Fulvestrant and Ipatasertib for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor

Study Overview
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Brief Summary
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The purpose of this study is to find out whether a new drug, Ipatasertib, can slow the growth of advanced breast cancer when added to standard therapy (Fulvestrant).

Detailed Description
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Patients enrolled in this study will receive either Ipatasertib plus Fulvestrant or placebo (a substance that looks like the study drug but does not have any active or medicinal ingredient) plus Fulvestant. The study will provide information about the ability of Ipatasertib plus Fulvestrant to control the cancer, the side effects and safety of the treatment, how patients feel while taking the treatment and associated costs.

Official Title
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Double-Blind Placebo-Controlled Randomized Phase III Trial of Fulvestrant and Ipatasertib as Treatment for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor

Conditions
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Breast Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically and/or cytologically confirmed ER positive, HER-2 negative breast cancer Female patients must be post-menopausal; female patients who are pre-menopausal must have ovarian suppression using LHRH agonist while on study Clinical and/or radiographic progression during treatment with or within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an aromatase inhibitor (AI) for advanced/metastatic disease Evidence of clinically and/or radiologically documented disease ≥ 18 years of age ECOG performance status of 0 or 1 No concurrent anti-cancer therapy and must satisfy the following criteria for previous therapy Must not have received more than one prior line of treatment with a CDK 4/6 inhibitor and an AI in the advanced disease setting. Treatment with CDK 4/6 inhibitor and AI must have been the most recent treatment prior to registration for this study Adequate hematology and organ function, in the absence of growth factors Absolute neutrophils > 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L Hemoglobin > 90 g/L Total Bilirubin ≤ 1.5 x ULN (upper limit of normal) or ≤ 3 x ULN if confirmed Gilbert's Syndrome ALT and AST ≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver or bone metastasis) Alkaline phosphatase ≤ 2.0 x ULN (or ≤ 5.0 x ULN if liver metastases, ≤ 7.0 x ULN if bone metastasis) Fasting glucose ≤ 8.3 mmol/L HbA1c ≤ 7.5% Serum albumin ≥ 30 g/L INR ≤ 1.2 Serum Creatinine or Creatinine clearance ≤ 1.5 x ULN or ≥ 50 mL/min; measured directly by 24-hour urine sampling or as calculated by Crockcroft and Gault equation Exclusion Criteria: Untreated or symptomatic CNS metastases, radiation treatment for CNS metastases within 28 days Active inflammatory bowel disease, bowel inflammation, inability to swallow oral medication or GI condition that alters oral absorption Prior treatment with fulvestrant, selective estrogen receptor degraders (SERDs) or known inhibitors of the PI3K pathway including PI3K inhibitors, AKT inhibitors, or mTOR inhibitors Mean QT interval corrected for heart rate (QTc) ≥ 480 msec by ECG or history of familial long QT syndrome Active or uncontrolled infections or serious illnesses or medical conditions Clinically significant liver diseases History of lung disease or history of opportunistic infections Type 1 or Type 2 diabetes mellitus requiring insulin Grade ≥ 2 uncontrolled hypercholesterolemia or hypertriglyceridemia Known abnormalities in coagulation History of hypersensitivity to the study drugs or components Pregnant or lactating women

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: Ipatasertib + Fulvestrant<br> | Drug: Ipatasertib<br>* 400 mg PO QD days 1-21 every 28 days<br>Drug: Fulvestrant<br>* 500 mg IM cycle 1 days 1 and 15 followed by 500 mg IM day 1 q 28 days subsequent cycles<br>|
| Placebo Comparator: Placebo<br> | Drug: Fulvestrant<br>* 500 mg IM cycle 1 days 1 and 15 followed by 500 mg IM day 1 q 28 days subsequent cycles<br>Other: Placebo<br>* PO QD days 1-21 every 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) using RECIST 1.1 |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the two treatment arms with respect to investigator assessed PFS (per RECIST 1.1) in the PIK3CA/AKT1/PTEN altered cohort |  | 5 years | 
| Investigator assessed PFS (per RECIST 1.1) in the PIK3CA/AKT1/PTEN non-altered cohort |  | 5 years | 
| PFS as assessed by blinded central radiology review in all enrolled patients, PIK3CA/AKT1/PTEN altered and non-altered cohorts |  | 5 years | 
| Response rate (RR) (per RECIST 1.1) |  | 5 years | 
| Duration of Response (DoR) |  | 5 years | 
| Clinical Benefit Rate (CBR); |  | 5 years | 
| Overall survival (OS) |  | 5 years | 
| Time to commencement of subsequent line of systemic therapy or death (TSST) |  | 5 years | 
| Number of participants with treatment-related adverse events as assessed by CTCAE version 5.0 |  | 5 years | 
| Quality of Life (QOL) as measured using EORTC QLQ-C30 questionnaire |  | 5 years | 
| Adverse events as measured using NCI PRO-CTCAE questionnaire |  | 5 years | 
| Economic Evaluation of healthcare utilization using average cost per study subject by treatment arm to estimate an overall mean cost per study arm. |  | 5 years | 
| Economic Evaluation of health utilities measured using EQ-5D-5L |  | 5 years |