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 (Morpheus-TNBC)

• ClinicalTrials.gov Identifier: NCT03424005
• Recruitment Status: Active, not recruiting
• First Posted: February 6, 2018
• Last Update Posted: May 6, 2023
• Sponsor: Hoffmann-La Roche
• Collaborators: Seagen Inc.; Gilead Sciences
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 30, 2018
• First Posted Date: February 6, 2018
• Last Update Posted Date: May 6, 2023
• Actual Study Start Date: April 2, 2018
• Estimated Primary Completion Date: May 3, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 8, 2020)

• Objective Response Rate (ORR) [ Time Frame: Baseline until disease progression or loss of clinical benefit (approximately 5 years) ]
• Number of Participants With Adverse Events [ Time Frame: Baseline to end of study (approximately 5 years) ]

• Original Primary Outcome Measures (submitted: February 5, 2018): Objective Response Rate (ORR) [ Time Frame: Baseline until disease progression or loss of clinical benefit ( approximately 4 years) ]

Current Secondary Outcome Measures (submitted: January 7, 2021)

• 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 (approximately 5 years) as determined by the investigator according to RECIST v1.1 ]
• Disease Control Rate (DCR) [ Time Frame: Baseline through end of study (approximately 5 years) ]
• Overall Survival (OS) [ Time Frame: Randomization to death from any cause, through the end of study (approximately 5 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 (approximately 5 years) ]

Original Secondary Outcome Measures (submitted: February 5, 2018)

• 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 (approximately 4 years) as determined by the investigator according to RECIST v1.1 ]
• Disease Control Rate (DCR) [ Time Frame: Baseline through end of study (approximately 4 years) ]
• Overall Survival (OS) [ Time Frame: Randomization to death from any cause, through the end of study (approximately 4 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 (approximately 4 years) ]
• Percentage of Participants with Adverse Events [ Time Frame: Baseline to end of study (approximately 4 years) ]
• Serum Concentration of Atezolizumab [ Time Frame: Day 1, Cycle 1 pre-treatment and 30 mins post-infusion; Day 1 of Cycles 2,3,4,8,12, and 16 pre-treatment; through end of study (~ 4 years); 120 days after last dose ]
• Plasma Concentration of Ipatasertib [ Time Frame: Day 15, Cycle 1 pre treatment and 1-3 hours after Ipatasertib dose; ]
• Plasma or Serum Concentration of SNG-LIV1A [ Time Frame: Day 1 Cycle, 1 pre-treatment and 30 minutes after SGN-LIV1A infusion ]
• Plasma Concentration of Cobimetinib [ Time Frame: Day 15, Cycle 1 Pre- Cobimetinib dose and 2-4 hours after Cobimetinib dose ]
• Plasma Concentration of Capecitabine [ Time Frame: Day 1, Cycle 1, 2 hours after capecitabine dose ]

Current Other Pre-specified Outcome Measures (submitted: April 19, 2021)

• Serum Concentration of Atezolizumab [ Time Frame: Day 1, Cycle 1: pre-treatment and 30 mins post-infusion; Day 1 of Cycles 2,3,4,8,12, and 16: pre-treatment (Cycles = 21 or 28 days); through end of study (~ 5 years); 120 days after last dose ]
• Plasma Concentration of Ipatasertib [ Time Frame: Day 15, Cycle 1: pre treatment and 1-3 hours after Ipatasertib dose (Cycle = 28 days) ]
• Plasma or Serum Concentration of SGN-LIV1A [ Time Frame: Day 1 Cycles 1-2: pre-treatment and 30 minutes after SGN-LIV1A infusion; Days 8 and 15, Cycle 1 at visit; Day 1 of Cycles 3, 4, 8, 12, and 16 pretreatment (Cycle = 21 days); 30 days after last dose of SGN-LIV1A; 120 days after last dose of atezolizumab ]
• Serum Concentration of Selicrelumab [ Time Frame: Pre-treatment on Day 1 of Cycles 1, 2, 4, 8, 12, and 16 (Cycle = 28 days); 30 days after last dose ]
• Serum Concentration of Bevacizumab [ Time Frame: Pre-treatment on Day 1 of Cycles 1 and 4 (Cycles = 21 or 28 days); 30 days after last dose ]
• Serum Concentration of Tocilizumab [ Time Frame: Day 1 of Cycles 1, 2, 4, 6, 8, 10, 12, 14, and 16 pre-treatment (Cycle = 28 days); 30 days after last dose ]
• Serum Concentration of Sacituzumab Govitecan [ Time Frame: Day 1 of Cycles 1, 3 5, 7, 9, and 11 and every third cycle thereafter pre-treatment and 30 minutes after sacituzumab govitecan infusion (Cycle = 21 days); 30 days after last dose ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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 Triple-Negative Breast Cancer (Morpheus-TNBC)

