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

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ClinicalTrials.gov Identifier: NCT03280563
Recruitment Status : Recruiting
First Posted : September 12, 2017
Last Update Posted : September 24, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE September 11, 2017
First Posted Date  ICMJE September 12, 2017
Last Update Posted Date September 24, 2019
Actual Study Start Date  ICMJE December 26, 2017
Estimated Primary Completion Date February 19, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 11, 2017)
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) ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03280563 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 7, 2019)
  • 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) ]
  • 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) ]
  • Overall Survival during Stage 1 [ Time Frame: From randomization until death from any cause (up to 6 years overall) ]
  • Percentage of Participants Alive at 18 Months during Stage 1 [ Time Frame: 18 months ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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 = 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) ]
  • Entinostat Serum and Plasma Concentration during Stage 1 [ Time Frame: Serum predose (0 h) and plasma postdose (2-4 h) on Day 1 of Cycle 1; plasma predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) ]
  • Fulvestrant Plasma Concentration during Stage 1 [ Time Frame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days) ]
  • Ipatasertib Plasma Concentration during Stage 1 [ Time Frame: Predose (0 h) and postdose (1, 2, 4, 6 h) on Day 15 of Cycle 1; postdose (1-3 h) on Day 15 of Cycle 3 ]
  • 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) ]
  • 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) ]
  • Exemestane Plasma Concentration during Stage 2 [ Time Frame: Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) ]
  • Fulvestrant Plasma Concentration during Stage 2 [ Time Frame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days) ]
  • Tamoxifen Plasma Concentration during Stage 2 [ Time Frame: Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • Abemaciclib Serum Concentration during Stage 1 [ Time Frame: Predose (0 h), Postdose (30 minutes post infusion), and 4-8 hours after dose on Day 1 Cycle 1; Predose on Day 15 Cycle 1 and Day 1 of Cycles 2 and 3 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 11, 2017)
  • 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) ]
  • 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) ]
  • Overall Survival during Stage 1 [ Time Frame: From randomization until death from any cause (up to 6 years overall) ]
  • Percentage of Participants Alive at 18 Months during Stage 1 [ Time Frame: 18 months ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • Fulvestrant Plasma Concentration during Stage 1 [ Time Frame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days) ]
  • 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 ]
  • 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) ]
  • 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) ]
  • 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) ]
  • Fulvestrant Plasma Concentration during Stage 2 [ Time Frame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
Brief Summary This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with inoperable 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Neoplasms
Intervention  ICMJE
  • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.
    Other Name: Tecentriq
  • Drug: Bevacizumab
    Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.
    Other Name: Avastin
  • Drug: Entinostat
    Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21 day cycle.
  • Drug: Exemestane
    Exemestane will be given as 25 mg orally QD in each 21-day cycle.
  • Drug: Fulvestrant
    Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.
  • Drug: Ipatasertib
    Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
  • Drug: Tamoxifen
    Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.
  • Drug: Abemaciclib
    Abemaciclib will be given as 150mg twice daily during each 28-day cycle.
Study Arms  ICMJE
  • Active Comparator: Stage 1: Fulvestrant
    Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.
    Intervention: Drug: Fulvestrant
  • Experimental: Stage 1: Atezolizumab + Entinostat
    Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
    Interventions:
    • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    • Drug: Entinostat
  • Experimental: Stage 1: Atezolizumab + Fulvestrant
    Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
    Interventions:
    • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    • Drug: Fulvestrant
  • Experimental: Stage 1: Atezolizumab + Ipatasertib
    Participants 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.
    Interventions:
    • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    • Drug: Ipatasertib
  • Experimental: Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
    Participants 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.
    Interventions:
    • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    • Drug: Fulvestrant
    • Drug: Ipatasertib
  • Experimental: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
    Those 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.
    Interventions:
    • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    • Drug: Bevacizumab
    • Drug: Exemestane
    • Drug: Fulvestrant
    • Drug: Tamoxifen
  • Experimental: Stage 1: Mandatory On-Treatment Biopsy
    For 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.
    Interventions:
    • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    • Drug: Entinostat
    • Drug: Fulvestrant
    • Drug: Ipatasertib
    • Drug: Abemaciclib
  • Experimental: Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
    Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
    Interventions:
    • Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
    • Drug: Fulvestrant
    • Drug: Abemaciclib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 7, 2019)
126
Original Estimated Enrollment  ICMJE
 (submitted: September 11, 2017)
111
Estimated Study Completion Date  ICMJE October 5, 2022
Estimated Primary Completion Date February 19, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for Both Stages:

  • Measureable disease per RECIST v1.1
  • Adequate hematologic and end organ function
  • Disease progression during or after first- or second-line hormonal therapy with CDK4/6 inhibitor

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 first- or second-line hormonal therapy for locally advanced or metastatic disease
  • Postmenopausal according to protocol-defined criteria
  • Life expectancy >3 months
  • 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 test
  • Active hepatitis B or C
  • Active tuberculosis
  • 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
  • For patients entering Stage 2, recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent

Exclusion Criteria for Stage 1:

  • 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
  • Eligibility only for the control arm
  • Prior treatment with inhibitors as specified in the protocol

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
  • Grade 2 or higher proteinuria
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: CO39611 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE Israel,   Korea, Republic of,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03280563
Other Study ID Numbers  ICMJE CO39611
2017-000335-14 ( 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  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP