a phase i study of mk-2206, an oral potent allosteric akt inhibitor in patients with advanced solid...
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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
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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
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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
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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