This is an open-label, multicenter, Phase Ib, dose-escalation study designed to assess the safety, tolerability, and pharmacokinetics of oral ipatasertib (GDC-0068) administered in combination with either docetaxel (Arm A), or oxaliplatin, leucovorin, 5-fluorouracil (5-FU) (mFOLFOX6 chemotherapy) (Arm B), or paclitaxel (Arm C), in participants with advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable. Arm D will assess the safety, tolerability, and pharmacokinetics of ipatasertib administered in combination with enzalutamide in participants with metastatic castration-resistant prostate cancer (CRPC). There will be two stages within each arm of this study: a dose-escalation stage (Stage 1) and a cohort-expansion stage (Stage 2). In Stage 1, approximately 3 to 6 cohorts in Arms A and B and 1 to 2 cohorts in Arms C and D will be evaluated to determine the maximum tolerated dose (MTD) of ipatasertib in a given combination. Additional participants will be enrolled in Stage 2 (cohort expansion), to further characterize the safety and tolerability of ipatasertib in these combinations and to confirm a potential recommended Phase II dose of ipatasertib for each regimen. NOTE: Arms A, B, and C are closed.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
122
5-FU at a dose level of 400 mg/m\^2 as intravenous (IV) injection followed by a dose of 2400 mg/m\^2 as IV infusion over 46 hrs will be administered on Day 1 of each 14-day cycle until disease progression or unacceptable toxicity.
Docetaxel will be administered at dose level of 75 mg/m\^2 as IV infusion over 1 hr on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.
Enzalutamide will be administered orally at a dose level of 160 mg once daily continuously as per schedule defined in respective arm until disease progression or unacceptable toxicity.
Ipatasertib will be administered orally (in escalating doses during Stage 1 followed by at a dose decided during Stage 1) as per schedule defined in the respective arms.
Leucovorin at a dose level of 400 mg/m\^2 as IV infusion over 2 hrs will be administered on Day 1 of each 14-day cycle until disease progression or unacceptable toxicity.
Oxaliplatin at a dose level of 85 mg/m\^2 as IV infusion over 2 hours will be administered on Day 1 of each 14-day cycle until disease progression or unacceptable toxicity.
Paclitaxel at a dose of 90 mg/m\^2 as IV infusion over 1 hr will be administered on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
California Pacific Med Center
San Francisco, California, United States
Florida Cancer Specialists - Sarasota
Sarasota, Florida, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
University Of Michigan
Ann Arbor, Michigan, United States
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States
SCRI
Nashville, Tennessee, United States
Virginia Oncology Associates
Norfolk, Virginia, United States
Institut Gustave Roussy; Departement Oncologie Medicale
Villejuif, France
Hospital Universitari Vall d'Hebron
Barcelona, Spain
Hospital Clinico Universitario de Valencia
Valencia, Spain
...and 1 more locations
Number of Participants With Dose Limiting Toxicities (DLTs)
Time frame: Arm A: Days 2-21 of Cycle 1 (cycle length=21 days); Arm B: Days 1-14 of Cycles 1 and 2 (cycle length=14 days); Arm C: Days 1-28 of Cycle 1 (cycle length=28 days); Arm D: Days 1-35 of Cycle 1 (cycle length=28 days except for Cycle 1=35 days)
Maximum Tolerated Dose (MTD) of Ipatasertib
Time frame: Arm A: Days 2-21 of Cycle 1 (cycle length=21 days); Arm B: Days 1-14 of Cycles 1 and 2 (cycle length=14 days); Arm C: Days 1-28 of Cycle 1 (cycle length=28 days); Arm D: Days 1-35 of Cycle 1 (cycle length=28 days except for Cycle 1=35 days)
Recommended Phase II Dose (RP2D) of Ipatasertib
Time frame: Arm A: Days 2-21 of Cycle 1 (cycle length=21 days); Arm B: Days 1-14 of Cycles 1 and 2 (cycle length=14 days); Arm C: Days 1-28 of Cycle 1 (cycle length=28 days); Arm D: Days 1-35 of Cycle 1 (cycle length=28 days except for Cycle 1=35 days)
Number of Participants With Adverse Events (AEs)
Time frame: Baseline up until 30 days following the last administration of study treatment or until initiation of another anti-cancer therapy, whichever occurs first (up to a maximum of 9.25 years).
Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Docetaxel (Arm A)
Time frame: Immediately prior to docetaxel infusion, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours (hrs) after start of docetaxel infusion on Day 1 Cycles 1 and 2 (1 cycle=21 days)
Plasma Terminal Half-Life (t1/2) of Docetaxel (Arm A)
Time frame: Immediately prior to docetaxel infusion, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours (hrs) after start of docetaxel infusion on Day 1 Cycles 1 and 2 (1 cycle=21 days)
Plasma Clearance (CL) of Docetaxel (Arm A)
Time frame: Immediately prior to docetaxel infusion, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours (hrs) after start of docetaxel infusion on Day 1 Cycles 1 and 2 (1 cycle=21 days)
Volume of Distribution (Vz) of Docetaxel (Arm A)
Time frame: Immediately prior to docetaxel infusion, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours (hrs) after start of docetaxel infusion on Day 1 Cycles 1 and 2 (1 cycle=21 days)
Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Total Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Plasma Terminal Half-Life (t1/2) of Total Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Plasma CL of Total Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Vz of Total Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Maximum Observed Plasma Concentration (Cmax) of Total Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Free Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Plasma Terminal Half-Life (t1/2) of Free Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Plasma CL of Free Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Vz of Free Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Maximum Observed Plasma Concentration (Cmax) of Free Platinum (Arm B)
Time frame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Cmax of 5-FU (Arm B)
Time frame: 2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Steady-State Concentration (Css) of 5-FU (Arm B)
Time frame: 2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of 5-FU (Arm B)
Time frame: 2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Cmax of Paclitaxel (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Cmax of Paclitaxel Metabolite (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
AUC(0-inf) of Paclitaxel (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
AUC(0-inf) of Paclitaxel Metabolite (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Plasma CL of Paclitaxel (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Plasma CL of Paclitaxel Metabolite (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Vz of Paclitaxel (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Vz of Paclitaxel Metabolite (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Plasma t1/2 of Paclitaxel (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Plasma t1/2 of Paclitaxel Metabolite (Arm C)
Time frame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
AUC(0-24) of Enzalutamide (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
AUC(0-24) of Enzalutamide Metabolite (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Time to Reach Cmax (Tmax) of Enzalutamide (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Tmax of Enzalutamide Metabolite (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Cmax at Steady State (Cmax,ss) of Enzalutamide (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Cmax,ss of Enzalutamide Metabolite (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
AUC(0-24) of Ipatasertib (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
AUC(0-24) of Ipatasertib Metabolite (G037720) (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Tmax of Ipatasertib (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Tmax of Ipatasertib Metabolite (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Cmax,ss of Ipatasertib (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Cmax,ss of Ipatasertib Metabolite (Arm D)
Time frame: Day 8 Cycle 1,2 and Day 1 Cycle 3: Immediately prior to ipatasertib dose, 1,2,3,4,6,24 hours post dose (Cycle=28 days except for Cycle 1=35 days)
Tmax of Ipatasertib (Arm A)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Tmax of Ipatasertib (Arm B)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Tmax of Ipatasertib (Arm C)
Time frame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
Tmax of Ipatasertib Metabolite (Arm A)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Tmax of Ipatasertib Metabolite (Arm B)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Tmax of Ipatasertib Metabolite (Arm C)
Time frame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (cycles=21 days, Cycle 1=35 days)
Cmax,ss of Ipatasertib (Arm A)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Cmax,ss of Ipatasertib (Arm B)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Cmax,ss of Ipatasertib (Arm C)
Time frame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
Cmax,ss of Ipatasertib Metabolite (Arm A)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Cmax,ss of Ipatasertib Metabolite (Arm B)
Time frame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Cmax,ss of Ipatasertib Metabolite (Arm C)
Time frame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
Number of Participants With Objective Response as Determined by Investigator Review of Tumor Assessments Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
Time frame: Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
Duration of Response (DOR) as Determined by Investigator Review of Tumor Assessments Using RECIST v1.1
Time frame: Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
Progression-free Survival (PFS) as Determined by Investigator Review of Tumor Assessments Using RECIST v1.1
Time frame: Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
Radiographic Progression-free Survival (rPFS) as Determined by Investigator (Arm D only)
Time frame: Baseline up to radiographic disease progression or death, whichever occurs first (up to approximately 6 years)
Time to Treatment Failure (TTF)
Time frame: Baseline up to treatment discontinuation for any reason (up to approximately 6 years)
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