Safety and Efficacy of Carboplatin/Paclitaxel and Carboplatin/Paclitaxel/Bevacizumab With and Without Pictilisib in Previously Untreated Advanced or Recurrent Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind, placebo-controlled trial will evaluate the efficacy and safety of carboplatin/paclitaxel and carboplatin/paclitaxel/bevacizumab with and without pictilisib in particpants with previously untreated advanced or recurrent non-small cell lung cancer (NSCLC). Particpants will be randomized to receive 4 cycles of carboplatin (C)/paclitaxel (P) and either pictilisib or placebo, with (participants with non-squamous NSCLC) or without (participants with squamous NSCLC) bevacizumab (B). Anticipated time on study treatment is until disease progression or intolerable toxicity occurs. Participants in placebo arms with disease progression may cross over to open-label active pictilisib.

Official Title
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A Phase II, Double-Blind, Placebo-Controlled, Randomized Study Evaluating the Safety and Efficacy of Carboplatin/Paclitaxel and Carboplatin/Paclitaxel/Bevacizumab With and Without GDC-0941 in Patients With Previously Untreated Advanced or Recurrent Non-small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: pictilisib
* Drug: Placebo
* Drug: bevacizumab
* Drug: carboplatin
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented advanced (Stage IV) or recurrent squamous (Arms A and B) or non-squamous (Arms C, D, E, and F) non-small cell lung cancer (NSCLC) Consent to the collection of an archival formalin-fixed paraffin-embedded (FFPE) block or freshly cut unstained tumor slides from archival tumor tissue or a newly collected tumor sample Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Disease that is measurable per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 Adequate hematologic and end organ function Use of two effective forms of contraception Exclusion Criteria: NSCLC with documented epidermal growth factor receptor (EGFR) mutation associated with response to EGFR inhibitors or documented fusion gene involving anaplastic lymphoma kinase (ALK) gene Prior therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, radiotherapy, immunotherapy, hormonal therapy, or investigational therapy) before Day 1 of Cycle 1 for the treatment of advanced (Stage IV) or recurrent NSCLC Known central nervous system (CNS) disease except for treated brain metastases Type I diabetes Type II diabetes requiring chronic therapy with insulin Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk for treatment complications Medical conditions that would contraindicate bevacizumab therapy in non-squamous NSCLC (Arms C, D, E, and F)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: 340 mg pictilisib + CP<br>Participants with advanced (Stage IV) or recurrent squamous NSCLC will be administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). | Drug: pictilisib<br>* Pictilisib, 260 milligrams (mg) or 340 mg, will be taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, pictilisib will be taken once daily continuously.<br>* Other names: GDC-0941;Drug: carboplatin<br>* Carboplatin will be administered IV to achieve an initial target area under the concentration curve (AUC) of 6 milligrams per milliliter per minute (mg/mL per min) on Day 1 of each 21-day cycle for a maximum of four cycles.<br>Drug: paclitaxel<br>* Paclitaxel will be administered at 200 milligrams per square meter (mg/m^2) IV on Day 1 of each 21-day cycle for a maximum of four cycles.<br>|
| Placebo Comparator: Arm B: Placebo + CP<br>Participants with advanced (Stage IV) or recurrent squamous NSCLC will be administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Participants with investigator assessed radiographic progression of NSCLC per RECIST 1.1 will be allowed to cross over to Arm A during the first 4 cycles with carboplatin + paclitaxel or after chemotherapy has been completed (Cycle >/= 5). | Drug: Placebo<br>* Placebo corresponding to 260 mg or 340 mg pictilisib will be taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, placebo will be taken once daily continuously.<br>Drug: carboplatin<br>* Carboplatin will be administered IV to achieve an initial target area under the concentration curve (AUC) of 6 milligrams per milliliter per minute (mg/mL per min) on Day 1 of each 21-day cycle for a maximum of four cycles.<br>Drug: paclitaxel<br>* Paclitaxel will be administered at 200 milligrams per square meter (mg/m^2) IV on Day 1 of each 21-day cycle for a maximum of four cycles.<br>|
| Experimental: Arm C: 340 mg pictilisib + CPB<br>Participants with advanced (Stage IV) or recurrent non-squamous NSCLC will be administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B). | Drug: pictilisib<br>* Pictilisib, 260 milligrams (mg) or 340 mg, will be taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, pictilisib will be taken once daily continuously.<br>* Other names: GDC-0941;Drug: bevacizumab<br>* Bevacizumab, 15 milligrams per kilogram (mg/kg) will be administered intravenously (IV) at Day 1 of each 21-day cycle for a maximum of 34 cycles.<br>* Other names: Avastin;Drug: carboplatin<br>* Carboplatin will be administered IV to achieve an initial target area under the concentration curve (AUC) of 6 milligrams per milliliter per minute (mg/mL per min) on Day 1 of each 21-day cycle for a maximum of four cycles.<br>Drug: paclitaxel<br>* Paclitaxel will be administered at 200 milligrams per square meter (mg/m^2) IV on Day 1 of each 21-day cycle for a maximum of four cycles.<br>|
