12 th Annual CTOS Meeting 2006 Session 7. 12 th Annual CTOS Meeting 2006 AP23573 Induced Long-term Stability in 2 Patients with Desmoplastic Small Round

12th Annual CTOS Meeting 2006

Session 7


AP23573 Induced Long-term Stability in 2 Patients with Desmoplastic Small Round Cell Tumor (#561)

Scott Schuetze, Warren Chow, Jean-Yves Blay, George Demetri and Suzanne George

• DSRCT is an aggressive sarcoma arising in young adults and is frequently advanced at diagnosis.• AP23573 is a novel non-prodrug inhibitor of mTOR.• Patients with advanced/metastatic sarcoma were enrolled in a Phase II trial of AP23573 infused on days 1-5 and 15-19 every 28 days.• 4 patients with metastatic DSRCT were enrolled and the clinical course on treatment with AP23573 was reviewed.


Results of AP23573 treatment in 4 patients with DSRCT

Demographics

Age (range) 29 – 34

Sex (M / F) 3 / 1

# prior therapies (range)

1 – 5

Median 2

EWS-WTI fusion confirmed (Y / N)

3 / 1

AP23573 Therapy

Maximum # of cycles received

# of patients

2 2

8 1

16+ 1

• 2 of the 4 patients with DSRCT had stable disease for more than 6 months• 1 of the patients remains on treatment with stable disease for more than 16 months• mTor inhibitor may benefit some patients with advanced DSRCT


Clinical characteristics and outcomes of advanced sarcoma patients who achieved clinical benefit response (CBR) while receiving AP23573 in a phase 2 trial (#675)

Background & Methods• AP23573 is a novel, non-prodrug mTOR inhibitor• 212 patients treated with AP23573 QDx5 every other week

– Fixed dose, intravenous infusion of 12.5 mg over 30 minutes

– 4 histological cohorts (Bone, Leiomyosarcoma, Liposarcoma, Other STS)

• CBR was primary endpoint– Defined as CR, PR or SD ≥4 months by RECIST

– 25% CBR in a cohort was considered success

Objectives• Describe clinical features of patients who achieved CBR, including

safety and efficacy following prolonged exposure (>4 mos)• Characterize the PFS of CBR patients to assess utility of this

endpoint as a surrogate for PFS


• 61 / 212 advanced sarcoma patients achieved CBR, most had prolonged stable disease with some partial responses observed

– CBR patients were similar to overall population in extent of disease and # of prior therapies received

• AP23573 was well tolerated over time, without cumulative toxicity or need for continuous dose adjustments or delays

• CBR designation is a useful surrogate for PFS in this population

• Long term follow-up for survival is ongoing, further analyses planned

Disease cohort

Overall trial population (N=212) CBR patients (n=61)

PFS rate at 6 months

Median (wks) PFS rate at 6 months

Median (wks)

Bone sarcoma 25% 16 63% 34

All soft-tissue sarcoma

24% 15 73% 39

Leiomyosarcoma 22% 16 67% 33

Liposarcoma 30% 16 88% 40

Other STS 23% 15 75% 48

Overall 24% 15 70% 36

• Median PFS ~20 weeks longer for the CBR subset of trial population relative to the overall population

Data available in study database as of 25Aug2006


Phase I study of trabectidin in combination with doxorubicin in patients with soft tissue sarcoma (#612)

Rationale• Trabectedin (ET-743, YONDELIS®), an alkaloid compound derived

from the marine ascidian Ecteinascidia turbinata, is a first-in-class antitumor agent with a complex mechanism of action1,2:

– Binds to the minor groove of DNA– Inhibits gene activation via a promoter-specific mechanism and

transcription-dependent nucleotide excision repair• Trabectedin has demonstrated consistent single-agent activity in

patients with chemotherapy-naïve and -pretreated STS in several Phase II trials3-6

• Doxorubicin is considered a standard of care for the treatment of STS, and synergistic effects have been observed in vitro between doxorubicin and trabectedin against STS cells

• Thus, the combination of trabectedin and doxorubicin may fulfill the need for a more active regimen to treat STS


• The combination of trabectedin and doxorubicin with G-CSF support is safe and well tolerated

• After institution of G-CSF, there were no DLTs in Cohort 1 (doxorubicin 60 mg/m2 + trabectedin 0.9 mg/m2) or Cohort 2 (doxorubicin 60 mg/m2 + trabectedin 1.1 mg/m2)

• MTD of trabectedin is 1.1 mg/m2 in combination with doxorubicin 60 mg/m2, both administered every 3 weeks

• Preliminary data suggest activity for the trabectedin/doxorubicin combination in patients with recurrent or persistent STS, with 4 patients achieving a partial response and 32 maintaining stable disease (13 patients with stable disease 6 months)

Conclusions


• AP23573 (n=4)

• ET-743 (n=2)• ET743 in myxoid liposarcomas (n=2)

