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A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Triple-Negative Breast Cancer (Morpheus-TNBC) (Morpheus-TNBC)

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ClinicalTrials.gov Identifier: NCT03424005
Recruitment Status : Recruiting
First Posted : February 6, 2018
Last Update Posted : September 7, 2018
Sponsor:
Collaborator:
Seattle Genetics, Inc.
Information provided by (Responsible Party):
Hoffmann-La Roche

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 TNBC who had disease progression during or following first-line metastatic treatment with chemotherapy.

The study will be performed in two stages. During Stage 1, participants will be randomized to capecitabine (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 doublet 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.


Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: Capecitabine Drug: Atezolizumab Drug: Ipatasertib Drug: SGN-LIV1A Drug: Bevacizumab Drug: Cobimetinib Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin) Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 260 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 30, 2018
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : August 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Capecitabine

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

Drug: Capecitabine
Capecitabine will be administered 1250 mg/m2 orally twice daily on Days 1−14, of each 21 day cycle

Experimental: Atezolizumab + Ipatasertib

Participants will receive doublet combination treatment with atezolizumab + Capecitabine 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

Drug: Atezolizumab

For Atezolizumab + SGN-LIV1A, Bevacizumab, Capecitabine, or Chemo arms: Atezolizumab will be administered by IV, 1200 mg, on Day 1 of each 21-day cycle.

For Atezolizumab + Bevacizumab+ Cobimetinib, or + Ipatasertib arms: Atezolizumab will be administered by 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

Experimental: Atezolizumab + SGN-LIV1A

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

Drug: Atezolizumab

For Atezolizumab + SGN-LIV1A, Bevacizumab, Capecitabine, or Chemo arms: Atezolizumab will be administered by IV, 1200 mg, on Day 1 of each 21-day cycle.

For Atezolizumab + Bevacizumab+ Cobimetinib, or + Ipatasertib arms: Atezolizumab will be administered by IV, 840 mg on Days 1 and 15, of each 28 day cycle


Drug: SGN-LIV1A
SGN-LIV1A will be administered by IV, 2.5 mg/kg (maximum calculated dose 200 mg), on Day 1 of each 21 day cycle

Experimental: Atezolizumab + Bevacizumab
Participants will receive doublet combination treatment with atezolizumab plus 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
Drug: Atezolizumab

For Atezolizumab + SGN-LIV1A, Bevacizumab, Capecitabine, or Chemo arms: Atezolizumab will be administered by IV, 1200 mg, on Day 1 of each 21-day cycle.

For Atezolizumab + Bevacizumab+ Cobimetinib, or + Ipatasertib arms: Atezolizumab will be administered by IV, 840 mg on Days 1 and 15, of each 28 day cycle


Drug: Bevacizumab
When given as a doublet combination, Bevacizumab will be administered by IV, 15 mg/kg, on Day 1 of each 21 day cycle. When given as a triplet combination, Bevacizumab will be administered by IV, 10 mg/kg, on Days 1 and 15 of each 28 day cycle.

Experimental: Atezolizumab + Bevacizumab + Cobimetinib

Participants will receive doublet combination treatment with atezolizumab + Bevacizumab + Cobimetinib 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

Drug: Atezolizumab

For Atezolizumab + SGN-LIV1A, Bevacizumab, Capecitabine, or Chemo arms: Atezolizumab will be administered by IV, 1200 mg, on Day 1 of each 21-day cycle.

For Atezolizumab + Bevacizumab+ Cobimetinib, or + Ipatasertib arms: Atezolizumab will be administered by IV, 840 mg on Days 1 and 15, of each 28 day cycle


Drug: Bevacizumab
When given as a doublet combination, Bevacizumab will be administered by IV, 15 mg/kg, on Day 1 of each 21 day cycle. When given as a triplet combination, Bevacizumab will be administered by IV, 10 mg/kg, on Days 1 and 15 of each 28 day cycle.

Drug: Cobimetinib
Cobimetinib will be administered orally, once per day, 60 mg, on Days 1-21 of a 28-day cycle.

Experimental: Atezolizumab + Capecitabine

Participants will receive doublet combination treatment with atezolizumab + Capecitabine 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

Drug: Capecitabine
Capecitabine will be administered 1250 mg/m2 orally twice daily on Days 1−14, of each 21 day cycle

Drug: Atezolizumab

For Atezolizumab + SGN-LIV1A, Bevacizumab, Capecitabine, or Chemo arms: Atezolizumab will be administered by IV, 1200 mg, on Day 1 of each 21-day cycle.

For Atezolizumab + Bevacizumab+ Cobimetinib, or + Ipatasertib arms: Atezolizumab will be administered by IV, 840 mg on Days 1 and 15, of each 28 day cycle


Experimental: Atezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin)
Participants will 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.
Drug: Atezolizumab

For Atezolizumab + SGN-LIV1A, Bevacizumab, Capecitabine, or Chemo arms: Atezolizumab will be administered by IV, 1200 mg, on Day 1 of each 21-day cycle.

