A Phase I/II Study to Investigate the Safety and Clinical Activity of the Protein Arginine Methyltransferase 5

Inhibitor GSK3326595 in Subjects with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Justin M. Watts1, Terrence J. Bradley

1, Amber Thomassen

1, Andrew M. Brunner

2, Mark D. Minden

3, Nikolaos Papadantonakis

4, Sameem Abedin

5, Amanda J. Baines

6, Olena Barbash

7, Shelby Gorman

7, Brandon E. Kremer

7, Gautam M. Borthakur

8

1Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA;

2Dana-Farber Cancer Institute, Boston, MA, USA;

3Princess Margaret Hospital, Toronto, ON, Canada;

4O'Neal Comprehensive Cancer Center, Birmingham, AL, USA;

5Medical College of Wisconsin, Milwaukee, WI, USA;

6GlaxoSmithKline, Stevenage, UK;

7GlaxoSmithKline, Collegeville, PA, USA;

8MD Anderson Cancer Center, Houston, TX, USA

Background

Myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML)

• Closely related neoplastic diseases of hematopoietic myeloid progenitors

• Despite current therapies, overall long-term survival is poor1,2

Protein arginine methyltransferase 5 (PRMT5)

• Primary enzyme responsible for symmetric arginine dimethylation of multiple proteins that impact cell proliferation

3

• Its substrates include proteins involved in mRNA splicing, signal transduction, gene transcription, and DNA repair (Figure 1)

4,5

• Overexpressed in many cancers, including myeloid malignancies, and correlates with poor prognosis

6

• Implicated in the pathogenesis of AML6,7

• Inhibition leads to decreased proliferation and cell death in preclinical models of AML

6,7

Presented at the American Society of Hematology Annual Meeting • Orlando, FL, USA • December 7‒10, 2019

Study Overview

References

1. Ball B et al. Leuk Lymphoma 2017;58:1022–36; 2. Shabbir MH et al. Cancer 2009;115:2903–11; 3. Bezzi M et al. Genes Dev 2013;27:1903–16; 4. Karkhanis V et al. Trends Biochem Sci 2011;36:633–41; 5. Pal S et al. EMBO 2007;26:3558–69; 6. Tarighat SS et al. Leukemia 2016;30:789–99; 7. Kaushik S et al. Leukemia 2018;32:499–509; 8. Inoue D et al. Genes Dev 2016;30:989–1001; 9. Yoshida K et al. Nature 2011;478:64–9; 10. Abu Kar S et al. Haematologica 2013;98:107–13; 11. Patnaik MM et al. Am J Hematol 2013;88:201–6.

Disclosures JMW is a consultant of Jazz Pharmaceuticals (Jazz); has received research funding from Takeda Pharmaceutical Company; and holds membership on the board of directors or has participated in speakers bureaus or advisory boards for Celgene Corporation (Celgene), Jazz, and Pfizer; TJB is a consultant of and has served on advisory boards for AbbVie Inc.; AT has nothing to disclose; AMB has received research funding from AstraZeneca, Celgene, and Jazz; holds membership on the board of directors or has participated in advisory boards for Celgene, Forty Seven Inc., and Jazz; MDM has received honoraria from Astellas Pharma; NP has received honoraria from and participated in advisory boards for Agios Pharmaceuticals (Agios); SA has received research funding from Actinium Pharmaceuticals, Helsinn Healthcare, and Pfizer; and has received honoraria from Agios and Jazz; AJB is an employee of and stockholder with GlaxoSmithKline (GSK); OB is an employee of and stockholder with GSK; she has received research funding from GSK; and has patents/royalties with GSK; SG is an employee of and stockholder with GSK; BEK is an employee of and stockholder with GSK; GMB and his institution have received research funding from GSK.

Key Inclusion Criteria Key Exclusion Criteria

• Age: ≥18 years

• MDS, CMML, or AML diagnosis (see specific criteria by Study Part in Table 4)

• ECOG performance status: 0‒2

• Prior treatment-related toxicities ≤ Grade 1 (NCI-CTCAE v4), except:

− Alopecia (permissible at any Grade)

− Peripheral neuropathy (must be ≤ Grade 2)

• Adequate organ system functions

• Prior history of stem cell transplant allowed if transplant occurred ˃3 months prior and participant has recovered from all transplant-associated toxicities

• History of prior organ transplant

• History of a second malignancy, excluding nonmelanoma skin cell cancer ≤3 years

• Active severe or uncontrolled infection

• Symptomatic or untreated CNS disease

• Prior therapy with any PRMT5 inhibitor

• Recent prior therapy including nonmonoclonal anticancer therapy ≤14 days or 5 half-lives; biologic agent ≤28 days; radiotherapy ≤14 days; or surgery ≤28 days

