A Study of Ipatasertib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Hormone Receptor Positive and HER2 Negative Locally Advanced Unresectable or Metastatic Breast Cancer

Study Overview
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Brief Summary
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The open-label Phase Ib portion of this study will evaluate the safety and pharmacokinetics of ipatasertib in combination with palbociclib and fulvestrant to identify a dose of ipatasertib that can be combined with palbociclib and fulvestrant in the Phase III portion. The randomized Phase III portion of this study will evaluate the efficacy, safety, and patient-reported outcome (PRO) objectives of ipatasertib + palbociclib + fulvestrant compared with placebo + palbociclib + fulvestrant in patients with HR+ HER2-, locally advanced unresectable or metastatic breast cancer who had relapsed during adjuvant endocrine therapy or progressed during the initial 12 months of first-line endocrine therapy in locally advanced unresectable or metastatic breast cancer.

Official Title
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A Phase Ib/III Study of Ipatasertib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Hormone Receptor Positive and HER2 Negative Locally Advanced Unresectable or Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ipatasertib
* Drug: Placebo
* Drug: Palbociclib
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HR+ HER2- adenocarcinoma of the breast that is locally advanced unresectable or metastatic For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm Radiologic/objective relapse during adjuvant endocrine therapy or disease progression during the initial 12 months of 1L endocrine therapy in locally advanced unresectable or metastatic breast cancer At least one measurable lesion via Response Evaluation Criteria in Solid Tumors, Version 1.1 Phase III only: Tumor specimen from the most recently collected, available tumor tissue Exclusion Criteria: Pregnant or breastfeeding, or intending to become pregnant Prior treatment with fulvestrant or other selective estrogen receptor down-regulator Prior treatment with PI3K inhibitor, mTOR inhibitor or AKT inhibitor Phase III only: Prior treatment with CDK4/6 inhibitor for locally advanced unresectable or metastatic breast cancer Prior treatment with a cytotoxic chemotherapy regimen for metastatic breast cancer History of Type I or Type II diabetes mellitus requiring insulin History of or active inflammatory bowel disease or active bowel inflammation Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b and Phase 3: Ipatasertib + Palbociclib +Fulvestrant<br> | Drug: Ipatasertib<br>* Phase 1b: Ipatasertib, 300 mg starting dose administered orally once daily (PO QD) during an initial 5-7 day run-in period, then continued on Days 1-21 during the first cycle. Starting with Cycle 2, Day 1 ipatasertib will be taken orally once daily on Days 1-21 of each 28-day cycle. Phase 3: Ipatasertib, administered PO QD on Days 1-21 of each 28-day cycle at the dose confirmed in the Phase Ib portion.<br>* Other names: RO5532961, GDC-0068;Drug: Palbociclib<br>* Palbociclib, administered PO QD on Days 1-21 of each 28-day cycle.<br>Drug: Fulvestrant<br>* Fulvestrant, 500 mg administered as two intramuscular injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day cycle.<br>|
| Placebo Comparator: Phase 3: Placebo + Palbociclib + Fulvestrant<br> | Drug: Placebo<br>* Phase 3: Matching placebo, administered PO QD on Days 1-21 of each 28-day cycle at the dose confirmed in the Phase Ib portion.<br>Drug: Palbociclib<br>* Palbociclib, administered PO QD on Days 1-21 of each 28-day cycle.<br>Drug: Fulvestrant<br>* Fulvestrant, 500 mg administered as two intramuscular injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) in Intent-to-Treat (ITT), as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) |  | From randomization in Phase 3 until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 64 months | 
| Progression-Free Survival (PFS) in Patients with PIK3CA/AKT1/PTEN Altered Tumors, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) |  | From randomization in Phase 3 until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 64 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) |  | From randomization in Phase 3 until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 64 months | 
| Duration of Objective Response (DOR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) |  | From randomization in Phase 3 until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 64 months | 
| Clinical Benefit Rate (CBR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) |  | From randomization in Phase 3 until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 64 months | 
| Overall Survival (OS) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1 |  | From randomization in Phase 3 until the first occurrence of disease progression or death from any cause, whichever occurs earlier, up to approximately 64 months | 
| Time to Deterioration (TTD) in Severity of Pain, according to the Brief Pain Inventory-Short Form (BPI-SF) |  | From randomization in Phase 3 to the first documentation of a 2-point or more increase in pain scale from baseline, up to approximately 64 months | 
| TTD in presence and interference of pain according to the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) Pain Scale |  | From randomization in Phase 3 to the first documentation of a 10-point or more increase from baseline, up to approx 64 months | 
| Time to deterioration (TTD) in physical functioning (PF) |  | From randomization in Phase 3 to the first documentation of a 10-point or more decrease from baseline in the PF scale of the EORTC QLQ-C30, up to approx 64 months | 
| TTD in Role Functioning (RF) |  | From randomization in Phase 3 to the first documentation of a 10-point or more decrease from baseline in the RF scale of the EORTC QLQ-C30, up to approx 64 months | 
| TTD in Global Health Status (GHS)/Quality of Life (QoL) |  | From randomization in Phase 3 to the first documentation of a 10-point or more decrease from baseline in the GHS/HRQoL scale of the EORTC QLQ-C30, up to approx 64 months | 
| Number of Participants with Adverse Events |  | From baseline to end of study, up to approximately 64 months | 
| Phase 1b: Plasma Concentration of Ipatasertib and its Metabolite, G-037720 and Palbociclib |  | Ipatasertib & G-037720: predose, postdose at 0.5,1,2,3,4,6hr of Cycle(C) 1 (each cycle is 28 days), Day(D) 1, postdose at 0.5,1,2,3,4,6hr of C1D15, 2hr post-dose on C3D15; Palbociclib: predose on C1D15, C2D15 & C3D15 | 
| Phase 3: Plasma Concentration of Ipatasertib or its Placebo and its Metabolite, G-037720 |  | 2-4 hrs after ipatasertib or its placebo on C1D1 (each cycle is 28 days), C1D15 and C2D15, Predose on C1D15, C2D15 |