Clinical trial NCT01362374: Safety and Clinical Pharmacology of GDC-0068 in Combination With Docetaxel, Fluoropyrimidine Plus Oxaliplatin, Paclitaxel, or Enzalutamide in Participants With Advanced Solid Tumors
Official title: A Phase Ib, Open-label, Dose-escalation Study of the Safety and Pharmacology of Ipatasertib (GDC-0068) in Combination With Docetaxel, Fluoropyrimidine Plus Oxaliplatin, Paclitaxel, or Enzalutamide in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2011-05-30
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening
* Histologically or cytologically documented advanced or metastatic solid tumors for which established therapy either does not exist or has proven ineffective or intolerable
* Life expectancy greater than or equal to (\>=) 12 weeks
* Adequate hematologic and end organ function
* For female participants of childbearing potential and male participants with partners of childbearing potential, agreement (by participant and/or partner) to use highly effective forms of contraception and to continue its use for the duration of the study and for 4 months after last dose of study treatment (for females) and 6 months after last dose of study treatment (for males)

Exclusion Criteria:

* Prior anti-cancer therapy that fulfills the following criteria: a total of more than three (Arms A and B) or two (Arms C and D) prior cytotoxic chemotherapy regimens, high-dose chemotherapy requiring stem-cell support, and irradiation to \>=25 percent (%) of bone marrow-bearing areas
* Treatment with chemotherapy, hormonal therapy (except hormone replacement therapy, oral contraceptives, or gonadotropin-releasing hormone (GnRH) agonists or antagonists for prostate cancer), immunotherapy, biologic therapy, radiation therapy (except palliative radiation to bony metastases), or herbal therapy as cancer therapy within 4 weeks prior to initiation of ipatasertib. Exceptions are kinase inhibitors approved by local regulatory authorities, which may be used within 2 weeks prior to initiation of ipatasertib, provided that any clinically-relevant drug-related toxicity has completely resolved and prior approval is obtained from the Medical Monitor
* Palliative radiation to bony metastases within 2 weeks prior to initiation of ipatasertib
* History of Type 1 or Type 2 diabetes requiring regular medication
* Grade \>= 2 heart failure or history of unstable angina
* History of clinically significant ventricular arrhythmias or active ventricular arrhythmia requiring medication
* For Arm D only: History of seizure, unexplained loss of consciousness, transient ischemic attack within 12 months of enrollment, cerebral vascular accident, and any brain metastases