• History of HIV, presence of hepatitis B surface antigen, or positive hepatitis C test

• History of acute coronary syndrome, coronary angioplasty or stenting (≤6 months); baseline corrected QT (Fridericia’s formula) interval ≥480 msec; uncontrolled arrhythmias; class II, III, or IV heart failure

Table 3. Key Eligibility Criteria – Overall Study

Figure 1. Symmetric Arginine Dimethylation by PRMT5 Regulates a Range of Cellular Processes

This figure was previously presented in a related oral presentation at the European Society of Medical Oncology Annual Meeting held in Barcelona, Spain from 27 Sep‒01 Oct 2019.

Acknowledgements Funding for this study (NCT03614728 available at ClinicalTrials.gov) was provided by GlaxoSmithKline (GSK). Medical editorial support (Sarah Hummasti, PhD, and Allyson Lehrman, DPM) and graphic services were provided by AOIC, LLC, and were funded by GSK.

• Mutations in splicing factors are frequent in myeloid malignancies

− MDS: approximately 45–85%8,9

− CMML: 50–60%10,11

GSK3326595

• Potent, selective, and reversible inhibitor of PRMT5 (Figure 2)

• Inhibits proliferation and induces cell death in solid and hematologic tumor cell lines

• Exhibits potent antitumor activity in vitro and in vivo in preclinical models of myeloid malignancies

Figure 2. GSK3326595 is a Potent and Selective Inhibitor of PRMT5

This figure was previously presented in a related oral presentation at the European Society of Medical Oncology Annual Meeting held in Barcelona, Spain from 27 Sep‒01 Oct 2019.

• Phase I/II open-label, multipart study of GSK3326595 as monotherapy and in combination with other agents in participants with myeloid malignancies (Figure 3)

Part 2: Further exploration of efficacy in myeloid neoplasms

• Part 2A: Head-to-head vs BAC in relapsed/refractory MDS, CMML, and hypoproliferative AML

− Participants randomized 2:1 to GSK3326595 (at recommended dose identified in Part 1) or investigator’s choice of BAC

• Part 2B: Single-arm dose escalation and dose expansion combined with standard-of-care in newly diagnosed MDS

− Abbreviated dose escalation to select a safe GSK3326595 dose in combination with approved dose of 5-azacitidine

○ Starting dose of GSK3326595 will be 2 dose levels below the recommended dose from Part 1

○ N-CRM used to guide dose escalation decisions up to the recommended dose from Part 1

○ 28-day dose-limiting toxicity (DLT) window

− Dose expansion

○ GSK3326595 plus 5-azacitidine administered at recommended dose identified in dose confirmation phase until progression, unacceptable toxicity, withdrawal of consent, or termination of study

• Part 2C: Single-arm dose expansion in participants with relapsed and/or refractory AML whose disease harbor mutations in proteins of the spliceosomal machinery

− GSK3326595 monotherapy (at recommended dose identified in Part 1) until progression, unacceptable toxicity, or withdrawal of consent

AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; MDS, myelodysplastic syndrome.

Diagnosis Prior Therapy

Parts 1 and 2A

• MDS: intermediate/high/very high-risk by IPSS-revised criteria

• CMML: intermediate-2 or high-risk per CPSS or CPSS-mol criteria

• MDS/CMML: secondary to prior antineoplastic therapy, of any risk score

• AML: evolved from an antecedent MDS/MPN with myeloblast percentage in the marrow ≤30% or peripheral white blood cell count <20,000 cells/μL in the absence of leukoreducing therapy

• Disease that failed to respond to, or progressed despite, treatment with ≥1 systemic therapy

Part 2B • MDS: high/very high-risk by IPSS-revised criteria

• CMML: intermediate-2 or high-risk per CPSS or CPSS-mol criteria

• MDS/CMML: secondary to prior antineoplastic therapy, of any risk score

• No prior therapy, or have completed ≤1 cycle of a hypomethylating agent

Part 2C • AML (irrespective of antecedent MDS and myeloblast percentage in the marrow, irrespective of hydroxyurea therapy) with a documented loss-of-function mutation(s) in ≥1 gene/protein (ie, SF3B1, SRSF2, U2AF1, or ZRSR2)

• Disease that has failed to respond to, or progressed despite, treatment with ≥1 but ≤4 prior lines of systemic therapy

Table 4. Eligibility Criteria by Study Part

AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; IPSS, International Prognostic Scoring System; CPSS, CMML-specific prognostic scoring system; CPSS-mol, clinical/molecular CPSS; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms.