• Chordomas & imatinib , nilotinib (n=2)• TKIs: imatinib- nilotinib, sorafenib…(n=3)

• New agents: bendamustine, ZIO-101 (n=2)

• Chemotherapy in bone sarcomas (n=4)

• Combination CT: hyperthermia, RT

• Fascinoma (ASPS,angiosarcoma,chordoma)

Session 7: cytotoxic chemotherapy(25 abstracts)


F Grosso*, I Judson°, R Jones°, S Stacchiotti*, R Bertulli*, J Jimeno^, M D'Incalci**, S Pilotti*, A Gronchi* & PG Casali*. *Istituto Nazionale Tumori, Milan, Italy; °Royal Marsden Hospital, London, United Kingdom; ^Pharma Mar, Madrid, Spain; **Istituto Ricerche Farmacologiche Mario Negri, Milano, Italy.

THE UTILITY OF “TISSUE RESPONSE” IN CONJUNCTION WITH STANDARD DIMENSIONAL CRITERIA IN THE

INITIAL ASSESSMENT OF PATIENTS WITH

ADVANCED MYXOID/ROUND CELL LIPOSARCOMA (MRCL)

TREATED WITH TRABECTEDIN

Istituto Nazionale Tumori Milan, Italy

[email protected]


ObjectivesTo investigate the role of initial tumor response (“tissue

response”) as a predictor of outcome in advanced MRCL treated with Trabectedin within a compassionate use programme.

Tissue response was defined as: decrease in contrast enhancement on MRI decrease in contrast uptake or in density

measured in Hounsfield Unit (HU) on CT scan

64 HU

75 HU

25 HU

19 HU


response at first assessmenttime of first assessment months, median (range) = 1,6 (0,7-3,2)

SD 17%

MR 12%

PR 38%

SD + tissue response 70%best response

PD9%

SD 9%PR 12%

CR 3%

delayed response

Results


+2 c0

+5 c

+8 c

+11 c

delayed responsefollowing tissue response


PFS according to BR

OR

SDPD


Bendamustine (589)• Multicentric trial• N=32, refractory sarcoma• 1 PR (3%), 10SD (34%)

PFS Rate

BendamustinEORTC

Active Agent EORTC

Inactive Agent

Number of Patients 32 146 234

3 Months 34% 39% 21%


Phase I Trials of ZIO-201 (Iphosphoramide Mustard-Lysine):

The Active Moiety of Ifosfamide•Ifosfamide is activated to iphosphoramide mustard (IPM)

•Byproducts of the activation lead to toxicity

•Chloracetaldehyde - neurotoxicity

•Acrolein - hemorrhagic cystitis

•IPM is unstable, but is stabilized by mixing it with lysine

•Phase I trials using a daily x 3 schedule q 3 weeks

•Doses from 78-787 mg/me2


• MTD is estimated at 400 mg/me2 without mesna.

• ZIO-201 achieved Cmax-values about 25-fold greater than the IC50 of human sarcoma cell lines.

• The MTD is comparable to IFOS doses of ≥25 g/me2 with little bladder

and no bone marrow or CNS toxicity.

• At doses >MTD, proximal renal tubular acidosis (RTA) was the DLT, interesting since prior studies have ascribed RTA to toxic metabolites other than IPM.

• These data form the basis for further phase-I studies to more clearly

define the MTD and to investigate strategies to avoid proximal renal tubular acidosis, followed by phase-II studies in sarcomas.

Conclusions


Bone sarcoma (1)

• 596: Obata et al– Retrospective study 1981-2003

– 243 patients with EWS treated with IfoVP16

– VACD-IE>other regimens

• 608 : Guillaume et al– Non osteogenic sarcoma of bone-Single institution study

– N=53, neoadjuvant / adjuvant CT

– Median OS: 12 years, survival at 5 years: 70%


Bone sarcoma (2)

• 623: Ferrari et al– Retrospective study Rizzoli

– Gender related hematological toxicity in pts with non met osteosarcomas

– N=75, HDMTX, A/P, Ifo

– Female: higher incidence of G4 leukopenia, thrombopenia, febrile neutropenia, RBC, Plt transfusions,

• 639 : Ohno et al– Intrarterial CT in osteosarcomas since 1968

– 3 groups of CT: 1: MMC-VCR, 2: ADR-VCR, 3: CDDP-ADR-VCR

– OS and DFS: G1: 45% both, G2: 54%-44%, G3: 76%-64%


Bone sarcoma (3)

• 712: Khamly et al– Retrospective study-outcome of adolescent young adult patients with

osteosarcoma

– N=309, OS and EFT

– 5 year OS: Female, 91%, males, 52%

– Non lean body mass lower in males, correlated to tox and histological response

– Pubertal related changes in NLBM may result in underdosing in young male patients


Alveolar Soft Part Sarcoma (ASPS). Experience of the Institut Gustave Roussy (IGR)

Ruiz-Soto Rodrigo1 , Cioffi Angela1, Bonvalot Sylvie2, Vanel Daniel3, Le Péchoux Cecile4, Terrier Phillipe5, Domont Julien1 and Le Cesne Axel1. Departments of

Medicine1, Surgery2, Radiology3, Radiotherapy4 and Pathology5. Institut Gustave Roussy, Villejuif, France.

