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Abstract #3503. A Phase I Study of MK-2206, an Oral Potent Allosteric Akt Inhibitor in Patients with Advanced Solid Tumors.

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Abstract 3503

Abstract #3503

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

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


Abstract 3503

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

PDK 1

PH

N

PDK 2

MK-2206

T308

P

S473

P

ATP

C

PH

Kinase

N

Kinase

Active AKT

Inhibited AKT

(Incapable of membrane localization)

  • 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

2


Mk 2206 inhibits pakt downstream signaling pathways in human tumor cells

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

LNCaP (prostate)

A2780 (Ovarian)

0

14

41

123

370

1111

3333

10000

MK-2206 (nM)

0

14

41

123

370

1111

3333

10000

pAkt(T308)

pAkt(S473)

Akt

pTSC(T1462)

pPRAS40(T246)

pS6 (S235,236)

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


Mk 2206 compound profile preclinical

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


Phase i study objectives

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


Major eligibility criteria

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

†Upper limits of normal


Treatment schema

Treatment Schema

Oral MK-2206 administered in 28-day treatment cycles

†Patients permitted to continue beyond 6 cycles


Study design

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


Definition of dlt

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


Pk pharmacodynamic pd sampling

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


Patient demographics

Patient Demographics


Dose escalation phase

Dose Escalation Phase


Hematologic toxicity dose escalation and expansion phase

Hematologic Toxicity: Dose Escalation and Expansion Phase


Non hematologic toxicity dose escalation and expansion phase

Non-Hematologic Toxicity: Dose Escalation and Expansion Phase


Skin rash

Skin Rash


Non hematologic toxicity dose escalation and expansion phase1

Non-Hematologic Toxicity: Dose Escalation and Expansion Phase


Non hematologic toxicity dose escalation and expansion phase2

Non-Hematologic Toxicity: Dose Escalation and Expansion Phase


Abstract 3503

Preliminary PK Summary of MK-2206


Preliminary pd summary of mk 2206 60 mg qod tumor

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

18.000

16.000

14.000

12.000

10.000

Cycle 1 Baseline

8.000

6.000

Cycle 1 D15

4.000

2.000

0.000

0.250

0.200

0.150

0.100

0.050

0.000

Cycle 1 Screening

Cycle 1 D15

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

pAkt unit

(normalized to total protein)

7

4

5

6

2

1

3

Patient

Pt 1 – Kaposi sarcoma

Pt 2 – DSRCT sarcoma

Pt 3 – Pheochromocytoma

Pt 4 – Breast

Pt 5 – Breast

Pt 6 – Melanoma

Pt 7 – Breast

*

Pt 1

* C1D15 pAKT value was below LLOD

19


Circulating nucleic acid pik3ca mutations

Circulating Nucleic Acid PIK3CA Mutations

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


Anti tumor activity of mk 2206

Anti-Tumor Activity of MK-2206

30 mg QOD dose level


Anti tumor activity of mk 2206 ca125 ovarian cancer patients 3 3

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


Conclusions

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


Acknowledgments

Acknowledgments

The 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 Claiborne

Ms. Brianne Kaiser Mr. James Agnew

Ms. Rachel Pesek

Royal Marsden Hospital and The Institute of Cancer Research

Ms. Lauren BrittonMs Samantha Costigan Ms. Sue Chen

Ms. Liz SheridanMr. Shaun Decordova Ms. Joana Moreira

Dr. Michelle GarrettMs. Philippa Grainger Ms. Juliet Dukes

Mr. Simon HeatonDr. Nina Tunariu

H. Lee Moffitt Cancer Center & Research Institute

Dr. Dan Sullivan

Mr. Rich Lush

Ms. Michelle Mintz


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