• The decision to proceed to Part 2 will be based on the totality of data, including safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data

− Demonstrated preliminary clinical activity based on clinical benefit rate (percentage of participants achieving a complete remission, complete marrow remission, partial remission, stable disease lasting ≥8 weeks, or hematologic improvement)

○ ≥14 participants meeting the criteria of clinical benefit out of 35 participants

− Can be safely and tolerably administered to the study population at a dose expected to achieve therapeutic concentrations

Primary Endpoint Secondary Endpoints

Part 1 • Clinical benefit ratea • Frequency and severity of AEs

• Frequency of DLTs

• ORRc

• PFSd

• OSb

• PK parameters (single- and repeat-dose)

Part 2A • OSb • ORR

c

• PFSd

• Frequency and severity of AEs

• Health-related quality of life

Part 2B • ORRc

• Frequency and severity of AEs

• Frequency of DLTs

• Single- and repeat-dose PK parameters (GSK3326595 and 5-azacitidine)

• PFS

Part 2C • ORRc

• PFSd

• OSb

• Frequency and severity of AEs

Table 2. Study Endpoints

aClinical benefit rate defined as the percentage of participants achieving a complete remission, complete

marrow remission, partial remission, stable disease lasting ≥8 weeks, or hematologic improvement, as per standard criteria. bOS defined as time from first dose to death due to any cause.

cORR defined as percentage of participants achieving a partial response or better.

dPFS defined as time from first dose to disease progression or death.

eHealth-related quality of life as measured by the European Organisation for Research and Treatment of

Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F). AE, adverse event; DLT, dose-limiting toxicity; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic.

Additional Analyses

Target Enrollment

• Up to 302 participants enrolled: − Part 1: ≤41 participants

− Part 2A: ≤192 participants − Part 2B: ≤41 participants − Part 2C: ≤28 participants

• Evaluation of symmetric dimethylated arginine (SDMA), the enzymatic product of PRMT5

− A PD marker of PRMT5 inhibition in plasma and tumor tissue

• Stratification based on the presence or absence of spliceosome mutations to evaluate the effect of these mutations on clinical benefit

• Measurement of transcriptome to elucidate known and novel mechanisms of action and inform future combinations

Additional Information About the Trial and Participating Sites

• As of December 2, 2019, recruitment is ongoing (into Part 1 of the study) across 6 centers in the United States and Canada

• In total, 21 participants have been enrolled (all into Part 1):

− 13 participants enrolled in the Dose Confirmation cohort

− 8 participants enrolled in the Dose Expansion cohort

• ClinicalTrials.gov identifier: NCT03614728

Study Design

Figure 3. Study Design

AML, acute myeloid leukemia; BAC, best available care; CBR, clinical benefit rate; CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome; ORR, overall response rate; OS, overall survival; PD, pharmacodynamic; PFS, progression-free survival; PK, pharmacokinetic; R/R, relapsed/refractory; WT, wild-type; 1L, first-line.

• Dose confirmation (safety run-in-cohort)

− Dosing will start at 400mg GSK3326595 daily

− Neuenschwander-continual reassessment method (N-CRM) used to guide dose escalation/de-escalation decisions

− 28-day dose-limiting toxicity (DLT) window

− Dose confirmed if posterior probability of excessive or unacceptable toxicity is no more than 25%

○ The excessive or unacceptable toxicity is defined as DLT rate exceeding 33%

• Dose expansion

− GSK3326595 monotherapy administered at recommended dose identified in dose confirmation phase until progression, unacceptable toxicity, or withdrawal of consent

Objectives

Part 1 • Safety evaluation and single-arm dose expansion to identify a tolerated dose and establish preliminary evidence of efficacy in participants with relapsed/ refractory MDS, CMML, and hypoproliferative AML

Part 2A • Phase II, randomized, head-to-head comparison to evaluate efficacy, safety, and health-related quality of life of GSK3326595 monotherapy vs best available care (BAC) in participants with relapsed/refractory MDS, CMML, and hypoproliferative AML

Part 2B • Single-arm investigation of GSK3326595 plus 5-azacitidine to evaluate the safety and efficacy of GSK3326595 plus 5-azacitidine as first-line therapy in participants with newly diagnosed high-risk MDS

Part 2C • Single-arm dose expansion study evaluating clinical activity and safety of GSK3326595 monotherapy in participants with relapsed or refractory AML whose tumors harbor mutations in components of the pre-mRNA splicing machinery

Table 1. Study Objectives

Poster #2656

Part 1: Dose confirmation and single-arm dose expansion in relapsed/refractory MDS, CMML, and hypoproliferative AML

AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome.