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

NCT00960960 | Completed Phase 1

• 3 other identifiers: GDC4629gGO013042009-010781-38
• Study Type: interventional
• Target: 71
• Locations: 3 countries
• Sites: 5

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.

Conditions

Breast Cancer

Keywords

MBC; PI3K; Avastin; Herceptin

Outcome Measures

Primary Outcomes (5)

• Percentage of Participants With Dose-Limiting Toxicities (DLTs)

  First treatment cycle (Day 1 up to Day 29)

• Maximum Tolerated Dose (MTD) of Pictilisib

  First treatment cycle (Day 1 up to Day 29)

• Recommended Phase II Dose (RP2D) of Pictilisib

  Baseline up to 54.2 months

• Number of Cycles of Each Component of the Treatment Regimen

  Baseline up to 54.2 months

• Dose Intensity of Each Component of the Treatment Regimen

  Baseline up to 54.2 months

Secondary Outcomes (13)

• Minimum Observed Plasma Concentration (Cmin) of Pictilisib

  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

  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

  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

  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]

• AUClast of Paclitaxel

  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]

Study Arms (11)

Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab

EXPERIMENTAL

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; Drug: Pictilisib; Drug: Paclitaxel

Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab

EXPERIMENTAL

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; Drug: Pictilisib; Drug: Paclitaxel

Part 2 (Arm A: Cohort 1a): Pictilisib 165 mg + Paclitaxel

EXPERIMENTAL

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; Drug: Paclitaxel

Part 2 (Arm A: Cohort 2a): Pictilisib 250 mg + Paclitaxel

EXPERIMENTAL

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; Drug: Paclitaxel

Part 2 (Arm A: Cohort 3a): Pictilisib 330 mg + Paclitaxel

EXPERIMENTAL

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; Drug: Paclitaxel

Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab

EXPERIMENTAL

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; Drug: Pictilisib; Drug: Paclitaxel

Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab

EXPERIMENTAL

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; Drug: Pictilisib; Drug: Paclitaxel

Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab

EXPERIMENTAL

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; Drug: Pictilisib; Drug: Paclitaxel

Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab

EXPERIMENTAL

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; Drug: Paclitaxel; Drug: Trastuzumab

Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab

EXPERIMENTAL

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; Drug: Paclitaxel; Drug: Trastuzumab

Part 3: Pictilisib 260 mg + Letrozole

EXPERIMENTAL

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; Drug: Letrozole

Interventions

Bevacizumab DRUG

Bevacizumab will be administered IV at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.

Also known as: Avastin

Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab; Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab; Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab; Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab; Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab

Pictilisib DRUG

Pictilisib will be administered PO QD on escalating doses.

Also known as: GDC-0941

Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab; Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab; Part 2 (Arm A: Cohort 1a): Pictilisib 165 mg + Paclitaxel; Part 2 (Arm A: Cohort 2a): Pictilisib 250 mg + Paclitaxel; Part 2 (Arm A: Cohort 3a): Pictilisib 330 mg + Paclitaxel; Part 3: Pictilisib 260 mg + Letrozole; Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab; Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab; Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab; Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab; Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab

Letrozole DRUG

Letrozole will be administered PO at a dose of 2.5 mg QD for for each 28-day cycle.

Part 3: Pictilisib 260 mg + Letrozole

Paclitaxel DRUG

Paclitaxel will be administered IV at a dose of 90 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle.

Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab; Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab; Part 2 (Arm A: Cohort 1a): Pictilisib 165 mg + Paclitaxel; Part 2 (Arm A: Cohort 2a): Pictilisib 250 mg + Paclitaxel; Part 2 (Arm A: Cohort 3a): Pictilisib 330 mg + Paclitaxel; Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab; Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab; Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab; Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab; Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab

Trastuzumab DRUG

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.

Also known as: Herceptin

Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab; Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (5)

Unknown Facility

Peoria, Illinois, 61615, United States

Location

Unknown Facility

Boston, Massachusetts, 02115, United States

Location

Unknown Facility

Nashville, Tennessee, 37232, United States

Location

Unknown Facility

Leuven, 3000, Belgium

Location

Unknown Facility

Milan, Lombardy, 20133, Italy

Location

Related Publications (1)

• Schoffski 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.

  PMID: 30185228 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Bevacizumab; 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; Letrozole; Paclitaxel; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Officials

• Stina Singel, M.D., Ph.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: August 13, 2009
• First Posted: August 18, 2009
• Study Start: August 1, 2009
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: December 15, 2016

Record last verified: 2016-12

Locations

US (3); BE (1); IT (1)