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

Genentech

Status and phase: Completed; Phase 1

Conditions: Breast Cancer

Treatments: Drug: Paclitaxel; Drug: Trastuzumab; Drug: Letrozole; Drug: Bevacizumab; Drug: Pictilisib

Study type: Interventional

Funder types: Industry

Identifiers

NCT00960960

2009-010781-38 (EudraCT Number)

GO01304 (Other Identifier)

GDC4629g

Details and patient eligibility

About

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.

Enrollment: 71 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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71 participants in 11 patient groups

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Bevacizumab

Drug: Paclitaxel

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Bevacizumab

Drug: Paclitaxel

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

Experimental group

Description:

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

Treatment:

Drug: Pictilisib

Drug: Paclitaxel

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Paclitaxel

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Paclitaxel

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Bevacizumab

Drug: Paclitaxel

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Bevacizumab

Drug: Paclitaxel

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Bevacizumab

Drug: Paclitaxel

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Paclitaxel

Drug: Trastuzumab

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

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Paclitaxel

Drug: Trastuzumab

Part 3: Pictilisib 260 mg + Letrozole

Experimental group

Description:

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.

Treatment:

Drug: Pictilisib

Drug: Letrozole