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

Genentech

Status and phase: Completed; Phase 1

Conditions: Neoplasms

Treatments: Drug: Ipatasertib; Drug: Oxaliplatin; Drug: Leucovorin; Drug: Docetaxel; Drug: Paclitaxel; Drug: Enzalutamide; Drug: 5-FU

Study type: Interventional

Funder types: Industry

Identifiers

NCT01362374

GO27845 (Other Identifier)

PAM4983g

2011-000782-13 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 122 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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122 participants in 13 patient groups

Arm A (Doc + Ipat 100mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 100 milligrams (mg) once daily for 14 consecutive days (beginning on Day 2) in combination with docetaxel on Day 1, in 21-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Ipatasertib

Drug: Docetaxel

Arm A (Doc + Ipat 200mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 200mg once daily for 14 consecutive days (beginning on Day 2) in combination with docetaxel on Day 1, in 21-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Ipatasertib

Drug: Docetaxel

Arm A (Doc + Ipat 400mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 400mg once daily for 14 consecutive days (beginning on Day 2) in combination with docetaxel on Day 1, in 21-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Ipatasertib

Drug: Docetaxel

Arm A (Doc + Ipat 600mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 600mg once daily for 14 consecutive days (beginning on Day 2) in combination with docetaxel on Day 1, in 21-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Ipatasertib

Drug: Docetaxel

Arm B (mFOLFOX + Ipat 100mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 100mg once daily for 7 consecutive days (beginning on Day 1) in combination with mFOLFOX6 chemotherapy (comprising of oxaliplatin, leucovorin, and 5-FU) on Day 1, in 14-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Leucovorin

Drug: Ipatasertib

Drug: Oxaliplatin

Drug: 5-FU

Arm B (mFOLFOX + Ipat 200mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 200mg once daily for 7 consecutive days (beginning on Day 1) in combination with mFOLFOX6 chemotherapy (comprising of oxaliplatin, leucovorin, and 5-FU) on Day 1, in 14-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Leucovorin

Drug: Ipatasertib

Drug: Oxaliplatin

Drug: 5-FU

Arm B (mFOLFOX + Ipat 400mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 400mg once daily for 7 consecutive days (beginning on Day 1) in combination with mFOLFOX6 chemotherapy (comprising of oxaliplatin, leucovorin, and 5-FU) on Day 1, in 14-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Leucovorin

Drug: Ipatasertib

Drug: Oxaliplatin

Drug: 5-FU

Arm B (mFOLFOX + Ipat 600mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 600mg once daily for 7 consecutive days (beginning on Day 1) in combination with mFOLFOX6 chemotherapy (comprising of oxaliplatin, leucovorin, and 5-FU) on Day 1, in 14-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Leucovorin

Drug: Ipatasertib

Drug: Oxaliplatin

Drug: 5-FU

Arm C (Pac + Ipat 400mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 400mg once daily for 21 consecutive days (beginning on Day 1) in combination with paclitaxel on Days 1, 8, and 15, in 28-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Paclitaxel

Drug: Ipatasertib

Arm C (Pac + Ipat 600mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 600mg once daily for 21 consecutive days (beginning on Day 1) in combination with paclitaxel on Days 1, 8, and 15, in 28-day continuous cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first.

Treatment:

Drug: Paclitaxel

Drug: Ipatasertib

Arm D (Enza + Ipat 400mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 400mg once daily alone for 8 days, then from Day 9, ipatasertib will be administered in combination with enzalutamide once daily for 27 days (Cycle 1 duration = 35 days). Participants received both ipatasertib and enzalutamide once daily continuously in subsequent 28-days cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first. Higher (up to 600 mg) or lower dose of ipatasertib may be evaluated in subsequent cycles depending upon safety, tolerability, and pharmacokinetics of the first cycle.

Treatment:

Drug: Ipatasertib

Drug: Enzalutamide

Arm D (Enza + Ipat 600mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 600mg once daily alone for 8 days, then from Day 9, ipatasertib will be administered in combination with enzalutamide once daily for 27 days (Cycle 1 duration = 35 days). Participants received both ipatasertib and enzalutamide once daily continuously in subsequent 28-days cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first. Higher (up to 600 mg) or lower dose of ipatasertib may be evaluated in subsequent cycles depending upon safety, tolerability, and pharmacokinetics of the first cycle.

Treatment:

Drug: Ipatasertib

Drug: Enzalutamide

Arm D (Enza + Ipat 400-600mg)

Experimental group

Description:

Participants received ipatasertib at a dose of 400-600mg once daily alone for 8 days, then from Day 9, ipatasertib will be administered in combination with enzalutamide once daily for 27 days (Cycle 1 duration = 35 days). Participants received both ipatasertib and enzalutamide once daily continuously in subsequent 28-days cycles, until disease progression, unacceptable toxicity, or use of another anti-cancer therapy, whichever occurred first. Higher (up to 600 mg) or lower dose of ipatasertib may be evaluated in subsequent cycles depending upon safety, tolerability, and pharmacokinetics of the first cycle.

Treatment:

Drug: Ipatasertib

Drug: Enzalutamide