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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

NCT03424005

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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)

Clinical Trial IDs

  • ORG STUDY ID: CO40115
  • SECONDARY ID: 2017-002038-21
  • NCT ID: NCT03424005

Conditions

  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
CapecitabineCapecitabine
AtezolizumabAtezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin)
IpatasertibAtezolizumab + Ipatasertib
SGN-LIV1AAtezolizumab + SGN-LIV1A
BevacizumabAtezolizumab + Selicrelumab + Bevacizumab
Chemotherapy (Gemcitabine + Carboplatin or Eribulin)Atezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin)
SelicrelumabAtezolizumab + Selicrelumab + Bevacizumab
TocilizumabAtezolizumab + Nab-Paclitaxel + Tocilizumab
Nab-PaclitaxelAtezolizumab + Nab-Paclitaxel
Sacituzumab GovitecanAtezolizumab + Sacituzumab Govitecan

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab + Nab-PaclitaxelActive Comparator1L 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.
  • Atezolizumab
  • Nab-Paclitaxel
Atezolizumab + Nab-Paclitaxel + TocilizumabExperimental1L 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.
  • Atezolizumab
  • Tocilizumab
  • Nab-Paclitaxel
Atezolizumab + Sacituzumab GovitecanExperimental1L 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.
  • Atezolizumab
  • Sacituzumab Govitecan
CapecitabineActive Comparator2L 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.
  • Capecitabine
Atezolizumab + IpatasertibExperimental2L 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.
  • Atezolizumab
  • Ipatasertib
Atezolizumab + SGN-LIV1AExperimental2L 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.
  • Atezolizumab
  • SGN-LIV1A
Atezolizumab + Selicrelumab + BevacizumabExperimental2L-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.
  • Atezolizumab
  • Bevacizumab
  • Selicrelumab
Atezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin)Experimental2L 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.
  • Atezolizumab
  • Chemotherapy (Gemcitabine + Carboplatin or Eribulin)

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

          -  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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Baseline until disease progression or loss of clinical benefit (approximately 5 years)
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure:Disease Control Rate (DCR)
Time Frame:Baseline through end of study (approximately 5 years)
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Randomization to death from any cause, through the end of study (approximately 5 years)
Safety Issue:
Description:
Measure:Overall Survival (at specific time-points)
Time Frame:12 and 18 months
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Plasma Concentration of Ipatasertib
Time Frame:Day 15, Cycle 1: pre treatment and 1-3 hours after Ipatasertib dose (Cycle = 28 days)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

April 8, 2020