A Italiano1, J R Infante2, G I Shapiro3, K N Moore4, P M LoRusso5, E Hamilton2, S Cousin6, M Toulmonde6, S Postel-Vinay7, S Tolaney3, E M Blackwood8, S Mahrus8, F V Peale8, X Lu8, A Moein8, J Epler8, K DuPree8, M Tagen8, E R Murray8, J L Schutzman8, J O Lauchle8, A Hollebecque9, J-C Soria10. 1. Early Phase Trials and Sarcoma Units, Institut Bergonié, Bordeaux, France. Electronic address: a.italiano@bordeaux.unicancer.fr. 2. Sarah Cannon Research Institute, Nashville; Tennessee Oncology, Nashville. 3. Early Drug Development Center; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston. 4. Stevenson Oklahoma Cancer Center, Oklahoma City; University of Oklahoma, Oklahoma City. 5. Smilow Cancer Center, New Haven; Yale University, New Haven, USA. 6. Early Phase Trials and Sarcoma Units, Institut Bergonié, Bordeaux, France. 7. Départemement d'Innovation Thérapeutique et des Essais Précoces (DITEP), Villejuif; Gustave Roussy, Villejuif; Université Paris Saclay, Villejuif; INSERM, U981, Villejuif, France. 8. Genentech, Inc., South San Francisco, USA. 9. Départemement d'Innovation Thérapeutique et des Essais Précoces (DITEP), Villejuif; Gustave Roussy, Villejuif; Université Paris Saclay, Villejuif. 10. INSERM, U981, Villejuif, France.
Abstract
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.
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.
Authors: Kathleen N Moore; David S Hong; Manish R Patel; Shubham Pant; Susanna V Ulahannan; Suzanne Jones; Funda Meric-Bernstam; Judy S Wang; Raid Aljumaily; Erika P Hamilton; Erika S Wittchen; Xuejing Wang; Aimee Bence Lin; Johanna C Bendell Journal: Target Oncol Date: 2021-09-24 Impact factor: 4.493
Authors: Alexandre André B A da Costa; Dipanjan Chowdhury; Geoffrey I Shapiro; Alan D D'Andrea; Panagiotis A Konstantinopoulos Journal: Nat Rev Drug Discov Date: 2022-10-06 Impact factor: 112.288
Authors: Stanislav Drápela; Prashant Khirsariya; Wytske M van Weerden; Radek Fedr; Tereza Suchánková; Diana Búzová; Jan Červený; Aleš Hampl; Martin Puhr; William R Watson; Zoran Culig; Lumír Krejčí; Kamil Paruch; Karel Souček Journal: Mol Oncol Date: 2020-07-16 Impact factor: 6.603