A Phase I Study of MK-2206, an Oral Potent Allosteric Akt Inhibitor in Patients

with Advanced Solid Tumors

Anthony W. Tolcher,1 Timothy A. Yap,2 Ivy Fearen,3 Adekemi Taylor,3 Chris Carpenter,3 Andre T. Brunetto,2 Muralidham Beeram,1 Kyriakos Papdopoulos,1 Li Yan,3

Johann S. de Bono2

Abstract #3503

1START (South Texas Accelerated Research Therapeutics), San Antonio, TX 2Royal Marsden Hospital and The Institute of Cancer

Research, Sutton, Surrey, UK , 3Merck & Co., Inc., North Wales, PA

2

MK-2206, a novel oral, potent, allosteric inhibitor of AKT

Active AKT Inhibited AKT(Incapable of membrane localization)

NKinase

PH

AT

PA

TP

PDK 1PDK 2

PP S473

N

Kinase

PH

T308

C

MK-2206

Novel MOA Compound binds at an allosteric, PH domain dependent site Akt PH domains not highly conserved Highly selective for Akt with little off-target kinase activities

IC50 for AKT1 = 5 nM; AKT2 = 12 nM; AKT3 = 65 nM

May be less vulnerable to feedback activation on Akt compared to ATP-competitive inhibitors

MK-2206 Inhibits pAKT & Downstream Signaling Pathways in Human Tumor Cells

0 14 41 123 370 1111 3333 10000 MK-2206 (nM)

pAkt(S473)

pAkt(T308)

Akt

pTSC(T1462)

pPRAS40(T246)

pS6 (S235,236)

A2780 (Ovarian)

0 14 41 123 370 1111 3333 10000

LNCaP (prostate)

GaoZhen Hang & Wei Lu, Merck & Co., Inc.

MK-2206 Compound Profile – Preclinical

• Potent anti-proliferative activity against multiple tumor cell lines (breast, ovarian, prostate, lung & gastric)

– IC50 is dependent on PI3K pathway activation events (PIK3CA mutation/amplification, PTEN loss) and wild type Ras/Raf in some cases

• Single agent anti-tumor activity in xenograft models

• Synergistic or additive with chemotherapeutic and targeted agents in vitro and in vivo

4

5

Phase I Study Objectives

• Primary

– Determine the safety and pharmacokinetics (PK) of

oral MK-2206 administered every other day (QOD)

– Define the dose-limiting toxicity (DLT) and maximum

tolerated dose (MTD) of oral MK-2206 administered

QOD

• Secondary

– Assess target engagement in whole blood and tumor

– Describe any preliminary anti-tumor activity

6

Major Eligibility Criteria

• Advanced or metastatic solid tumors

• Age 18 years, ECOG PS 1

• At least 4 weeks since prior chemotherapy, irradiation, or biologic therapy

• No primary CNS tumor, QTc prolongation, bradycardia (<50 bpm), hepatitis

• No history of diabetes

Test Level

Hgb 9 g/dL

ANC 1500/µL

Platelets 100,000/µL

AST and ALT 2.5 x ULN† or 5 x ULN

Fasting serum glucose

110% of ULN

HgbA1c 8%

Potassium and Magnesium

Within normal range

†Upper limits of normal

7

Treatment Schema

Cycle 17-Day Drug

Holiday Cycles 2 - 6†

Schedule Days 1 - 28 Days 29 - 35 Days 36 -175

MK-2206 QOD

Dose QOD beginning

Day 1 Off

Drug

Dose QOD beginning

Day 36

Oral MK-2206 administered in 28-day treatment cycles

†Patients permitted to continue beyond 6 cycles

8

Study Design

• Dose escalation in cohorts of 3 to 6 patients

– Planned doses: 30, 60, 90, 200, and 300 mg

– Intermediate dose levels incorporated after DLT

• DLT observation period in first 28 days

• Dose confirmation in a total of 18 patients

– MTD determined using a dose-response curve for the percentage of patients experiencing a DLT †

• Target toxicity rate of ~17%†Ji et al. Clin Trials 2007; 4:235-44

9

Definition of DLT

Grade 4 hematologic toxicity

• Grade 3 neutropenia with fever and/or infection

Grade 3 non-hematologic toxicity, including Grade 3 signs and symptoms of glucose intolerance

– Fasting glucose >250 mg/dL or 13.9 mmol/L

– Non-fasting glucose >500 mg/dL or 27.8 mmol/L

• Diagnosis of lactoacidosis or ketoacidosis

• QTc interval increase >60 ms, and/or >500 ms

• Clinically significant bradycardia

10

PK/Pharmacodynamic (PD) Sampling

• Serial PK/PD sampling between Days 1 and 35

– Plasma for PK

– Peripheral whole blood for PD

• P-AKT activity (MESO-scale assay method)

• Tumor biopsy performed: baseline, Cycle 1 D 15

• Circulating nucleic acids for PIK3CA mutation

• Results pending– Plucked hair for pAkt inhibition performed at baseline and Cycle

1 Days 7 and 15, Cycle 2 Day 1– Circulating tumor cells and circulating endothelial cells

performed at baseline and Day 1 of each cycle

11

Patient Demographics

Characteristics:

Number of patients 34

Age, median (range) 56 (25 to 84)

Male, n (%) 19 (56)

ECOG PS, n (%)

0

1

12 (35)

22 (65)

Prior chemotherapy regimens, n (%)

1

2

3

2 (6)

3 (9)

29 (85)

Diagnosis:

Tumor TypeNumber of

Patients

Breast

Melanoma

Neuroendocrine

Prostate

Ovarian

Colorectal

Parotid

7

4

3

3

3

2

2

Other:lung, pancreatic, GIST, Kaposi’s sarcoma, renal cell, DSRCT, pheochromocytoma, synovial cell sarcoma, squamous cell carcinoma transitional of urothelium

10

12

Dose Escalation Phase

Dose (mg)

No. of Patients

No. of Cycles

No. of DLTsEnrolled

Dose Reduced

30 QOD

60 QOD

90 QOD

75 QOD

3

6 (12+)

7

3

0

0

6

3

10

13

13

9

0

0

4

2

13

Hematologic Toxicity: Dose Escalation and Expansion Phase

Adverse Experience

30 mg QOD

(n=3)

60 mg QOD

(n=18)

75 mg QOD (n=3)

90 mg QOD (n=7)

Anemia

Grade 2 1

Leukopenia

Grade 1 2

ANC

Grade 1 1

Thrombocytopenia

Grade 1 1

14

Non-Hematologic Toxicity: Dose Escalation and Expansion Phase

Adverse Experience

30 mg QOD

(n=3)

60 mg QOD

(n=18)

75 mg QOD (n=3)

90 mg QOD (n=7)

Skin rash

Grade 1

Grade 2

Grade 3

Grade 4

2

3

2

1

2

1

1

3

1

Mucosal inflammation

Grade 1

Grade 2

Grade 3

3

1

15

Skin Rash

16

Non-Hematologic Toxicity: Dose Escalation and Expansion Phase

Adverse Experience

30 mg QOD

(n=3)

60 mg QOD

(n=18)

75 mg QOD (n=3)

90 mg QOD (n=7)

Hyperglycemia

Grade 1

Grade 2

Grade 3

1

1

1

1

2

Pruritus

Grade 1

Grade 2

3

1

1

Diarrhea

Grade 1

Grade 2

1

1 1

2

2

17

Non-Hematologic Toxicity: Dose Escalation and Expansion Phase

Adverse Experience

30 mg QOD

(n=3)

60 mg QOD

(n=18)

75 mg QOD (n=7)

90 mg QOD (n=3)

Vomiting

Grade 1

Grade 2 1

1

2

Nausea

Grade 1

Grade 21

1

3

1

2

1

Fatigue

Grade 1

Grade 2 1 1

1

Nominal Time (hr)

0 8 16 24 32 40 48

Mea

n (S

D)

Pla

sma

MK

-220

6 C

once

ntra

tion

(nm

ol/l

)

0

50

100

150

200

250

30 mg QOD (n = 3)60 mg QOD (n = 9)75 mg QOD (n = 2)90 mg QOD (n = 7)

Preliminary PK Summary of MK-2206

19

Preliminary PD Summary of MK-2206 60 mg QOD – Tumor

pAkt

uni

t (

norm

aliz

ed t

o to

tal p

rote

in)

~ 90% tumor pAkt inhibition in 5 out of 7 patients

Pt 1

* C1D15 pAKT value was below LLOD

Pt 1 – Kaposi sarcomaPt 2 – DSRCT sarcomaPt 3 – PheochromocytomaPt 4 – BreastPt 5 – BreastPt 6 – MelanomaPt 7 – Breast

0.000

2.000

4.000

6.000

8.000

10.000

12.000

14.000

16.000

18.000

Cycle 1 Baseline

Cycle 1 D15

1 2 3 4 5 6 7

Patient

0.000

0.050

0.100

0.150

0.200

0.250

Cycle 1 Screening Cycle 1 D15

*

Circulating Nucleic Acid PIK3CA Mutations

Tumor Gene Exon Comment Response

Breast PIK3CA Exon 9 BRCA2 + PD

Breast PIK3CA Exon 9 PD

Melanoma PIK3CA Exon 20

Colon PIK3CA Exon 20

20

7 patients had CNA blood samples drawn, 4 positive for PIK3CA mutations

21

Anti-Tumor Activity of MK-220630 mg QOD dose level

Anti-tumor Activity of MK-2206: CA125Ovarian Cancer Patients (3/3)

Tumor DoseCA 125

BaselineCA 125

Nadir Comment

Ovarian 90 1572 534 DLT off study

Ovarian 90 1729 1142 DLT off study

Ovarian 60 225 155 Continues

22

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Conclusions

• The MTD of oral MK-2206 QOD is 60 mg

– Predominant toxicities at MTD were mild to moderate skin rash, GI symptoms, fatigue, and hyperglycemia

– Severe toxicity of skin rash above the MTD

• Dose proportional PK

• pAkt inhibition in whole blood and tumor

• Early indications of anti-tumor activity

AcknowledgmentsThe study investigators would like to thank the patients for participating in this trial as well as the nurses and clinical research associates who contributed to the implementation of this study.

START (Southern Texas Accelerated Research Therapeutics)Dr. Amita Patnaik Ms. Cally ClaiborneMs. Brianne Kaiser Mr. James AgnewMs. Rachel Pesek

Royal Marsden Hospital and The Institute of Cancer ResearchMs. Lauren Britton Ms Samantha Costigan Ms. Sue Chen Ms. Liz Sheridan Mr. Shaun Decordova Ms. Joana MoreiraDr. Michelle Garrett Ms. Philippa Grainger Ms. Juliet DukesMr. Simon Heaton Dr. Nina Tunariu

H. Lee Moffitt Cancer Center & Research InstituteDr. Dan Sullivan

Mr. Rich Lush Ms. Michelle Mintz