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A Study of PI3-Kinase Inhibitor GDC-0941 in Combination With Paclitaxel, With and Without Bevacizumab or Trastuzumab, and With Letrozole, in Participants With Locally Recurrent or Metastatic Breast Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00960960
First received: August 13, 2009
Last updated: December 14, 2016
Last verified: December 2016
  Purpose
This is an open-label, multicenter, Phase Ib dose-escalation study to assess the safety, tolerability, and pharmacokinetics of oral (PO) pictilisib administered with letrozole or intravenous (IV) paclitaxel with and without IV bevacizumab or IV trastuzumab in participants with locally recurrent or metastatic breast cancer. The study consists of three parts. Part 1 (pictilisib will be administered in 21+7 schedule along with paclitaxel and/or bevacizumab), Part 2 (pictilisib will be administered in 5+2 schedule along with paclitaxel and/or bevacizumab or trastuzumab) and Part 3 (pictilisib will be administered in combination with letrozole). Part 1 and Part 2 consists of two stages; a dose escalation stage and a cohort-expansion stage.

Condition Intervention Phase
Breast Cancer
Drug: Bevacizumab
Drug: Pictilisib
Drug: Letrozole
Drug: Paclitaxel
Drug: Trastuzumab
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of PI3-Kinase Inhibitor GDC-0941 (Pictilisib) in Combination With Paclitaxel, With and Without Bevacizumab or Trastuzumab, and With Letrozole in Patients With Locally Recurrent Or Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Percentage of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: First treatment cycle (Day 1 up to Day 29) ]
  • Maximum Tolerated Dose (MTD) of Pictilisib [ Time Frame: First treatment cycle (Day 1 up to Day 29) ]
  • Recommended Phase II Dose (RP2D) of Pictilisib [ Time Frame: Baseline up to 54.2 months ]
  • Number of Cycles of Each Component of the Treatment Regimen [ Time Frame: Baseline up to 54.2 months ]
  • Dose Intensity of Each Component of the Treatment Regimen [ Time Frame: Baseline up to 54.2 months ]

Secondary Outcome Measures:
  • Minimum Observed Plasma Concentration (Cmin) of Pictilisib [ Time Frame: Parts 1 and 2 (dose escalation): predose (0 hours [h]) on Day (D) 1,3,16, and 17 of Cycle (C) 1. Part 2 (dose expansion): predose (0h) on D3,16,17 of C1; Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months) ]
  • Cmin of Paclitaxel [ Time Frame: Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h) on D2 and D16 of C1. Part 2 (dose expansion): pre-paclitaxel infusion (0 h) on D1 and D16 of C1 (cycle length=28 days) ]
  • Cmin of Letrozole [ Time Frame: Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months) ]
  • Area Under the Curve From Time Zero to Last Measurable Concentrations (AUClast) of Pictilisib [ Time Frame: Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description] ]
    Parts 1 and 2 (dose escalation): predose (0 h) and 1,2,3,6 h postdose on D1 and D16 of C1, 24h postdose on D1 of C1; predose (0h) on D3,17 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): predose (0h) and 1,2,3,6h postdose on D16 of C1; predose (0h) on D3, D17 of C1; study completion (up to 55.5 months). Part 3: 3h postdose on D1 of C1; 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)

  • AUClast of Paclitaxel [ Time Frame: Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description] ]
    Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2,4,6,24 h post-paclitaxel infusion on D2 and D16 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 1,2,3,6,24 h post-paclitaxel infusion on D1 of C1; pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2, 4, 6, 24 h post-paclitaxel infusion on D16 of C1; study completion (cycle length=28 days; up to 55.5 months)

  • AUClast of Letrozole [ Time Frame: Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months) ]
  • Maximum Observed Plasma Concentration (Cmax) of Pictilisib [ Time Frame: Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description] ]
    Parts 1 and 2 (dose escalation): predose (0 h) and 1,2,3,6 h postdose on D1 and D16 of C1, 24h postdose on D1 of C1; predose (0h) on D3,17 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): predose (0h) and 1,2,3,6h postdose on D16 of C1; predose (0h) on D3, D17 of C1; study completion (up to 55.5 months). Part 3: 3h postdose on D1 of C1; 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)

  • Cmax of Paclitaxel [ Time Frame: Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description] ]
    Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2,4,6,24 h post-paclitaxel infusion on D2 and D16 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 1,2,3,6,24 h post-paclitaxel infusion on D1 of C1; pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2, 4, 6, 24 h post-paclitaxel infusion on D16 of C1; study completion (cycle length=28 days; up to 55.5 months)

