A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic or Inoperable Locally Advanced Triple-Negative Breast Cancer

• Status: Recruiting
• Trial end date: 2023-01-03
• Target enrollment: 0
• Participant gender: All

Summary

This is a Phase Ib/II, open-label, multicenter, randomized umbrella study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with metastatic or inoperable locally advanced TNBC.

The study will be performed in two stages. During Stage 1, two cohorts will be enrolled in parallel in this study: one cohort 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), and one cohort will consist of participants who had disease progression during or following 1L treatment with chemotherapy (e.g., paclitaxel, nab-paclitaxel, carboplatin) and have not received cancer immunotherapy (CIT) (second-line [2L] CIT-naive cohort). In addition, participants in the 2L CIT-naive 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 (Stage 2), provided Stage 2 is open for enrollment.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Hoffmann-La Roche
• Collaborators: Gilead Sciences; Seagen Inc.; Seattle Genetics, Inc.
• Treatments: Antibodies, Monoclonal; Atezolizumab; Bevacizumab; Capecitabine; Carboplatin; Gemcitabine; Immunoconjugates; Paclitaxel

Criteria

Inclusion Criteria Stage 1

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Metastatic or inoperable locally advanced, histologically documented TNBC (absence of HER2, ER, and PR expression)

• For the 1L PD L1+ cohort: no prior systemic treatment for metastatic or inoperable locally advanced TNBC

• For the 2L CIT-naive cohort: Eligible for capecitabine monotherapy

• For the 2L CIT-naive cohort: Radiologic/objective evidence of recurrence or disease progression after 1L treatment with chemotherapy, for a total of one line of therapy for inoperable locally advanced or metastatic breast cancer

• Life expectancy =/> 3 months, as determined by the investigator

• Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status via central testing

• For the 1L PD L1+ cohort: Positive PD-L1 expression, defined as >/= 1% of the tumor area occupied by PD L1-expressing tumor-infiltrating immune cells of any intensity, as determined through use of the U.S. Food and Drug Administration-approved or CE-marked Ventana PD-L1 (SP142) Assay

Inclusion Criteria for Stage 1 (both cohorts) and Stage 2 (2L CIT-naive cohort)

• Measurable disease (at least one target lesion)

• Tumor accessible for biopsy

• Adequate hematologic and end-organ function, laboratory test results, obtained within 14 days prior to initiation of study treatment.

• Negative HIV test at screening

• Negative hepatitis B surface antigen test

• Negative total hepatitis B core antibody (HBcAb)

• Negative hepatitis C virus (HCV) antibody test at screening

• 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

Inclusion Criteria Stage 2 (2L CIT-naive cohort)

• ECOG Performance Status of 0, 1, or 2

• Patients randomly allocated to the control arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity, provided that Medical Monitor approval for entry into Stage 2 is obtained, or disease progression per RECIST v1.1 while receiving control treatment

• Patients randomly allocated to an experimental arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab, disease progression per RECIST v1.1, or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment

• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 (if deemed clinically feasible by the investigator)

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

• Treatment with investigational therapy within 28 days prior to initiation of study treatment

• 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

• Adverse events from prior anti-cancer therapy that have not resolved to Gradebetter with the exception of alopecia of any grade and Gradeneuropathy

• Eligibility only for the control arm

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

• 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

• 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

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study

Exclusion Criteria for the 2L CIT-naive cohort, Stage 1

• Prior treatment with capecitabine,

• Treatment with sorivudine or its chemically related analogues, such as brivudine

• History of severe and unexpected reactions to fluoropyrimidine therapy

• Known complete absence of dihydropyrimidine dehydrogenase activity

Exclusion Criteria for Stage 2

• Inability to tolerate atezolizumab during Stage 1

• For patients receiving eribulin: congenital long QT syndrome

Additional drug-specific exclusion criteria may apply to Stage 1 and 2