A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer

Hoffmann-La Roche144 enrolled

Overview

This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with inoperable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have progressed during or following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

144

Conditions

Breast Neoplasms

Interventions

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria for Both Stages: * Measurable disease per RECIST v1.1 * Adequate hematologic and end organ function * Disease progression during or after first- or second-line hormonal therapy with CDK4/6 inhibitor Inclusion Criteria for Stage 1: * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Metastatic or inoperable, locally advanced, histologically or cytologically confirmed invasive HR-positive HER2-negative breast cancer * Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study entry * Recurrence or progression following most recent systemic breast cancer therapy * Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease * Postmenopausal according to protocol-defined criteria * Life expectancy \>3 months * Available tumor specimen for determination of PD-L1 status Inclusion Criteria for Stage 2: * ECOG performance status of 0-2 * Ability to initiate treatment within 3 months after disease progression or unacceptable toxicity on a Stage 1 regimen Exclusion Criteria for Both Stages: * Significant or uncontrolled comorbid disease as specified in the protocol * Uncontrolled tumor-related pain * Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes mellitus, or certain dermatologic conditions * Positive human immunodeficiency virus test * Active hepatitis B or C * Active tuberculosis * Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study treatment * Prior allogeneic stem cell or solid organ transplantation * History of malignancy other than breast cancer within 2 years prior to screening except those with negligible risk of metastasis/death * History of or known hypersensitivity to study drug or excipients * For patients entering Stage 2, recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent Exclusion Criteria for Stage 1: * Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain other agents as specified in the protocol * Unresolved AEs from prior anti-cancer therapy * Eligibility only for the control arm * Prior treatment with inhibitors as specified in the protocol Exclusion Criteria for Stage 2: * Unacceptable toxicity with atezolizumab during Stage 1 * Uncontrolled cardiovascular disease or coagulation disorder, including use of anticoagulants as specified in the protocol * Significant abdominal or intestinal manifestations within 6 months prior to treatment * Grade 2 or higher proteinuria

Outcomes

Primary Outcomes

Stage 1: Percentage of Participants With Objective Response

Objective response rate (ORR) was defined as the percentage of participants with an objective response of complete response (CR) or partial response (PR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) that have a reduction in short axis to \< 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. Percentages have been rounded off to the nearest whole number.

Time frame: Up to 50.4 months

Secondary Outcomes

Stage 1: Progression-free Survival (PFS)

PFS was defined as the time from randomization to the date of the first recorded occurrence of PD or death from any cause (whichever occurred first) in Stage 1, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS.

Time frame: From randomization to the first occurrence of PD or death (up to 51.9 months)

Stage 1: Clinical Benefit Rate (CBR)

CBR was defined as the percentage of participants with stable disease (SD) ≥ 24 weeks or with confirmed CR or PR, as determined by the investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Percentages have been rounded off to the nearest whole number.

Time frame: Up to 51.9 months

Stage 1: Overall Survival (OS)

Time frame: From randomization to death (up to 62.2 months)

Stage 1: Percentage of Participants Event-free for OS at Month 18

OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS at Month 18. Percentages have been rounded off to the nearest whole number.

Time frame: At Month 18

Stage 1: Duration of Response (DOR)

DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to the first date of recorded PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, DOR was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for DOR.

Time frame: From first occurrence of a documented OR to the first date of recorded PD or death (up to 50.4 months)

Stages 1 and 2: Number of Participants With Adverse Events (AEs)

An AE was any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE = serious adverse events; AESIs = adverse events of special interest.

Time frame: From baseline until 30 days (for AEs) or 135 days (for SAEs & AESIs) after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurred first (Stage 1: up to 52 months; Stage 2: up to 21.7 months)

Stage 1: Plasma Concentration of Entinostat

Time frame: Predose on Day 1 of Cycles 1 and 2; 2-4 hours postdose on Day 1 Cycle 1 (Cycle length = 21 days)

Stage 1: Plasma Concentration of Abemaciclib

Time frame: Predose on Day 1 of Cycles 1, 2 and 3, and on Day 15 Cycle 1; 4-8 hours postdose on Day 1 Cycle 1 (Cycle length = 28 days)

Stage 1: Plasma Concentration of Ipatasertib

Time frame: Predose and Postdose at 1 Hour, 2 Hour, 4 Hour, and 6 Hour on Day 15 Cycle 1; Post dose at 1-3 Hour on Day 15 Cycle 3 (Cycle length = 28 days)

Stage 1: Plasma Concentration of Fulvestrant

Time frame: Predose on Day 1 of Cycle 2 and Cycle 3 (Cycle length = 28 days)

Stage 2: Plasma Concentration of Fulvestrant

Nominal time restarted to 0 at Stage 2. PK data for Stage was analyzed and reported for the subgroups \[crossover arms (Stage 1 to Stage 2)\] only.

Time frame: Predose on Day 1 of Cycles 2 and 3 (Cycle length = 21 days)

Stage 2: Serum Concentration of Atezolizumab

Nominal time restarted to 0 at Stage 2; RO5541267 = atezolizumab. PK data for Stage was analyzed and reported for the subgroups \[crossover arms (Stage 1 to Stage 2)\] only.

Time frame: Predose on Day 1 of Cycles 1, 2, 3, 4, 8 and 12; 30 minutes (mins) postdose on Day 1 Cycle 1; postdose on Day 120 and Treatment Discontinuation Visit (Cycle length = 21 days)

Stage 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab

Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 t.u. greater than the titer of the baseline sample (treatment unaffected). Participants with a positive post-baseline sample has been reported here.

Time frame: Post-baseline (up to approximately 134 days)