A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer

Official title

A Phase Ib/II, Open-label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic Breast Cancer (Morpheus-panBC)

Overview

This is an umbrella study evaluating the efficacy and safety of multiple treatment combinations in participants with metastatic or inoperable locally advanced breast cancer. The study will be performed in two stages. During Stage 1, seven cohorts will be enrolled in parallel in this study: Cohort 1 will consist of programmed death-ligand 1 (PD-L1)-positive participants who have received no prior systemic therapy for metastatic or inoperable locally advanced triple-negative breast cancer (TNBC) (first-line \[1L\] PD-L1+ cohort). Cohort 2 will consist of participants who had disease progression during or following 1L treatment with chemotherapy for metastatic or inoperable locally-advanced TNBC and have not received cancer immunotherapy (CIT) (second-line \[2L\] CIT-naïve cohort). Cohort 3, 5, 6 and 7 will consist of participants with locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative disease with one or more PIK3CA mutations. Cohort 4 will consist of participants with locally advanced or metastatic HER2+ /HER2-low disease with one or more PIK3CA mutations who had disease progression on standard-of-care therapies (HER2+ /HER2-low cohort). In each cohort, eligible participants will initially be assigned to one of several treatment arms (Stage 1). During Stage 2, participants in the 2L CIT-naïve cohort who experience disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment combination, provided Stage 2 is open for enrollment and all eligibility criteria are met.

Interventions

• Drug Capecitabine
  Capecitabine will be administered 1250 milligrams per square meter (mg/m\^2) orally twice daily on Days 1-14 of each 21-day cycle.
• Drug Atezolizumab
  For Atezolizumab + SGN-LIV1A, Atezolizumab + Sacituzumab Govitecan, or Atezolizumab + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezolizumab + Nab-Paclitaxel, Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Ipatasertib, or Atezolizumab + Nab-Paclitaxel + Tocilizumab arms: atezolizumab will be administered IV, 840 mg on Days 1 and 15 of each 28-day cycle.
• Drug Ipatasertib
  Ipatasertib will be administered by mouth 400 mg once a day, on Days 1-21 of each 28-day cycle.
• Drug SGN-LIV1A
  SGN-LIV1A will be administered IV, 2.5 milligrams per kilogram (mg/kg) (maximum calculated dose 250 mg), on Day 1 of each 21-day cycle.
• Drug Bevacizumab
  Bevacizumab will be administered IV, 10 mg/kg, on Days 1 and 15 of each 28-day cycle.
• Drug Chemotherapy (Gemcitabine + Carboplatin or Eribulin)
  Gemcitabine will be administered by IV, 1000 mg/m\^2, along with carboplatin, by IV, on Days 1 and 8 of each 21-day cycle. Or Eribulin will be administered IV, 1.4 mg/m\^2 on Days 1 and 8 of each 21-day cycle.
• Drug Selicrelumab
  Selicrelumab will be administered by subcutaneous (SC) injection, at a fixed dose of 16 mg on Day 1 of Cycles 1 to 4 and every third cycle thereafter (Cycle = 28 days).
• Drug Tocilizumab
  Tocilizumab will be administered IV, 8 mg/kg on Day 1 of each 28-day cycle.
• Drug Nab-Paclitaxel
  Nab-Paclitaxel will be administered IV, 100 mg/m\^2, on Days 1, 8, and 15 of each 28-day cycle.
• Drug Sacituzumab Govitecan
  Sacituzumab govitecan will be administered by IV infusion, 10 mg/kg, on Days 1 and 8 of each 21-day cycle.

Primary outcome measures

• Objective Response Rate (ORR) [Time frame: Baseline until disease progression or loss of clinical benefit (up to approximately 12 years)]

Secondary outcome measures (6)

• Progression Free Survival (PFS) [Time frame: Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (up to approximately 12 years) as determined by the investigator according to RECIST v1.1]
• Disease Control Rate (DCR) [Time frame: Baseline through end of study (up to approximately 12 years)]
• Overall Survival (OS) [Time frame: Randomization to death from any cause, through the end of study (up to approximately 12 years)]
• Overall Survival (at specific time-points) [Time frame: 12 and 18 months]
• Duration of Response (DOR) [Time frame: Randomization until first occurrence of a documented objective response to the first recorded occurrence of disease progression or death from any cause (whichever occurs first), through end of study (up to approximately 12 years)]
• Percentage of Participants with Adverse Events [Time frame: Baseline to end of study (up to approximately 12 years)]