Rare

Frequently metastatic

Slowly growing


PROTOCOL EORTC 62961/ESHO

A RANDOMISED STUDY COMPARING NEOADJUVANT CHEMOTHERAPY ETOPOSIDE + IFOSFAMIDE + ADRIAMYCIN (EIA)

COMBINED WITH REGIONAL HYPERTHERMIA (RHT) VERSUS

NEOADJUVANT CHEMOTHERAPY ALONE IN THE TREATMENT OF HIGH-RISK SOFT TISSUE SARCOMAS IN ADULTS

_____________________________________________________________________________AN INTERGROUP STUDY WITH THE EUROPEAN SOCIETY FOR HYPERTHERMIC ONCOLOGY

Study Coordinator: Data Centre and Biometry: Randomisation of ESHO-Centres: Prof. Dr.med. R. Issels Prof. Dr. rer. hum. biol. D. Hölzel, M. Schmidt Herr Markus Pfirrmann Klinikum Großhadern IBE, Institut für Med. Informationsver- GIS, Gesellschaft für Informationsver- Med. Klinik III arbeitung, Biometrie und Epidemiologie arbeitung und Statistik in der Medizin e.V. Hyperthermie Klinikum Großhadern Pettenkoferstrasse 35 Marchioninistr. 15 Marchioninistr. 15 D-80336 Munich D-81377 Munich D-81377 Munich Germany Germany Germany phone: (+49) 89 5442 01 – 40 phone: (+49) 89 7095 – 4768 phone: (+49) 89 7095 – 7757 [email protected] (+49) 89 7095 – 4776 Fax (+49) 89 7095 – [email protected] [email protected] Date of activation: July/01/1997

Date of closure:Status: Recruitment Phase

EORTC 62961/ESHO /High-Risk Soft Tissue Sarcoma Study IBE, TRM, 31.10.2003 Page 1


STAGING

Biopsy

Histology

CT/MR

Responder:

CR, PRor

Stable Disease

RADIATION

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA EIA EIA EIA

Arm A:

Arm B:

FOLLOW

Up

RESECTION

REGISTRATION

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA EIA EIA EIA

Arm A:

Arm B:

R ESPONSE

EVALUATION

13th

week

CYCLE I II III IV



STAGING

Biopsy

Histology

CT/MR

Responder:

CR, PRor

Stable Disease

RADIATION

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA EIA EIA EIA

Arm A:

Arm B:

FOLLOW

Up

RESECTION

REGISTRATION

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA+

RHT

EIA EIA EIA EIA

Arm A:

Arm B:

R ESPONSE

EVALUATION

13th

week

CYCLE I II III IV



634: Phase I trial of gemcitabine +preop RT in extremity and trunk sarcoma

• Phase I• Preop EBRT 50 Gy + Gem, d1, 8,22, 29, 43, 50• N=36 patients• MTD: 600mg/m2 gemcitabine• 20% pCR + 23% 90-99% necrosis


Chordoma (725,728)

• Stacchioti et al., INT Milano

• Tumor control with addition of CDDP to imatinib in 2 imatinib refractory patients

• Nilotinib : a response in an imatinib refractory patient


Rationale

Nilotinib is a second-generation inhibitor of selected tyrosine kinases, including KIT, PDGFR, and Bcr-Abl

In vitro data in human GIST882 cells show reduction of KIT autophosphorylation similar to imatinib

Nilotinib inhibits cell proliferation in imatinib sensitive and resistant GIST cell lines （ GIST882 GIST430 and GIST48 ） more potently than does imatinib

Nilotinib intracellular concentrations are higher than those of imatinib in GIST cell lines

N

NNH3C

HN

HN

O

NN CH3

N

NNH3C

HN

O

CH3

NH

N

N

FFF

Imatinib Nilotinib （ AMN107 ）


Sorafenib (732)• D’adamo et al. A phase II study of sorafenib in

metastatic reccurent sarcomas

– Sorafenib : 400mg BID– 6 arms, angio, MPNST, leiomyosarcomas, high

grade undiff. Sarcoma, synovial, other sarcomas– N=34, 3 RECIST responses, – Question : SD? RECIST?

If you insist using RECIST,

you’ll no more exist on this list

Documents

12 th Annual CTOS Meeting 2006 Session 7. 12 th Annual CTOS Meeting 2006 AP23573 Induced Long-term Stability in 2 Patients with Desmoplastic Small Round