Clinical Trials /

A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer

NCT03280563

Description:

This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with locally advanced or metastatic HR-positive, HER2-negative breast cancer who have progressed during or following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-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 Hormone Receptor-Positive HER2-Negative Breast Cancer (MORPHEUS-HR+ Breast Cancer)

Clinical Trial IDs

  • ORG STUDY ID: CO39611
  • SECONDARY ID: 2017-000335-14
  • NCT ID: NCT03280563

Conditions

  • Breast Neoplasms

Interventions

DrugSynonymsArms
Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibodyTecentriqStage 1: Atezolizumab + Cobimetinib
BevacizumabAvastinStage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
CobimetinibCotellicStage 1: Atezolizumab + Cobimetinib
ExemestaneStage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
FulvestrantStage 1: Fulvestrant
IpatasertibStage 1: Atezolizumab + Ipatasertib
TamoxifenStage 2: Atezolizumab + Bevacizumab + Endocrine Therapy

Purpose

This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with metastatic HR-positive, HER2-negative breast cancer who have progressed during or following first-line metastatic treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.

Trial Arms

NameTypeDescriptionInterventions
Stage 1: FulvestrantActive ComparatorParticipants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.
  • Fulvestrant
Stage 1: Atezolizumab + CobimetinibExperimentalParticipants will receive doublet combination treatment with atezolizumab plus cobimetinib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
  • Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
  • Cobimetinib
Stage 1: Atezolizumab + FulvestrantExperimentalParticipants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
  • Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
  • Fulvestrant
Stage 1: Atezolizumab + IpatasertibExperimentalParticipants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
  • Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
  • Ipatasertib
Stage 1: Atezolizumab + Ipatasertib + FulvestrantExperimentalParticipants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
  • Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
  • Fulvestrant
  • Ipatasertib
Stage 2: Atezolizumab + Bevacizumab + Endocrine TherapyExperimentalThose who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
  • Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
  • Bevacizumab
  • Exemestane
  • Fulvestrant
  • Tamoxifen
Stage 1: Mandatory On-Treatment BiopsyExperimentalFor experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.
  • Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
  • Cobimetinib
  • Fulvestrant
  • Ipatasertib

Eligibility Criteria

        Inclusion Criteria for Both Stages:

          -  Measureable disease per RECIST v1.1 with tumor accessible for biopsy

          -  Adequate hematologic and end organ function

        Inclusion Criteria for Stage 1:

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Metastatic or inoperable, locally advanced, histologically or cytologically confirmed
             invasive HR-positive HER2-negative breast cancer

          -  Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study
             entry

          -  Recurrence or progression following most recent systemic breast cancer therapy

          -  Disease progression during or after CDK4/6 inhibitor treatment for metastatic disease

          -  Postmenopausal according to protocol-defined criteria

          -  Life expectancy >3 years

          -  Available tumor specimen for determination of PD-L1 status

        Inclusion Criteria for Stage 2:

          -  ECOG performance status of 0-2

          -  Ability to initiate treatment within 3 months after disease progression or
             unacceptable toxicity on a Stage 1 regimen

        Exclusion Criteria for Both Stages:

          -  Significant or uncontrolled comorbid disease as specified in the protocol

          -  Uncontrolled tumor-related pain

          -  Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes
             mellitus, or certain dermatologic conditions

          -  Positive human immunodeficiency virus or hepatitis B or C

          -  Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study
             treatment

          -  Prior allogeneic stem cell or solid organ transplantation

          -  History of malignancy other than breast cancer within 2 years prior to screening
             except those with negligible risk of metastasis/death

          -  History of or known hypersensitivity to study drug or excipients

        Exclusion Criteria for Stage 1:

          -  HER2-positive breast cancer

          -  Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain
             other agents as specified in the protocol

          -  Unresolved AEs from prior anti-cancer therapy

        Exclusion Criteria for Stage 2:

          -  Unacceptable toxicity with atezolizumab during Stage 1

          -  Uncontrolled cardiovascular disease or coagulation disorder, including use of
             anticoagulants as specified in the protocol

          -  Significant abdominal or intestinal manifestations within 6 months prior to treatment

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

Primary Outcome Measures

Measure:Percentage of Participants with Objective Response during Stage 1 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
Time Frame:From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression-Free Survival during Stage 1 According to RECIST v1.1
Time Frame:From randomization until disease progression or death from any cause (up to 6 years overall)
Safety Issue:
Description:
Measure:Percentage of Participants with Clinical Benefit during Stage 1 According to RECIST v1.1
Time Frame:From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
Safety Issue:
Description:
Measure:Overall Survival during Stage 1
Time Frame:From randomization until death from any cause (up to 6 years overall)
Safety Issue:
Description:
Measure:Percentage of Participants Alive at 18 Months during Stage 1
Time Frame:18 months
Safety Issue:
Description:
Measure:Duration of Response during Stage 1 According to RECIST v1.1
Time Frame:From first objective response until disease progression or death from any cause (up to 6 years overall)
Safety Issue:
Description:
Measure:Percentage of Participants with Adverse Events (AEs) during Stage 1
Time Frame:From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
Safety Issue:
Description:
Measure:Percentage of Participants with AEs during Stage 2
Time Frame:From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
Safety Issue:
Description:
Measure:Atezolizumab Serum Concentration during Stage 1
Time Frame:Predose (0 hours [h]) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); postdose (30 minutes [min]) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Safety Issue:
Description:
Measure:Cobimetinib Plasma Concentration during Stage 1
Time Frame:Predose (0 h) and postdose (2-4 h) on Day 15 of Cycle 1 (cycle = 28 days)
Safety Issue:
Description:
Measure:Fulvestrant Plasma Concentration during Stage 1
Time Frame:Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
Safety Issue:
Description:
Measure:Ipatasertib Plasma Concentration during Stage 1
Time Frame:Predose (0 h) on Day 1 of Cycle 1 (cycle = 28 days); predose (0 h) and postdose (1-3, 4, 6 h) on Day 15 of Cycle 1; postdose (1-3 h) on Day 15 of Cycle 3
Safety Issue:
Description:
Measure:Atezolizumab Serum Concentration during Stage 2
Time Frame:Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Safety Issue:
Description:
Measure:Bevacizumab Serum Concentration during Stage 2
Time Frame:Predose (0 h) and postdose (30 min) (infusion = 30-90 min) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Safety Issue:
Description:
Measure:Exemestane Plasma Concentration during Stage 2
Time Frame:Predose (0 h) on Day 15 of Cycle 1 and Day 1 of Cycle 2 (cycle = 21 days)
Safety Issue:
Description:
Measure:Fulvestrant Plasma Concentration during Stage 2
Time Frame:Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
Safety Issue:
Description:
Measure:Tamoxifen Plasma Concentration during Stage 2
Time Frame:Predose (0 h) on Day 15 of Cycle 1 and Day 1 of Cycle 2 (cycle = 21 days)
Safety Issue:
Description:
Measure:Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab during Stage 1
Time Frame:Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Safety Issue:
Description:
Measure:Percentage of Participants with ADAs to Atezolizumab during Stage 2
Time Frame:Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Safety Issue:
Description:
Measure:Percentage of Participants with ADAs to Bevacizumab during Stage 2
Time Frame:Predose (0 h) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Safety Issue:
Description:

Details

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

Last Updated

October 24, 2017