| Placebo Comparator: Arm D: Placebo + CPB<br>Participants with advanced (Stage IV) or recurrent non-squamous NSCLC will be administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Participants with investigator assessed radiographic progression of NSCLC per RECIST 1.1 will be allowed to cross over to Arm C during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy has been completed (Cycle >/= 5). | Drug: Placebo<br>* Placebo corresponding to 260 mg or 340 mg pictilisib will be taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, placebo will be taken once daily continuously.<br>Drug: bevacizumab<br>* Bevacizumab, 15 milligrams per kilogram (mg/kg) will be administered intravenously (IV) at Day 1 of each 21-day cycle for a maximum of 34 cycles.<br>* Other names: Avastin;Drug: carboplatin<br>* Carboplatin will be administered IV to achieve an initial target area under the concentration curve (AUC) of 6 milligrams per milliliter per minute (mg/mL per min) on Day 1 of each 21-day cycle for a maximum of four cycles.<br>Drug: paclitaxel<br>* Paclitaxel will be administered at 200 milligrams per square meter (mg/m^2) IV on Day 1 of each 21-day cycle for a maximum of four cycles.<br>|
| Experimental: Arm E: 260 mg pictilisib + CPB<br>Participants with advanced (Stage IV) or recurrent non-squamous NSCLC will be administered 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B). | Drug: pictilisib<br>* Pictilisib, 260 milligrams (mg) or 340 mg, will be taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, pictilisib will be taken once daily continuously.<br>* Other names: GDC-0941;Drug: bevacizumab<br>* Bevacizumab, 15 milligrams per kilogram (mg/kg) will be administered intravenously (IV) at Day 1 of each 21-day cycle for a maximum of 34 cycles.<br>* Other names: Avastin;Drug: carboplatin<br>* Carboplatin will be administered IV to achieve an initial target area under the concentration curve (AUC) of 6 milligrams per milliliter per minute (mg/mL per min) on Day 1 of each 21-day cycle for a maximum of four cycles.<br>Drug: paclitaxel<br>* Paclitaxel will be administered at 200 milligrams per square meter (mg/m^2) IV on Day 1 of each 21-day cycle for a maximum of four cycles.<br>|
| Placebo Comparator: Arm F: Placebo + CPB<br>Participants with advanced (Stage IV) or recurrent non-squamous NSCLC will be administered placebo corresponding to 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Participants with investigator assessed radiographic progression of NSCLC per RECIST 1.1 will be allowed to cross over to Arm E during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy has been completed (Cycle >/= 5). | Drug: Placebo<br>* Placebo corresponding to 260 mg or 340 mg pictilisib will be taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, placebo will be taken once daily continuously.<br>Drug: bevacizumab<br>* Bevacizumab, 15 milligrams per kilogram (mg/kg) will be administered intravenously (IV) at Day 1 of each 21-day cycle for a maximum of 34 cycles.<br>* Other names: Avastin;Drug: carboplatin<br>* Carboplatin will be administered IV to achieve an initial target area under the concentration curve (AUC) of 6 milligrams per milliliter per minute (mg/mL per min) on Day 1 of each 21-day cycle for a maximum of four cycles.<br>Drug: paclitaxel<br>* Paclitaxel will be administered at 200 milligrams per square meter (mg/m^2) IV on Day 1 of each 21-day cycle for a maximum of four cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) |  | Up to approximately 2.5 years | 
| PFS in Participants with Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) Amplification |  | Up to approximately 2.5 years | 
| PFS in Participants with Phosphatase and Tensin Homolog (PTEN) Loss/Low |  | Up to approximately 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response |  | Up to approximately 2.5 years | 
| Objective Tumor Response in Participants with PIK3CA Amplification |  | Up to approximately 2.5 years | 
| Objective Tumor Response in Participants with PTEN Loss/low |  | Up to approximately 2.5 years | 
| Duration of Objective Response (DoR) |  | Up to approximately 2.5 years | 
| DoR in Participants with PIK3CA Amplification |  | Up to approximately 2.5 years | 
| DoR in Participants with PTEN Loss/low |  | Up to approximately 2.5 years | 
| Overall Survival (OS) |  | Up to approximately 2.5 years | 
| OS in Participants with PIK3CA Amplification |  | Up to approximately 2.5 years | 
| OS in Participants with PTEN Loss/low |  | Up to approximately 2.5 years | 
| Percentage of Participants with Adverse Events |  | Up to approximately 4 years |