Safety and Clinical Pharmacology of GDC-0068 in Combination With Docetaxel, Fluoropyrimidine Plus Oxaliplatin, Paclitaxel, or Enzalutamide in Participants With Advanced Solid Tumors

Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01362374
• Other study ID #: PAM4983g
• Secondary ID: GO278452011-0007
• Status: Completed
• Phase: Phase 1
• Start date: July 11, 2011
• Est. completion date: October 16, 2020

Study information

• Verified date: January 2022
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 122
• Est. completion date: October 16, 2020
• Est. primary completion date: October 16, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms

Intervention

Drug:
• 5-FU
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
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
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
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
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
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
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.

Locations

Country	Name	City	State
France	Institut Gustave Roussy; Departement Oncologie Medicale	Villejuif
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Clinico Universitario de Valencia	Valencia
United Kingdom	The Royal Marsden Hospital	Sutton
United States	University Of Michigan	Ann Arbor	Michigan
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	SCRI	Nashville	Tennessee
United States	Virginia Oncology Associates	Norfolk	Virginia
United States	California Pacific Med Center	San Francisco	California
United States	Florida Cancer Specialists - Sarasota	Sarasota	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Countries where clinical trial is conducted

United States,  France,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities (DLTs)		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)
Primary	Maximum Tolerated Dose (MTD) of Ipatasertib		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)
Primary	Recommended Phase II Dose (RP2D) of Ipatasertib		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)
Primary	Number of Participants With Adverse Events (AEs)		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	Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Docetaxel (Arm A)		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)
Secondary	Plasma Terminal Half-Life (t1/2) of Docetaxel (Arm A)		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)
Secondary	Plasma Clearance (CL) of Docetaxel (Arm A)		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)
Secondary	Volume of Distribution (Vz) of Docetaxel (Arm A)		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)
Secondary	Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Total Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Plasma Terminal Half-Life (t1/2) of Total Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Plasma CL of Total Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Vz of Total Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Maximum Observed Plasma Concentration (Cmax) of Total Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Free Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Plasma Terminal Half-Life (t1/2) of Free Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Plasma CL of Free Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Vz of Free Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Maximum Observed Plasma Concentration (Cmax) of Free Platinum (Arm B)		1, 2, 2.25, 2.5, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Cmax of 5-FU (Arm B)		2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Steady-State Concentration (Css) of 5-FU (Arm B)		2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of 5-FU (Arm B)		2, 2.25, 3, 4, 6, 24, 48 hrs after ipatasertib Day 1 dose in Cycle 1 (1 cycle=14 days)
Secondary	Cmax of Paclitaxel (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	Cmax of Paclitaxel Metabolite (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	AUC(0-inf) of Paclitaxel (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	AUC(0-inf) of Paclitaxel Metabolite (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	Plasma CL of Paclitaxel (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	Plasma CL of Paclitaxel Metabolite (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	Vz of Paclitaxel (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	Vz of Paclitaxel Metabolite (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	Plasma t1/2 of Paclitaxel (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	Plasma t1/2 of Paclitaxel Metabolite (Arm C)		1, 2, 3, 4, 6, 24 hrs after ipatasertib Day 8 dose in Cycle 1 (1 cycle=28 days)
Secondary	AUC(0-24) of Enzalutamide (Arm D)		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)
Secondary	AUC(0-24) of Enzalutamide Metabolite (Arm D)		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)
Secondary	Time to Reach Cmax (Tmax) of Enzalutamide (Arm D)		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)
Secondary	Tmax of Enzalutamide Metabolite (Arm D)		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)
Secondary	Cmax at Steady State (Cmax,ss) of Enzalutamide (Arm D)		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)
Secondary	Cmax,ss of Enzalutamide Metabolite (Arm D)		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)
Secondary	AUC(0-24) of Ipatasertib (Arm D)		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)
Secondary	AUC(0-24) of Ipatasertib Metabolite (G037720) (Arm D)		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)
Secondary	Tmax of Ipatasertib (Arm D)		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)
Secondary	Tmax of Ipatasertib Metabolite (Arm D)		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)
Secondary	Cmax,ss of Ipatasertib (Arm D)		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)
Secondary	Cmax,ss of Ipatasertib Metabolite (Arm D)		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)
Secondary	Tmax of Ipatasertib (Arm A)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Secondary	Tmax of Ipatasertib (Arm B)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Secondary	Tmax of Ipatasertib (Arm C)		PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
Secondary	Tmax of Ipatasertib Metabolite (Arm A)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Secondary	Tmax of Ipatasertib Metabolite (Arm B)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Secondary	Tmax of Ipatasertib Metabolite (Arm C)		PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (cycles=21 days, Cycle 1=35 days)
Secondary	Cmax,ss of Ipatasertib (Arm A)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Secondary	Cmax,ss of Ipatasertib (Arm B)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Secondary	Cmax,ss of Ipatasertib (Arm C)		PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
Secondary	Cmax,ss of Ipatasertib Metabolite (Arm A)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS on Day 2 Cycle 1 (1 cycle=21 days)
Secondary	Cmax,ss of Ipatasertib Metabolite (Arm B)		PRDS, 0.5, 1, 2, 3, 4, 6, 24 hrs PSDS Day 1 Cycle 1 (1 cycle=14 days)
Secondary	Cmax,ss of Ipatasertib Metabolite (Arm C)		PRDS, 1, 2, 3, 4, 6, 24 hrs PSDS Day 8 Cycle 1 (1 cycle=28 days)
Secondary	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)		Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
Secondary	Duration of Response (DOR) as Determined by Investigator Review of Tumor Assessments Using RECIST v1.1		Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
Secondary	Progression-free Survival (PFS) as Determined by Investigator Review of Tumor Assessments Using RECIST v1.1		Baseline up to disease progression or death, whichever occurs first (up to approximately 6 years)
Secondary	Radiographic Progression-free Survival (rPFS) as Determined by Investigator (Arm D only)		Baseline up to radiographic disease progression or death, whichever occurs first (up to approximately 6 years)
Secondary	Time to Treatment Failure (TTF)		Baseline up to treatment discontinuation for any reason (up to approximately 6 years)