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

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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 2011Abstract 6506.

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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.

Borthakur G et al. Proc ASCO 2011Abstract 6506.
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Phase I/II Study Design
Eligibility
Relapsed/refractory AML, poor-risk MDS (gt5 blasts), ALL, CMMLECOG PS 0-2Adequate organ function
Phase 1 Dose escalation
Phase 2 Expansion
Cohort 1RAS-mutant AML MDS
2 mg QDn 9
1 mg QDn 2
RP2D
Cohort 2RAS wild type or unknown
3 mg loading1 mg QDn 3
Cohort 3RAS-mutant CMML
3 3 doseescalation
Recommended Phase II dose 2 mg QD
ALL, acute lymphoblastic leukemia AML, acute
myeloid leukemia CMML, chronic myelomonocytic
leukemia MDS, myelodysplatic syndrome
Borthakur G et al. Proc ASCO 2011Abstract 6506.
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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 2011Abstract 6506.
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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)

• MLFS morphologic leukemic-free state
• ORR CR/CRp/MLFS/PR
• 6 patients not evaluable

Borthakur G et al. Proc ASCO 2011Abstract 6506.
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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
Occurring in greater than 20 of patients
Borthakur G et al. Proc ASCO 2011Abstract 6506.
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Events of Special Interest

• 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 2011Abstract 6506.
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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

Borthakur G et al. Proc ASCO 2011Abstract 6506.