Eligibility criteria

Inclusion criteria

Patients must meet all of the following criteria to qualify for Stage 1 (all cohorts) and to qualify for Stage 2 (2L CIT-naïve cohort):

• Age >/= 18 years at the time of signing Informed Consent Form
• Eastern cooperative oncology group (ECOG) performance status of 0 or 1
• Able to comply with the study protocol, in the investigator's judgment
• Metastatic or inoperable locally advanced adenocarcinoma of the breast
• Measurable disease (at least one target lesion) according to RECIST v1.1
• Life expectancy >/= 3 months, as determined by the investigator
• Tumor accessible for biopsy, unless archival tissue is available
• Availability of a representative tumor specimen that is suitable for biomarker analysis via central testing
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from breastfeeding and donating eggs, as outlined for each specific treatment arm
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm

Exclusion criteria

Exclusion Criteria for Stage 1

• Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, CD40 agonists or interleukin-2 (IL-2) or IL-2-like compounds
• Biologic treatment (e.g., bevacizumab) within 2 weeks prior to initiation of study treatment, or other systemic treatment for TNBC within 2 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study
• Eligibility only for the control arm

Exclusion Criteria for Stage 1 (both cohorts) and Stage 2 (2L CIT-naïve cohort)

• Adverse events from prior anti-cancer therapy that have not resolved to Grade </= 1 or better with the exception of alopecia of any grade and Grade </= 2 peripheral neuropathy
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Uncontrolled tumor-related pain
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• History of leptomeningeal disease
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Active tuberculosis
• Severe infection within 4 weeks prior to initiation of study treatment
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Significant cardiovascular disease
• Prior allogeneic stem cell or solid organ transplantation
• History of malignancy other than breast cancer within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 18 centers

• City of Hope — Duarte
• University of California San Diego Medical Center — La Jolla
• Stanford Cancer Institute — Stanford
• Rocky Mountain Cancer Center - Longmont — Longmont
• H. Lee Moffitt Cancer Center and Research Inst. — Tampa
• Metro-Minnesota Community Oncology Research Consortium — Saint Paul
• Renown Regional Medical Center — Reno
• Hackensack Univ Medical Center — Hackensack
• … and 10 more centers

Israel · 7 centers

• Rambam Medical Center — Haifa
• Shaare Zedek Medical Center — Jerusalem
• Hadassah University Medical Center — Jerusalem
• Rabin MC — Petah Tikva
• Sheba Medical Center — Ramat Gan
• Tel-Aviv Sourasky Medical Center — Tel Aviv
• Assuta Medical Centers — Tel Aviv

South Korea · 5 centers

• National Cancer Center Clinical Trials Center / Center for Breast Cancer — Goyang-si
• Seoul National University Hospital — Seoul
• Severance Hospital — Seoul
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul

Spain · 5 centers

• Hospital Universitario Virgen Macarena — Seville
• Hospital del Mar — Barcelona
• Vall d?Hebron Institute of Oncology (VHIO), Barcelona — Barcelona
• Hospital Universitario Ramon y Cajal — Madrid
• Centro Integral Oncológico Clara Campal Ensayos Clínicos START — Madrid

France · 4 centers

• Centre Léon Bérard — Lyon
• Institut régional du Cancer Montpellier — Montpellier
• Institut Universitaire du Cancer de Toulouse-Oncopole — Toulouse
• Gustave Roussy — Villejuif

Australia · 2 centers

• Peter MacCallum Cancer Centre-East Melbourne — Melbourne
• Fiona Stanley Hospital - Medical Oncology — Murdoch

Germany · 2 centers

• Universitätsklinikum Erlangen — Erlangen
• Universitätsklinikum Essen — Essen

Taiwan · 2 centers

• National Cheng Kung University Hospital — Tainan
• National Taiwan University Hospital — Taipei

United Kingdom · 2 centers

• Beatson West of Scotland Cancer Centre — Glasgow
• Barts Health NHS Trust - St Bartholomew's Hospital — London

Identifiers

NCT: NCT03424005 · CO40115 · 2017-002038-21 · 2023-503629-20-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