Reference Detail

Ref Type

Journal Article

PMID

(27815358)

Authors

Infante JR, Hollebecque A, Postel-Vinay S, Bauer TM, Blackwood EM, Evangelista M, Mahrus S, Peale FV, Lu X, Sahasranaman S, Zhu R, Chen Y, Ding X, Murray ER, Schutzman JL, Lauchle JO, Soria JC, LoRusso PM

Title

Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	10	2017 May 15	2423-2432	Clin Cancer Res

URL

Abstract Text

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. TP53 mutations 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/m2 Dose-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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
GDC-0425	GDC-0425	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
GDC-0425		RG7602	CHK1 Inhibitor 18	GDC-0425 (RG7602) is a selective CHK1 inhibitor, which may enhance chemosenstivity, potentially resulting in decreased tumor growth (PMID: 27815358).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 mutant	triple-receptor negative breast cancer	predicted - sensitive	GDC-0425 + Gemcitabine	Phase I	Actionable	In a Phase I trial, treatment with GDC-0425 followed by Gemzar (gemcitabine) resulted in a partial response in a patient with triple-receptor negative breast cancer harboring a TP53 mutation (PMID: 27815358).	27815358