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

Roche

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Metastatic Breast Cancer

Treatments: Drug: Letrozole; Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin); Drug: Palbociclib; Drug: Inavolisib (Dose #1); Drug: Atirmociclib; Drug: Empagliflozin; Drug: Abemaciclib; Drug: Capecitabine; Drug: Ribociclib (Dose #2); Drug: SGN-LIV1A; Drug: Inavolisib (Dose #2); Drug: Inavolisib; Drug: Ribociclib (Dose #1); Drug: Metformin; Drug: Fulvestrant; Drug: Atezolizumab; Drug: Trastuzumab Deruxtecan; Drug: Selicrelumab; Drug: Nab-Paclitaxel; Drug: Sacituzumab Govitecan; Drug: Bevacizumab; Drug: Ipatasertib; Drug: Tocilizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT03424005

2017-002038-21 (EudraCT Number)

2023-503629-20-00 (EU Trial (CTIS) Number)

CO40115

Details and patient eligibility

About

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, six 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, and 6 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.

Enrollment: 792 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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 breast cancer
• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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792 participants in 19 patient groups

Atezolizumab + Nab-Paclitaxel

Active Comparator group

Description:

1L PD-L1-positive participants will receive doublet combination treatment with atezolizumab plus nab-paclitaxel until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed.

Treatment:

Drug: Nab-Paclitaxel

Drug: Atezolizumab

Atezolizumab + Nab-Paclitaxel + Tocilizumab

Experimental group

Description:

1L PD-L1-positive participants will receive combination treatment with atezolizumab plus nab-paclitaxel and tocilizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed.

Treatment:

Drug: Tocilizumab

Drug: Nab-Paclitaxel

Drug: Atezolizumab

Atezolizumab + Sacituzumab Govitecan

Experimental group

Description:

1L PD-L1-positive participants will receive doublet combination treatment with atezolizumab plus sacituzumab govitecan until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed.

Treatment:

Drug: Sacituzumab Govitecan

Drug: Atezolizumab

Capecitabine

Active Comparator group

Description:

2L CIT-naïve participants will receive capecitabine until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1). Participants who progressed on treatment may have the option of receiving atezolizumab along with chemotherapy (chemo) during stage 2, provided they meet the eligibility criteria. Enrollment is closed.

Treatment:

Drug: Capecitabine

Atezolizumab + Ipatasertib

Experimental group

Description:

2L CIT-naïve participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed and participant follow-up is complete.

Treatment:

Drug: Ipatasertib

Drug: Atezolizumab

Atezolizumab + SGN-LIV1A

Experimental group

Description:

2L CIT-naïve participants will receive doublet combination treatment with atezolizumab plus SGNLIV1A until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Patients who experience loss of clinical benefit as determined by the investigator or unacceptable toxicity related to SGN-LIV1A will be given the option of receiving Atezolizumab + chemo during Stage 2, provided they meet the eligibility criteria. Enrollment is closed.

Treatment:

Drug: Atezolizumab

Drug: SGN-LIV1A

Atezolizumab + Selicrelumab + Bevacizumab

Experimental group

Description:

2L-CIT-naïve participants will receive doublet combination treatment with atezolizumab plus selicrelumab and bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed and participant follow-up is complete.

Treatment:

Drug: Bevacizumab

Drug: Selicrelumab

Drug: Atezolizumab

Atezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin)

Experimental group

Description:

2L CIT-naïve participants enrolled in the active comparator arm who experience disease progression per RECIST v1.1 and 2L CIT-naïve participants enrolled in an experimental arm who experience loss of clinical benefit as determined by the investigator may receive doublet combination treatment with atezolizumab plus chemo (gemcitabine + carboplatin or eribulin) until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed and participant follow-up is complete.

Treatment:

Drug: Atezolizumab

Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin)

Inavolisib + Abemaciclib + Fulvestrant

Experimental group

Description:

HR+ participants will receive treatment with inavolisib plus abemaciclib plus fulvestrant until unacceptable toxicity or disease progression determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Fulvestrant

Drug: Inavolisib

Drug: Abemaciclib

Inavolisib + Ribociclib (Dose #1) + Fulvestrant

Experimental group

Description:

HR+ participants will receive treatment with inavolisib plus ribociclib plus fulvestrant until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Fulvestrant

Drug: Ribociclib (Dose #1)

Drug: Inavolisib

Inavolisib + Ribociclib (Dose #1) + Letrozole

Experimental group

Description:

HR+ participants will receive treatment with inavolisib plus ribociclib plus letrozole until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Ribociclib (Dose #1)

Drug: Inavolisib

Drug: Letrozole

Inavolisib + Ribociclib (Dose #2) + Fulvestrant

Experimental group

Description:

HR+ participants will receive treatment with inavolisib plus ribociclib plus fulvestrant until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Fulvestrant

Drug: Inavolisib

Drug: Ribociclib (Dose #2)

Inavolisib + Ribociclib (Dose #2) + Letrozole

Experimental group

Description:

HR+ participants will receive treatment with inavolisib plus ribociclib plus letrozole until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Inavolisib

Drug: Ribociclib (Dose #2)

Drug: Letrozole

Inavolisib + Abemaciclib + Letrozole

Experimental group

Description:

HR+ participants will receive treatment with inavolisib plus abemaciclib plus letrozole until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Inavolisib

Drug: Abemaciclib

Drug: Letrozole

Inavolisib (Dose #1) + Trastuzumab Deruxtecan

Experimental group

Description:

HER2+/HER2-low participants will receive inavolisib + trastuzumab deruxtecan until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Trastuzumab Deruxtecan

Drug: Inavolisib (Dose #1)

Inavolisib (Dose #2) + Trastuzumab Deruxtecan

Experimental group

Description:

HER2+/HER2-low participants will receive inavolisib + trastuzumab deruxtecan until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Trastuzumab Deruxtecan

Drug: Inavolisib (Dose #2)

Empagliflozin (Empa) + Inavolisib (Inavo) + Fulvestrant (Fulv) ± Palbociclib (Palbo)

Experimental group

Description:

Participants with locally advanced or metastatic, HR+, HER2- participants will receive empagliflozin plus inavolisib plus fulvestrant with or without palbociclib until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Fulvestrant

Drug: Inavolisib

Drug: Empagliflozin

Drug: Palbociclib

Metformin (Metf) + Inavolisib + Fulvestrant ± Palbociclib

Experimental group

Description:

Participants with locally advanced or metastatic, HR+, HER2- participants will receive metformin plus inavolisib plus fulvestrant with or without palbociclib until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Fulvestrant

Drug: Metformin

Drug: Inavolisib

Drug: Palbociclib

Inavolisib + Atirmociclib (Atirmo) + Fulvestrant

Experimental group

Description:

Participants will receive inavolisib plus atirmociclib plus fulvestrant until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Treatment:

Drug: Fulvestrant

Drug: Inavolisib

Drug: Atirmociclib