  • Cmax of Letrozole [ Time Frame: Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months) ]
  • Percentage of Participants With Objective Response According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22−28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]) ]
  • Duration of Response According to Modified RECIST [ Time Frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22−28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]) ]
  • Percentage of Participants With Death or Disease Progression According to Modified RECIST [ Time Frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22−28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]) ]
  • Progression-free Survival According to Modified RECIST [ Time Frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22−28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]) ]

Enrollment: 71
Study Start Date: August 2009
Study Completion Date: December 2015
Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab
Pictilisib 60 mg will be administered orally (PO) once daily (QD) for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1, 8, and 15 and bevacizumab 10 milligrams per kilogram (mg/kg) IV on Days 1 and 15 of each 28-day cycle. In Cohort 1 (Part 1), pictilisib will be evaluated with paclitaxel only; participants in Cohort 1 (Part 1) will be eligible to receive bevacizumab starting at Cycle 2. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Bevacizumab
Bevacizumab will be administered IV at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.
Other Name: Avastin
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab
Pictilisib 100 mg will be administered PO QD for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Bevacizumab
Bevacizumab will be administered IV at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.
Other Name: Avastin
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part 2 (Arm A: Cohort 1a): Pictilisib 165 mg + Paclitaxel
Pictilisib 165 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part 2 (Arm A: Cohort 2a): Pictilisib 250 mg + Paclitaxel
Pictilisib 250 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part 2 (Arm A: Cohort 3a): Pictilisib 330 mg + Paclitaxel
Pictilisib 330 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab
Pictilisib 200 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Bevacizumab
Bevacizumab will be administered IV at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.
Other Name: Avastin
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab
Pictilisib 250 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Bevacizumab
Bevacizumab will be administered IV at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.
Other Name: Avastin
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Bevacizumab
Bevacizumab will be administered IV at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.
Other Name: Avastin
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Experimental: Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab
Pictilisib 180 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Drug: Trastuzumab
Trastuzumab will be administered IV at a dose of 2-4 mg/kg on on Days 1, 8, 15, and 22 of each 28-day cycle.
Other Name: Herceptin
Experimental: Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Paclitaxel
Paclitaxel will be administered IV at a dose of 90 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle.
Drug: Trastuzumab
Trastuzumab will be administered IV at a dose of 2-4 mg/kg on on Days 1, 8, 15, and 22 of each 28-day cycle.
Other Name: Herceptin
Experimental: Part 3: Pictilisib 260 mg + Letrozole
Pictilisib 260 mg will be administered PO QD continuously with letrozole 2.5 mg PO QD for each 28-day cycle. Study treatment will continue until disease progression or unacceptable toxicity.
Drug: Pictilisib
Pictilisib will be administered PO QD on escalating doses.
Other Name: GDC-0941
Drug: Letrozole
Letrozole will be administered PO at a dose of 2.5 mg QD for for each 28-day cycle.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease
  • Adequate organ and bone marrow function as assessed by laboratory tests
  • Evaluable disease or disease measurable per RECIST
  • Agreement to use an effective form of contraception for the duration of the study

Exclusion Criteria:

  • History of malabsorption syndrome or other condition that would interfere with enteral absorption
  • Any condition requiring full-dose anticoagulants, such as warfarin, heparin, or thrombolytic agents
  • Prior anti-cancer therapy (e.g., chemotherapy, biologic therapy, radiotherapy, or hormonal therapy) within 4 weeks or 5 half-lives (whichever is shorter) of the first dose of study treatment
  • Uncontrolled current illness
  • Active small or large intestine inflammation (such as Crohn's disease or ulcerative colitis)
  • Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
  • Known HIV infection
  • New York Heart Association (NYHA) Class II or greater congestive heart failure
  • Active ventricular arrhythmia requiring medication
  • Pregnancy, lactation, or breastfeeding
  • Known significant hypersensitivity to study drugs or excipients
  • History of arterial thromboembolic disease within 6 months of first study treatment
  • No more than two prior chemotherapy regimens for metastatic disease
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00960960

Locations
United States, Illinois
Peoria, Illinois, United States, 61615
United States, Massachusetts
Boston, Massachusetts, United States, 02115
United States, Tennessee
Nashville, Tennessee, United States, 37232
Belgium
Leuven, Belgium, 3000
Italy
Milano, Lombardia, Italy, 20133
Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Stina Singel, M.D., Ph.D. Genentech, Inc.
  More Information

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00960960     History of Changes
Other Study ID Numbers: GDC4629g
GO01304 ( Other Identifier: Hoffmann-La Roche )
2009-010781-38 ( EudraCT Number )
Study First Received: August 13, 2009
Last Updated: December 14, 2016

Keywords provided by Genentech, Inc.:
MBC
PI3K
Avastin
Herceptin

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Letrozole
Albumin-Bound Paclitaxel
Bevacizumab
Trastuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on March 24, 2017