Transcript Slide 1

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
MK-2206, a novel oral, potent, allosteric
inhibitor of AKT
PDK 1
PH
PDK 2
P
N
PH
Kinase
Active AKT
Novel MOA
T308
S473
ATP
P
MK-2206
N
C
Kinase
Inhibited AKT
(Incapable of membrane localization)
 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
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
• 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
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
5
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
6
Treatment Schema
Oral MK-2206 administered in 28-day treatment cycles
Cycle 1
Schedule
MK-2206
QOD
Days 1 - 28
Dose QOD
beginning
Day 1
†Patients
7-Day Drug
Holiday
Days 29 - 35
Off
Drug
Cycles 2 - 6†
Days 36 -175
Dose QOD
beginning
Day 36
permitted to continue beyond 6 cycles
7
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
8
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
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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
10
Patient Demographics
Characteristics:
Number of patients
Diagnosis:
34
Tumor Type
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
Breast
Melanoma
Neuroendocrine
Prostate
Ovarian
Colorectal
Parotid
Other:
2 (6)
3 (9)
29 (85)
lung, pancreatic, GIST,
Kaposi’s sarcoma, renal cell,
DSRCT, pheochromocytoma,
synovial cell sarcoma,
squamous cell carcinoma
transitional of urothelium
Number of
Patients
7
4
3
3
3
2
2
10
11
Dose Escalation Phase
No. of Patients
Dose
Dose
(mg)
Enrolled Reduced
30 QOD
3
0
No. of
Cycles
10
No. of
DLTs
0
60 QOD
6 (12+)
0
13
0
90 QOD
7
6
13
4
75 QOD
3
3
9
2
12
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
13
Non-Hematologic Toxicity:
Dose Escalation and Expansion Phase
Adverse Experience
Skin rash
Grade 1
Grade 2
Grade 3
Grade 4
Mucosal
inflammation
Grade 1
Grade 2
Grade 3
30 mg
QOD
(n=3)
60 mg
QOD
(n=18)
2
3
2
75 mg
QOD
(n=3)
90 mg
QOD
(n=7)
1
2
1
1
3
1
3
1
14
Skin Rash
15
Non-Hematologic Toxicity:
Dose Escalation and Expansion Phase
Adverse Experience
Hyperglycemia
Grade 1
Grade 2
Grade 3
30 mg
QOD
(n=3)
60 mg
QOD
(n=18)
75 mg
QOD
(n=3)
90 mg
QOD
(n=7)
1
1
1
2
1
Pruritus
Grade 1
Grade 2
3
1
1
Diarrhea
Grade 1
Grade 2
1
1
2
2
1
16
Non-Hematologic Toxicity:
Dose Escalation and Expansion Phase
Adverse Experience
30 mg
QOD
(n=3)
Vomiting
Grade 1
Grade 2
1
Nausea
Grade 1
Grade 2
1
1
Fatigue
Grade 1
Grade 2
60 mg
QOD
(n=18)
75 mg
QOD
(n=7)
90 mg
QOD
(n=3)
1
2
3
1
2
1
1
1
1
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Mean (SD) Plasma MK-2206 Concentration (nmol/l)
Preliminary PK Summary of MK-2206
30 mg QOD (n = 3)
60 mg QOD (n = 9)
75 mg QOD (n = 2)
90 mg QOD (n = 7)
250
200
150
100
50
0
0
8
16
24
Nominal Time (hr)
32
40
48
Preliminary PD Summary of MK-2206
60 mg QOD – Tumor
pAkt unit
(normalized to total protein)
~ 90% tumor pAkt inhibition in 5 out of 7 patients
18.000
16.000
14.000
12.000
10.000
8.000
Cycle 1 Baseline
6.000
Cycle 1 D15
4.000
2.000
0.000
1
2
3
4
5
7
Patient
0.250
0.200
Pt 1
6
*
0.150
0.100
0.050
0.000
Cycle 1 Screening
Cycle 1 D15
* C1D15 pAKT value was below LLOD
Pt 1 – Kaposi sarcoma
Pt 2 – DSRCT sarcoma
Pt 3 – Pheochromocytoma
Pt 4 – Breast
Pt 5 – Breast
Pt 6 – Melanoma
Pt 7 – Breast
19
Circulating Nucleic Acid PIK3CA Mutations
7 patients had CNA blood samples drawn, 4 positive for PIK3CA mutations
Tumor
Breast
Gene
PIK3CA
Exon
Exon 9
Breast
PIK3CA
Exon 9
Melanoma PIK3CA
Exon 20
Colon
Exon 20
PIK3CA
Comment Response
BRCA2 + PD
PD
20
Anti-Tumor Activity of MK-2206
30 mg QOD dose level
21
Anti-tumor Activity of MK-2206: CA125
Ovarian Cancer Patients (3/3)
Tumor
Ovarian
Dose
90
CA 125
Baseline
1572
CA 125
Nadir
534
Ovarian
90
1729
1142
DLT off
study
Ovarian
60
225
155
Continues
Comment
DLT off
study
22
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
23
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. Brianne Kaiser
Ms. Rachel Pesek
Ms. Cally Claiborne
Mr. James Agnew
Royal Marsden Hospital and The Institute of Cancer Research
Ms. Lauren Britton
Ms. Liz Sheridan
Dr. Michelle Garrett
Mr. Simon Heaton
Ms Samantha Costigan
Mr. Shaun Decordova
Ms. Philippa Grainger
Dr. Nina Tunariu
H. Lee Moffitt Cancer Center & Research Institute
Dr. Dan Sullivan
Mr. Rich Lush
Ms. Michelle Mintz
Ms. Sue Chen
Ms. Joana Moreira
Ms. Juliet Dukes