For Atezolizumab + Bevacizumab+ Cobimetinib, or + Ipatasertib arms: Atezolizumab will be administered by IV, 840 mg on Days 1 and 15, of each 28 day cycle


Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin)

Gemcitabine will be administered by IV, 1000 mg/m2, 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/m2 on days 1 and 8 of each 21 day cycle





Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Baseline until disease progression or loss of clinical benefit ( approximately 4 years) ]

Secondary Outcome Measures :
  1. 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 ]
  2. Disease Control Rate (DCR) [ Time Frame: Baseline through end of study (approximately 4 years) ]
  3. Overall Survival (OS) [ Time Frame: Randomization to death from any cause, through the end of study (approximately 4 years) ]
  4. Overall Survival (at specific time-points) [ Time Frame: 12 and 18 months ]
  5. 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) ]
  6. Percentage of Participants with Adverse Events [ Time Frame: Baseline to end of study (approximately 4 years) ]
  7. 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 ]
  8. Plasma Concentration of Ipatasertib [ Time Frame: Day 15, Cycle 1 pre treatment and 1-3 hours after Ipatasertib dose; ]
  9. Plasma or Serum Concentration of SNG-LIV1A [ Time Frame: Day 1 Cycle, 1 pre-treatment and 30 minutes after SGN-LIV1A infusion ]
  10. Plasma Concentration of Cobimetinib [ Time Frame: Day 15, Cycle 1 Pre- Cobimetinib dose and 2-4 hours after Cobimetinib dose ]
  11. Plasma Concentration of Capecitabine [ Time Frame: Day 1, Cycle 1, 2 hours after capecitabine dose ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria Stage 1

  • ECOG Performance Status of 0 or 1
  • Metastatic or locally advanced, histologically documented TNBC (absence of HER2, ER, and PR expression)
  • Radiologic/objective evidence of recurrence or disease progression after one line of chemotherapy for metastatic breast cancer MBC
  • Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status via central testing
  • Eligible for capecitabine monotherapy
  • 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 .
  • Negative hepatitis C virus (HCV) antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening

Inclusion Criteria for Stage 1 and Stage 2

  • Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
  • Tumor accessible for biopsy
  • For patients receiving therapeutic anticoagulation: stable anticoagulant regimen during the 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 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

  • 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 (see Section 3.1.1.1 for details) 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 any of the protocol-specified study treatments
  • Treatment with investigational therapy within 28 days prior to initiation of study treatment
  • Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
  • Treatment with sorivudine or its chemically related analogues, such as brivudine
  • History of severe and unexpected reactions to fluoropyrimidine therapy

Exclusion Criteria for Stage 1 and Stage 2

  • 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03424005


Contacts
Contact: Reference Study ID Number: CO40115 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
United States, California
University of California San Diego Medical Center; Moores Cancer Center Not yet recruiting
La Jolla, California, United States, 92093
United States, Florida
H. Lee Moffitt Cancer Center and Research Inst. Not yet recruiting
Tampa, Florida, United States, 33612
United States, New Jersey
Hackensack Univ Medical Center; John Theurer Cancer Ctr Recruiting
Hackensack, New Jersey, United States, 07601
Rutgers Cancer Institute of New Jersey Not yet recruiting
New Brunswick, New Jersey, United States, 08901
United States, New York
NYU Langone Medical Center; NYU Perlmutter Cancer Center Recruiting
New York, New York, United States, 10016
United States, Pennsylvania
Thomas Jefferson University Hospital Not yet recruiting
Philadelphia, Pennsylvania, United States, 19107
University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
The West Clinic; West Cancer Center Recruiting
Germantown, Tennessee, United States, 38138
Australia, Victoria
Peter MacCallum Cancer Centre-East Melbourne Recruiting
Melbourne, Victoria, Australia, 3000
France
Centre Léon Bérard Not yet recruiting
Lyon, France, 69008
Institut Universitaire du Cancer de Toulouse-Oncopole Recruiting
Toulouse, France, 31059
Gustave Roussy Not yet recruiting
Villejuif CEDEX, France, 94800
Germany
Universitätsklinikum Erlangen; Frauenklinik Not yet recruiting
Erlangen, Germany, 91054
Universitätsklinikum Essen Not yet recruiting
Essen, Germany, 45147
Korea, Republic of
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 03080
Severance Hospital Recruiting
Seoul, Korea, Republic of, 03722
University of Ulsan College of Medicine - Asan Medical Center Recruiting
Seoul, Korea, Republic of, 05505
Spain
Vall d´Hebron Institute of Oncology (VHIO), Barcelona Recruiting
Barcelona, Spain, 08035
Hospital Universitario Ramón y Cajal Recruiting
Madrid, Spain, 28034
Centro Integral Oncológico Clara Campal Ensayos Clínicos START Recruiting
Madrid, Spain, 28050
United Kingdom
Beatson West of Scotland Cancer Centre Not yet recruiting
Glasgow, United Kingdom, G12 0YN
Barts Health NHS Trust - St Bartholomew's Hospital Recruiting
London, United Kingdom, EC1A 7BE
Sponsors and Collaborators
Hoffmann-La Roche
Seattle Genetics, Inc.
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03424005     History of Changes
Other Study ID Numbers: CO40115
2017-002038-21 ( EudraCT Number )
First Posted: February 6, 2018    Key Record Dates
Last Update Posted: September 7, 2018
Last Verified: September 2018

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

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Gemcitabine
Capecitabine
Atezolizumab
Bevacizumab
Carboplatin
Antibodies, Monoclonal
Immunoconjugates
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors