)

OR Calc. Creatinine Clearance > 45 mL/min

UPC ≤ 45mg/mmol* Total Bilirubin ≤ 1.5 x upper limit of normal (ULN)**

AST / ALT ≤ 2.5 x upper limit of normal (ULN) Fasting triglyceride ≤ 200mg/dL* Fasting cholesterol ≤ 240mg/dL*

* Only applicable for patients with NF2 mutation (GSK2256098). ** Except in case of Gilbert’s disease

4.0 TREATMENT SCHEDULE

The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report).

5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors Each arm is a prospective, one-stage phase 2 study evaluating the efficacy of SMO or FAK inhibitors in patients with SMO-mutated or NF2-mutated meningiomas, respectively. There will be a separate phase 2 arm for each of the two tumor mutation groups and each tumor grade cohort. Patients with recurrent or progressive Grade I-III meningiomas will be eligible for this trial. Samples will undergo central pathology review. Patient’s tumor samples will be tested for the presence of SMO or NF2 mutations. Patients harboring SMO or NF2 mutations and who meet eligibility criteria will be enrolled. Within each arm, there will be two different patient cohorts based on histology: grade I versus II/III meningiomas. There is no planned interim analysis. The sample size calculation was done with EAST v6.3. The goal will be to enroll 12 patients per cohort within each arm. A total of 48 patients will be enrolled. There will be a separate Phase II arm for each group: patients with SMO mutations and patients with NF2 mutations. The design of each Phase II arm is identical. Each arm will require 24 patients. 5.2 Primary Endpoint The co-primary end points are progression-free survival at 6 months (PFS6) and response rate. PFS6 is defined as not having progressive disease or death within six months of the first day of treatment. A patient will be deemed to have a response if they have a confirmed PR or CR. Contrast-enhanced cranial magnetic resonance imaging (MRI) will be performed every 8 weeks. Standard response criteria will be used (see Section 11.0 of the protocol). All patients meeting the eligibility criteria that have signed the consent form and have begun treatment will be considered evaluable for the analysis of primary endpoint. Within each mutation defined treatment arm, there will be 12 accrued to a cohort of grade I patients and 12 accrued to a cohort of grade II/III patients, and the statistical design will be identical for the 2 mutation defined treatment arms.



Within each treatment arm, the trial will distinguish between tumor response rates of 20% vs. 2.5%. If at least 3 responses (at least 12.5%) are observed among the 24 evaluable patients, the agent will be considered worthy of further testing in this mutation defined treatment arm, yielding at least 89% power to detect a true response rate of at least 20%, with a significance level of .021 against the null hypothesis of 2.5% response rate. Within each grade II/III cohort of a treatment arm, the trial will distinguish between 6 month PFS rates of 55% vs. 15%. If at least 5 patients (at least 42%) demonstrate 6 month PFS, among the 12 evaluable patients, the agent will be considered worthy of further testing in this mutation defined grade II/III cohort, yielding at least 89% power to detect a true 6 month PFS rate of at least 55%, with a significance level of .024 against the null hypothesis of 15% 6 month PFS rate. Within each grade I cohort of a treatment arm, the trial will distinguish between 6 month PFS rates of 65% vs. 25%. If at least 7 patients (at least 58%) demonstrate 6 month PFS, among the 12 evaluable patients, the agent will be considered worthy of further testing in this mutation defined grade I cohort, yielding at least 79% power to detect a true 6 month PFS rate of at least 65%, with a significance level of .014 against the null hypothesis of 25% 6 month PFS rate. Thus, the trial has 89% power to detect a promising response rate in either mutation defined treatment group, 79% power to detect a promising 6 month PFS rate in either mutation defined grade I cohort, and 89% power to detect a promising 6 month PFS rate in either mutation defined grade II/III cohort, with an over-all type I error bound of 11%, against the over-all null hypothesis that neither agent is active with respect to either response rate or PFS. 5.3 Target Accrual There will be 24 evaluable patients assigned to each treatment group of the study based on their tumor mutations (total of 48 evaluable patients). With each mutation treatment arm group, there will be 12 patients accrued to the grade I cohort and 12 patients accrued to the grade II/III cohort. We anticipate accruing an additional 4 patients in each treatment group to account for ineligibilities or cancellations. Thus the maximum target accrual is 56 ((24+4) x 2) in total. Therefore, the target accrual for this study is 48 evaluable patients, with an anticipated maximum of 56 patients to get 48 evaluable, over approximately 2-3 years. The target accrual rate is about 1.5 patients per month. There is little information available for what the precise accrual rate will be.

6.0 CURRENT ACCRUAL

Study Activation Date 08/28/2015 Target Accrual (n) 48 Patients screened or pre-registered (n) 119 Current Accrual (n) 26 Expected Accrual Rate 1.5/month Accrual Rate – Since activation 2.0/month Accrual Rate – Past 12 months 2.0/month Accrual Rate – Past 6 months 3.5/month Projected closure date for a trial open for more than one year (based on accrual rate from past 12 months)

08/01/2025



7.0 CURRENT STUDY STATUS This study opened to accrual on 08/28/2015. As of 09/07/2016, 110 patients have been pre-registered for this study. Of these, 42 are still in pre-registration, and 45 are screening failures (40 did not meet eligibility criteria, 3 due to patient decision, 2 due to investigator decision). The 23 patients registered have been patients with NF2 mutation (5 grade I, 18 grade II/III). The study continues to accrue however testing for NF2 mutation among gr II/III patients is on hold since current accrual goals for this cohort have been met.

8.0 PATIENT CHARACTERISTICS At this time, there are no ineligibles or cancellations. Table 8a. Demographics

NF2, Grade I

(N=5) NF2, Grade II / III

(N=18) Total

(N=23) Age N 5 18 23 Mean (SD) 67.0 (8.2) 58.8 (15.7) 60.6 (14.7) Median 67.0 64.0 66.0 Q1, Q3 66.0, 73.0 52.0, 70.0 54.0, 71.0 Range (54.0-75.0) (23.0-75.0) (23.0-75.0) Race White 4 (80.0%) 14 (77.8%) 18 (78.3%)

0 0 0 0 1 0 0

4

4

7

5 1 1 0

Expected Accrual 48 Patients



NF2, Grade I

(N=5) NF2, Grade II / III

(N=18) Total

(N=23) Black or African American 0 (0.0%) 2 (11.1%) 2 (8.7%) Asian 0 (0.0%) 1 (5.6%) 1 (4.3%) American Indian or Alaska Native 1 (20.0%) 0 (0.0%) 1 (4.3%) Unknown: Patient unsure 0 (0.0%) 1 (5.6%) 1 (4.3%) Gender Female 3 (60.0%) 6 (33.3%) 9 (39.1%) Male 2 (40.0%) 12 (66.7%) 14 (60.9%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary At the time of this report, 21 patients have adverse event data available. No grade 4 or 5 AEs have been experienced in any cohort. No grade 3 have been reported by the 3 evaluable patients in the NF2, Grade I cohort. In the NF2, grade II/III cohort, seven patients have experienced at least one grade 3 AE. Four patients experienced an AE that was at least possibly related; these are: 1 nervous system disorders – other, 1 proteinuria, 1 aspartate aminotransferase increased and alanine aminotransferase increased, and 1 rash maculo-papular. No grade 3 or higher hematologic AE have been reported.

Table 9a. Summary of Grade 3+ Adverse Events Regardless of Attribution

Number of Evaluable Patients: Arm A (NF2, Grade I) =3

Arm B (NF2, Grade II/III) =18 Patients with a maximum: Arm n (%) Total

Grade 3 Event A 0 (0.0%) B 7 (38.9%)

Grade 4 Event A 0 (0.0%) B 0 (0.0%)

Grade 5 Event A 0 (0.0%) B 0 (0.0%)

Hematologic Adverse Events Grade 3 Event A 0 (0.0%)

B 0 (0.0%) Grade 4 Event A 0 (0.0%)

B 0 (0.0%) Grade 5 Event A 0 (0.0%)

B 0 (0.0%) Non-Hematologic Adverse Events

Grade 3 Event A 0 (0.0%) B 7 (38.9%)

Grade 4 Event A 0 (0.0%) B 0 (0.0%)



Table 9a. Summary of Grade 3+ Adverse Events Regardless of Attribution

Number of Evaluable Patients: Arm A (NF2, Grade I) =3

Arm B (NF2, Grade II/III) =18 Patients with a maximum: Arm n (%)

Grade 5 Event A 0 (0.0%) B 0 (0.0%)

Note: Summaries are based on available patient data

Table 9b. Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event

Regardless of Attribution Number of Evaluable Patients:

Arm A (NF2, Grade I) =3 Arm B (NF2, Grade II/III) =18

Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal

n (%) n (%) n (%) Non-Hematologic Adverse Events Gen disord and admin site cond

Fatigue A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%)

Investigations Alanine aminotransferase increased A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%) Aspartate aminotransferase increased A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%)

Nervous system disorders Headache A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%) Nervous system disorders - Oth spec A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%) Seizure A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 2 ( 11%) 0 ( 0%) 0 ( 0%)

Renal and urinary disorders Proteinuria A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%)

Skin and subcutan tiss disord Rash maculo-papular A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%)

Surgical and medical proced Surgical and medical proced - Oth spec A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 6%) 0 ( 0%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES



A071401-ST1 – Exploratory Identification of Molecular Biomarkers of Response and Circulating DNA This study is to perform several genome wide tests on both the primary meningioma resection sample and any samples from recurrent tumor. The goal is to identify genetic biomarkers that will predict response to therapy. We will look for common mutations that could predict resistance to the therapies. Patient participation is optional. A071401-IM1 – Imaging Biomarkers of Response We propose to investigate dynamic contrast enhanced (DCE) MRI as an early biomarker of treatment response. The objectives are (1) to determine if baseline K trans or Ve is associated with response; (2) to determine if change in K trans or Ve is associated with response. Patient participation if optional.

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