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: 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)
measure: Maximum Tolerated Dose (MTD) of Ipatasertib
timeFrame: 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)
measure: Recommended Phase II Dose (RP2D) of Ipatasertib
timeFrame: 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)
measure: Number of Participants With Adverse Events (AEs)
timeFrame: 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).
Secondary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Docetaxel (Arm A)
timeFrame: 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)
measure: Plasma Terminal Half-Life (t1/2) of Docetaxel (Arm A)
timeFrame: 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)
measure: Plasma Clearance (CL) of Docetaxel (Arm A)
timeFrame: 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)
measure: Volume of Distribution (Vz) of Docetaxel (Arm A)
timeFrame: 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)
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Total Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Plasma Terminal Half-Life (t1/2) of Total Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Plasma CL of Total Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Vz of Total Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Maximum Observed Plasma Concentration (Cmax) of Total Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Free Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Plasma Terminal Half-Life (t1/2) of Free Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Plasma CL of Free Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Vz of Free Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Maximum Observed Plasma Concentration (Cmax) of Free Platinum (Arm B)
timeFrame: 1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Cmax of 5-FU (Arm B)
timeFrame: 2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Steady-State Concentration (Css) of 5-FU (Arm B)
timeFrame: 2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of 5-FU (Arm B)
timeFrame: 2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
measure: Cmax of Paclitaxel (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: Cmax of Paclitaxel Metabolite (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: AUC(0-inf) of Paclitaxel (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: AUC(0-inf) of Paclitaxel Metabolite (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: Plasma CL of Paclitaxel (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: Plasma CL of Paclitaxel Metabolite (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: Vz of Paclitaxel (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: Vz of Paclitaxel Metabolite (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: Plasma t1/2 of Paclitaxel (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: Plasma t1/2 of Paclitaxel Metabolite (Arm C)
timeFrame: 1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
measure: AUC(0-24) of Enzalutamide (Arm D)
timeFrame: 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)
measure: AUC(0-24) of Enzalutamide Metabolite (Arm D)
timeFrame: 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)
measure: Time to Reach Cmax (Tmax) of Enzalutamide (Arm D)
timeFrame: 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)
measure: Tmax of Enzalutamide Metabolite (Arm D)
timeFrame: 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)
measure: Cmax at Steady State (Cmax,ss) of Enzalutamide (Arm D)
timeFrame: 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)
measure: Cmax,ss of Enzalutamide Metabolite (Arm D)
timeFrame: 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)
measure: AUC(0-24) of Ipatasertib (Arm D)
timeFrame: 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)
measure: AUC(0-24) of Ipatasertib Metabolite (G037720) (Arm D)
timeFrame: 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)
measure: Tmax of Ipatasertib (Arm D)
timeFrame: 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)
measure: Tmax of Ipatasertib Metabolite (Arm D)
timeFrame: 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)
measure: Cmax,ss of Ipatasertib (Arm D)
timeFrame: 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)
measure: Cmax,ss of Ipatasertib Metabolite (Arm D)
timeFrame: 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)
measure: Tmax of Ipatasertib (Arm A)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
measure: Tmax of Ipatasertib (Arm B)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
measure: Tmax of Ipatasertib (Arm C)
timeFrame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
measure: Tmax of Ipatasertib Metabolite (Arm A)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
measure: Tmax of Ipatasertib Metabolite (Arm B)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
measure: Tmax of Ipatasertib Metabolite (Arm C)
timeFrame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (cycles=21 days, Cycle 1=35 days)
measure: Cmax,ss of Ipatasertib (Arm A)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
measure: Cmax,ss of Ipatasertib (Arm B)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
measure: Cmax,ss of Ipatasertib (Arm C)
timeFrame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
measure: Cmax,ss of Ipatasertib Metabolite (Arm A)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
measure: Cmax,ss of Ipatasertib Metabolite (Arm B)
timeFrame: PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
measure: Cmax,ss of Ipatasertib Metabolite (Arm C)
timeFrame: PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
measure: 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)
timeFrame: Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
measure: Duration of Response (DOR) as Determined by Investigator Review of Tumor Assessments Using RECIST v1.1
timeFrame: Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
measure: Progression-free Survival (PFS) as Determined by Investigator Review of Tumor Assessments Using RECIST v1.1
timeFrame: Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
measure: Radiographic Progression-free Survival (rPFS) as Determined by Investigator (Arm D only)
timeFrame: Baseline up to radiographic disease progression or death, whichever occurs first (up to approximately 6 years)
measure: Time to Treatment Failure (TTF)
timeFrame: Baseline up to treatment discontinuation for any reason (up to approximately 6 years)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: California Pacific Med Center
state: California
city: Sarasota
country: United States
facility: Florida Cancer Specialists - Sarasota
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University Of Michigan
state: Michigan
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Nashville
country: United States
facility: SCRI
state: Tennessee
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Villejuif
country: France
facility: Institut Gustave Roussy; Departement Oncologie Medicale
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Sutton
country: United Kingdom
facility: The Royal Marsden Hospital
Study officials:
affiliation: Genentech, Inc.
name: Daniel Maslyar, M.D.
role: STUDY_DIRECTOR
References:
citation: Isakoff SJ, Tabernero J, Molife LR, Soria JC, Cervantes A, Vogelzang NJ, Patel MR, Hussain M, Baron A, Argiles G, Conkling PR, Sampath D, Maslyar D, Patel P, Chan W, Gendreau S, Musib L, Xu N, Ma H, Lin K, Bendell J. Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors. Ann Oncol. 2020 May;31(5):626-633. doi: 10.1016/j.annonc.2020.02.007. Epub 2020 Feb 20.