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Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with
A Italiano1, J R Infante2, G I Shapiro3
1Early Phase Trials and Sarcoma Units, Institut Bergonié, Bordeaux, France.
Background:
Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed.
Patients And Methods:
In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts.
Results:
Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2.
Conclusion:
GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine.
Clinical Trial Number:
NCT01564251.
Insights
This Phase I study found that GDC-0575, a Chk1 inhibitor, is safe alone or with gemcitabine. While tolerability with gemcitabine was modest, preliminary antitumor activity was seen in refractory solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Checkpoint kinase 1 (Chk1) inhibition enhances chemotherapy efficacy by overriding cell cycle arrest and inducing mitotic catastrophe.
- GDC-0575 is an oral, selective Chk1 inhibitor demonstrating antitumor activity in preclinical models.
- Evaluating GDC-0575 in combination with gemcitabine is crucial for potential therapeutic applications.
Purpose of the Study:
- To assess the safety, tolerability, and pharmacokinetics of GDC-0575 monotherapy and in combination with gemcitabine.
- To determine the maximum tolerated dose (MTD) of GDC-0575 in combination with gemcitabine.
- To evaluate preliminary antitumor activity and Chk1 pathway modulation.
Main Methods:
- Phase I, open-label, dose-escalation study (NCT01564251) with disease-specific cohorts.
- Patients received GDC-0575 monotherapy or in combination with gemcitabine at different doses.
- Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed.
Main Results:
- 102 patients treated; most common adverse events included neutropenia, anemia, nausea, fatigue, and thrombocytopenia.
- GDC-0575 exhibited a half-life of approximately 23 hours with no observed drug-drug interactions with gemcitabine.
- Four partial responses were observed in patients receiving GDC-0575 and gemcitabine, particularly in those with TP53-mutated tumors.
Conclusions:
- GDC-0575 is safely administered as monotherapy and in combination with gemcitabine.
- Tolerability with gemcitabine was modest, with manageable hematological toxicities.
- Preliminary antitumor activity warrants further investigation in refractory solid tumors.
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