Phase I/II Trial of the MEK1/2 Inhibitor GSK1120212 (GSK212) in Patients with Relapsed/Refractory Myeloid Malignancies: Evidence of Activityin Pts with RAS Mutation

Borthakur G et al.Proc ASCO 2011;Abstract 6506.

Borthakur G et al. Proc ASCO 2011;Abstract 6506.

Background

– Signaling through the RAS/RAF/MEK pathway is activated in many human cancers.

– GSK212 is a potent, selective allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro.

– A Phase I/II study of a single, daily, oral dosing regimen was conducted.

Study Objectives:– Define the recommended Phase II dose (RP2D) of GSK212.– Evaluate pharmacokinetics, toxicity and preliminary

activity in patients with previously treated hematologic malignancies.

Phase I/II Study Design

Eligibility

Relapsed/refractory AML, poor-risk MDS (>5% blasts), ALL, CMMLECOG PS 0-2Adequate organ function

Borthakur G et al. Proc ASCO 2011;Abstract 6506.

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; MDS, myelodysplatic syndrome

Recommended Phase II dose = 2 mg QD

3 mg loading1 mg QD

n = 3

1 mg QDn = 2

2 mg QDn = 9

Cohort 1RAS-mutant AML MDS

Cohort 2RAS wild type or unknown

Cohort 3RAS-mutant CMML

RP2D

3 + 3 doseescalation

Phase 1 — Dose escalation Phase 2 — Expansion

Patient Characteristics: 2 mg/Day Dose

Characteristic n = 47

Median age, years (range) 64 (21-87)

Number of prior therapies, median 2

ECOG PS, n (%) 0-1 2

34 (72)13 (28)

Diagnosis, n (%) AML Other

42 (89)5 (11)

RAS mutation, n (%) 16 (34)

FLT3 mutation, n (%) 18 (38)

Cytogenetics, n (%) Complex Core-binding factor Normal Other/unknown

9 (19)2 (4)

8 (17)17 (37)

Borthakur G et al. Proc ASCO 2011;Abstract 6506.

Clinical Activity

Best Response, n (%)N or KRAS Mutated

(n = 16)

RAS Wild Type or Unknown

(n = 31)

CR/CRp 3 (19) 0

MLFS 1 (6) 0

Partial response 0 1 (3)

HI/HI-N/HI-P 1 (6) 5 (16)

Stable disease 10 (63) 8 (26)

Progressive disease 0 13 (42)

Overall response rate 4 (25) 1 (3)

Borthakur G et al. Proc ASCO 2011;Abstract 6506.

• MLFS = morphologic leukemic-free state• ORR = CR/CRp/MLFS/PR

6 patients not evaluable

Select Adverse Events*

AEs (N = 47) All Grades Grade 3/4

Diarrhea 47% 4%

Pyrexia 30% 6%

Rash 26% 4%

Fatigue 25% 4%

AST increase 24% 11%

ALT increase 23% 11%

Pneumonia 23% 17%

Febrile neutropenia 23% 19%

Borthakur G et al. Proc ASCO 2011;Abstract 6506.

* Occurring in greater than 20% of patients

Events of Special Interest

Borthakur G et al. Proc ASCO 2011;Abstract 6506.

• Decrease in LVEF

– Six percent (3/47) of patients had drug-related left ventricular dysfunction (1 Grade 1 event and 2 Grade 2 events).

• Transaminase elevations

– Two patients had drug held due to transaminase elevations — on rechallenge, 1 positive and 1 negative.

• Ocular toxicity

– Central Serous Retinopathy: Fluid accumulation in the macular region between retinal pigment epithelium and out segment.

– One patient developed a reversible retinopathy.

Borthakur G et al. Proc ASCO 2011;Abstract 6506.

Author Conclusions

Acceptable safety profile:– Monotherapy safety profile suggests potential to

combine with other antileukemic therapies

Preliminary efficacy:– Overall response rates of 25 percent (4 of 16) among

patients with RAS mutation

Enrolling patients with RAS-mutant AML, MDS and CMML:– Centralized RAS mutation analysis– Up to 30 sites in US and Europe open to accrual