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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

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ClinicalTrials.gov Identifier: NCT00960960
Recruitment Status : Completed
First Posted : August 18, 2009
Last Update Posted : December 15, 2016
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Tracking Information
First Submitted Date  ICMJE August 13, 2009
First Posted Date  ICMJE August 18, 2009
Last Update Posted Date December 15, 2016
Study Start Date  ICMJE August 2009
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 14, 2016)
  • 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 17, 2009)
Incidence, nature, and severity of adverse events [ Time Frame: Through study completion or early study discontinuation ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2016)
  • 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]) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 17, 2009)
  • PK parameters of GDC-0941 and paclitaxel (total exposure, and maximum and minimum serum concentrations) [ Time Frame: Through study completion or early study discontinuation ]
  • Tumor response [ Time Frame: Assessed at periodic intervals ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • 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: Letrozole
    Letrozole will be administered PO at a dose of 2.5 mg QD for for each 28-day cycle.
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Bevacizumab
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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.
    Interventions:
    • Drug: Bevacizumab
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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
    Interventions:
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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.
    Interventions:
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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.
    Interventions:
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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.
    Interventions:
    • Drug: Bevacizumab
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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.
    Interventions:
    • Drug: Bevacizumab
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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.
    Interventions:
    • Drug: Bevacizumab
    • Drug: Pictilisib
    • Drug: Paclitaxel
  • 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.
    Interventions:
    • Drug: Pictilisib
    • Drug: Paclitaxel
    • Drug: Trastuzumab
  • 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.
    Interventions:
    • Drug: Pictilisib
    • Drug: Paclitaxel
    • Drug: Trastuzumab
  • 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.
    Interventions:
    • Drug: Pictilisib
    • Drug: Letrozole
Publications * Schöffski P, Cresta S, Mayer IA, Wildiers H, Damian S, Gendreau S, Rooney I, Morrissey KM, Spoerke JM, Ng VW, Singel SM, Winer E. A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. Breast Cancer Res. 2018 Sep 5;20(1):109. doi: 10.1186/s13058-018-1015-x.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 5, 2015)
71
Original Estimated Enrollment  ICMJE
 (submitted: August 17, 2009)
45
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Italy,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00960960
Other Study ID Numbers  ICMJE GDC4629g
GO01304 ( Other Identifier: Hoffmann-La Roche )
2009-010781-38 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Genentech, Inc.
Study Sponsor  ICMJE Genentech, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Stina Singel, M.D., Ph.D. Genentech, Inc.
PRS Account Genentech, Inc.
Verification Date December 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP