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

NCT01362374 | Completed Phase 1

• 3 other identifiers: PAM4983gGO278452011-000782-13
• Study Type: interventional
• Target: 122
• Locations: 4 countries
• Sites: 11

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

Outcome Measures

Primary Outcomes (4)

• 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)

• 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)

• 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)

• 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 Outcomes (56)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (13)

Arm A (Doc + Ipat 100mg)

EXPERIMENTAL

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.

Drug: Docetaxel; Drug: Ipatasertib

Arm A (Doc + Ipat 200mg)

EXPERIMENTAL

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.

Drug: Docetaxel; Drug: Ipatasertib

Arm A (Doc + Ipat 400mg)

EXPERIMENTAL

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.

Drug: Docetaxel; Drug: Ipatasertib

Arm A (Doc + Ipat 600mg)

EXPERIMENTAL

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.

Drug: Docetaxel; Drug: Ipatasertib

Arm B (mFOLFOX + Ipat 100mg)

EXPERIMENTAL

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.

Drug: 5-FU; Drug: Ipatasertib; Drug: Leucovorin; Drug: Oxaliplatin

Arm B (mFOLFOX + Ipat 200mg)

EXPERIMENTAL

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.

Drug: 5-FU; Drug: Ipatasertib; Drug: Leucovorin; Drug: Oxaliplatin

Arm B (mFOLFOX + Ipat 400mg)

EXPERIMENTAL

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.

Drug: 5-FU; Drug: Ipatasertib; Drug: Leucovorin; Drug: Oxaliplatin

Arm B (mFOLFOX + Ipat 600mg)

EXPERIMENTAL

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.

Drug: 5-FU; Drug: Ipatasertib; Drug: Leucovorin; Drug: Oxaliplatin

Arm C (Pac + Ipat 400mg)

EXPERIMENTAL

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.

Drug: Ipatasertib; Drug: Paclitaxel

Arm C (Pac + Ipat 600mg)

EXPERIMENTAL

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.

Drug: Ipatasertib; Drug: Paclitaxel

Arm D (Enza + Ipat 400mg)

EXPERIMENTAL

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.

Drug: Enzalutamide; Drug: Ipatasertib

Arm D (Enza + Ipat 600mg)

EXPERIMENTAL

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.

Drug: Enzalutamide; Drug: Ipatasertib

Arm D (Enza + Ipat 400-600mg)

EXPERIMENTAL

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.

Drug: Enzalutamide; Drug: Ipatasertib

Interventions

5-FU 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.

Also known as: Adrucil

Arm B (mFOLFOX + Ipat 100mg); Arm B (mFOLFOX + Ipat 200mg); Arm B (mFOLFOX + Ipat 400mg); Arm B (mFOLFOX + Ipat 600mg)

Docetaxel 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.

Arm A (Doc + Ipat 100mg); Arm A (Doc + Ipat 200mg); Arm A (Doc + Ipat 400mg); Arm A (Doc + Ipat 600mg)

Enzalutamide 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.

Arm D (Enza + Ipat 400-600mg); Arm D (Enza + Ipat 400mg); Arm D (Enza + Ipat 600mg)

Ipatasertib 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); Arm A (Doc + Ipat 200mg); Arm A (Doc + Ipat 400mg); Arm A (Doc + Ipat 600mg); Arm B (mFOLFOX + Ipat 100mg); Arm B (mFOLFOX + Ipat 200mg); Arm B (mFOLFOX + Ipat 400mg); Arm B (mFOLFOX + Ipat 600mg); Arm C (Pac + Ipat 400mg); Arm C (Pac + Ipat 600mg); Arm D (Enza + Ipat 400-600mg); Arm D (Enza + Ipat 400mg); Arm D (Enza + Ipat 600mg)

Leucovorin 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.

Also known as: Wellcovorin

Arm B (mFOLFOX + Ipat 100mg); Arm B (mFOLFOX + Ipat 200mg); Arm B (mFOLFOX + Ipat 400mg); Arm B (mFOLFOX + Ipat 600mg)

Oxaliplatin 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.

Also known as: Eloxatin

Arm B (mFOLFOX + Ipat 100mg); Arm B (mFOLFOX + Ipat 200mg); Arm B (mFOLFOX + Ipat 400mg); Arm B (mFOLFOX + Ipat 600mg)

Paclitaxel 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.

Also known as: Taxol

Arm C (Pac + Ipat 400mg); Arm C (Pac + Ipat 600mg)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (11)

California Pacific Med Center

San Francisco, California, 94115, United States

Location

Florida Cancer Specialists - Sarasota

Sarasota, Florida, 34232, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University Of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, 89128, United States

Location

SCRI

Nashville, Tennessee, 37203, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

Location

Institut Gustave Roussy; Departement Oncologie Medicale

Villejuif, 94805, France

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

Location

The Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 32205017 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

Fluorouracil; Docetaxel; enzalutamide; ipatasertib; Leucovorin; Oxaliplatin; Paclitaxel

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes

Study Officials

• Daniel Maslyar, M.D.

  Genentech, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2011
• First Posted: May 30, 2011
• Study Start: July 11, 2011
• Primary Completion: October 16, 2020
• Study Completion: October 16, 2020
• Last Updated: January 12, 2022

Record last verified: 2022-01

Locations

GB (1); US (7); FR (1); ES (2)