Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors.
Purpose:Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors.Experimental Design:Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2(Arm A), then increased to 1,000 mg/m2(Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability.TP53mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses.Results:Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2Dose-limiting toxicities included thrombocytopenia (n= 5), neutropenia (n= 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n= 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n= 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin.Conclusions:Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy.Clin Cancer Res; 23(10); 2423-32. ©2016 AACR.
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee. jinfante@tnonc.com.
Jeffrey R
JR
Infante
Départemement d'Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France.
Antoine
A
Hollebecque
Départemement d'Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France.|INSERM, U981, Villejuif, France.
Sophie
S
Postel-Vinay
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
Todd M
TM
Bauer
Genentech, Inc., South San Francisco, California.
Elizabeth M
EM
Blackwood
Genentech, Inc., South San Francisco, California.
Marie
M
Evangelista
Genentech, Inc., South San Francisco, California.
Sami
S
Mahrus
Genentech, Inc., South San Francisco, California.
Franklin V
FV
Peale
Genentech, Inc., South San Francisco, California.
Xuyang
X
Lu
Genentech, Inc., South San Francisco, California.
Srikumar
S
Sahasranaman
Genentech, Inc., South San Francisco, California.
Rui
R
Zhu
Genentech, Inc., South San Francisco, California.
Yuan
Y
Chen
Genentech, Inc., South San Francisco, California.
Xiao
X
Ding
Genentech, Inc., South San Francisco, California.
Elaine R
ER
Murray
Genentech, Inc., South San Francisco, California.
Jennifer L
JL
Schutzman
Genentech, Inc., South San Francisco, California.
Jennifer O
JO
Lauchle
Départemement d'Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France.|INSERM, U981, Villejuif, France.
Jean-Charles
JC
Soria
Karmanos Cancer Institute, Detroit, Michigan.
Patricia M
PM
LoRusso
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000093542:Gemcitabine
D006575:Heterocyclic Compounds, 3-Ring; D010880:Piperidines; D003841:Deoxycytidine; C000614032:GDC-0425; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D000093542:Gemcitabine