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

NCT ID: NCT01362374

Last Updated: 2022-01-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 122 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-07-11
• Study Completion Date: 2020-10-16

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.

Conditions

Neoplasms

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm B (mFOLFOX + Ipat 400mg)

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.

Group Type: EXPERIMENTAL

5-FU

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Arm B (mFOLFOX + Ipat 600mg)

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.

Group Type: EXPERIMENTAL

5-FU

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Arm C (Pac + Ipat 400mg)

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.

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

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.

Paclitaxel

Intervention Type: DRUG

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.

Arm C (Pac + Ipat 600mg)

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.

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

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.

Paclitaxel

Intervention Type: DRUG

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.

Arm D (Enza + Ipat 400mg)

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.

Group Type: EXPERIMENTAL

Enzalutamide

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Arm A (Doc + Ipat 100mg)

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.

Group Type: EXPERIMENTAL

Docetaxel

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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.

Arm A (Doc + Ipat 200mg)

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.

Group Type: EXPERIMENTAL

Docetaxel

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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.

Arm A (Doc + Ipat 400mg)

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.

Group Type: EXPERIMENTAL

Docetaxel

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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.

Arm A (Doc + Ipat 600mg)

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.

Group Type: EXPERIMENTAL

Docetaxel

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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.

Arm B (mFOLFOX + Ipat 100mg)

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.

Group Type: EXPERIMENTAL

5-FU

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Arm B (mFOLFOX + Ipat 200mg)

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.

Group Type: EXPERIMENTAL

5-FU

Intervention Type: DRUG

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.

Ipatasertib

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Arm D (Enza + Ipat 600mg)

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.

Group Type: EXPERIMENTAL

Enzalutamide

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Arm D (Enza + Ipat 400-600mg)

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.

Group Type: EXPERIMENTAL

Enzalutamide

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Other Intervention Names

Adrucil; Wellcovorin; Eloxatin; Taxol

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Daniel Maslyar, M.D.

Role: STUDY_DIRECTOR

Genentech, Inc.

Locations

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

The Royal Marsden Hospital

Sutton, , United Kingdom

Countries

United States; France; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 32205017 (View on PubMed)

Other Identifiers

GO27845

Identifier Type: OTHER

Identifier Source: secondary_id

2011-000782-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PAM4983g

Identifier Type: -

Identifier Source: org_study_id