Brief 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Triple Negative Breast Cancer

Intervention

• Drug: Capecitabine
  Capecitabine will be administered 1250 mg/m^2 orally twice daily on Days 1-14, of each 21 day cycle.
• Drug: Atezolizumab

  For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle.

  For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: 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 Day 1-21 of each 28 day cycle.
• Drug: SGN-LIV1A
  SGN-LIV1A will be administered IV, 2.5 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, AUC 2, on Days 1 and 8 of each 21 day cycle.

  Or

  Eribulin will be administered by 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 infusion on Day 1 of each 28 day cycle.
• Drug: Nab-Paclitaxel
  Nab-Paclitaxel will be administered by 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, 10 mg/kg, on Days 1 and 8 of each 21-day cycle.

Study Arms

• Active Comparator: Atezolizumab + Nab-Paclitaxel
  1L PD-L1-positive participants will receive doublet combination treatment with atezolizumab + nab-paclitaxel until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
  Interventions:

  • Drug: Atezolizumab
  • Drug: Nab-Paclitaxel
• Experimental: Atezolizumab + Nab-Paclitaxel + Tocilizumab
  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.
  Interventions:

  • Drug: Atezolizumab
  • Drug: Tocilizumab
  • Drug: Nab-Paclitaxel
• Experimental: Atezolizumab + Sacituzumab Govitecan
  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.
  Interventions:

  • Drug: Atezolizumab
  • Drug: Sacituzumab Govitecan
• Active Comparator: Capecitabine

  2L CIT-naive 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 + chemo, provided they meet the eligibility criteria.

  Enrollment is closed.

  Intervention: Drug: Capecitabine
• Experimental: Atezolizumab + Ipatasertib

  2L CIT-naive participants will receive doublet combination treatment with atezolizumab + 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.

  Interventions:

  • Drug: Atezolizumab
  • Drug: Ipatasertib
• Experimental: Atezolizumab + SGN-LIV1A

  2L CIT-naive participants will receive doublet combination treatment with atezolizumab plus SGNLIV1A 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.

  Interventions:

  • Drug: Atezolizumab
  • Drug: SGN-LIV1A
• Experimental: Atezolizumab + Selicrelumab + Bevacizumab

  2L-CIT-naive 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.

  Interventions:

  • Drug: Atezolizumab
  • Drug: Bevacizumab
  • Drug: Selicrelumab
• Experimental: Atezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin)
  2L CIT-naive participants enrolled in the active comparator arm who experience disease progression per RECIST v1.1 and 2L CIT-naive 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 chemotherapy (gemcitabine + carboplatin or eribulin) until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
  Interventions:

  • Drug: Atezolizumab
  • Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 7, 2023): 133
• Original Estimated Enrollment (submitted: February 5, 2018): 260
• Estimated Study Completion Date: May 3, 2024
• Estimated Primary Completion Date: May 3, 2024 (Final data collection date for primary outcome measure)

Eligibility 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
• Tumor accessible for biopsy
• 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)
• 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 Grade </= 1 or better with the exception of alopecia of any grade and Grade </= 2 peripheral neuropathy
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Germany, Israel, Korea, Republic of, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03424005
• Other Study ID Numbers: CO40115; 2017-002038-21 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current

Collaborators

• Seagen Inc.
• Gilead Sciences

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: May 2023