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A Study of Cobimetinib Administered as Single Agent and in Combination With Venetoclax, With or Without Atezolizumab, in Participants With Relapsed and Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03312530
Recruitment Status : Recruiting
First Posted : October 17, 2017
Last Update Posted : May 11, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This open-label, randomized, multicenter, triple-arm Phase Ib/II study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics of cobimetinib administered as a single agent (Arm A), cobimetinib plus venetoclax (Arm B), and cobimetinib plus venetoclax plus atezolizumab (Arm C) in participants with relapsed and refractory multiple myeloma. Two successive cohorts will evaluate the safety of cobimetinib plus venetoclax and that of cobimetinib plus venetoclax plus atezolizumab in the selected population during the safety run-in phase of the study. Once the dose levels have demonstrated acceptable safety during this phase, randomization will begin for all treatment arms (Arms A, B, and C).

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Cobimetinib Drug: Venetoclax Drug: Atezolizumab Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of Cobimetinib Administered as Single Agent and in Combination With Venetoclax, With or Without Atezolizumab, in Patients With Relapsed and Refractory Multiple Myeloma
Actual Study Start Date : November 13, 2017
Estimated Primary Completion Date : October 28, 2020
Estimated Study Completion Date : October 28, 2020


Arm Intervention/treatment
Experimental: A: Cobimetinib
Participants will receive the standard single-agent cobimetinib dose of 60 milligrams (mg) (3 tablets of 20 mg each) orally (PO) daily on Days 1-21 of each 28-day cycle until disease progression. Upon progression, participants will be allowed to receive treatment with cobimetinib and atezolizumab at the recommended Phase II dose of cobimetinib 60 mg PO on Days 1-21 plus atezolizumab intravenous (IV) infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Name: Cotellic®

Drug: Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.

Experimental: B: Cobimetinib + Venetoclax
Participants will receive cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Name: Cotellic®

Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Name: GDC-0199, ABT-199

Experimental: C: Cobimetinib + Venetoclax + Atezolizumab
Participants will receive cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase plus atezolizumab IV infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Name: Cotellic®

Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Name: GDC-0199, ABT-199

Drug: Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.

Experimental: Safety Run-In: Cobimetinib + Venetoclax
Participants will receive cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses, in 28-day cycles, to identify the dose level with acceptable safety.
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Name: Cotellic®

Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Name: GDC-0199, ABT-199

Experimental: Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab
Participants will receive cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses and atezolizumab (on Day 1 and Day 15) at a fixed dose of 840 mg IV, in 28-day cycles, to identify the dose level with acceptable safety.
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Name: Cotellic®

Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Name: GDC-0199, ABT-199

Drug: Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.




Primary Outcome Measures :
  1. Percentage of Participants With Adverse Events (AEs) [ Time Frame: Randomization up to end of study (up to approximately 24 months) ]
  2. Percentage of Participants With Overall Response as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria [ Time Frame: From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 24 months) ]

Secondary Outcome Measures :
  1. Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 24 months) ]
  2. Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 24 months) ]
  3. Duration of Response as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: Time from the first observation of partial response (PR) to the time of disease progression (up to approximately 24 months) ]
  4. Overall Survival [ Time Frame: From randomization until death from any cause (up to approximately 24 months) ]
  5. Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib [ Time Frame: Arm A: 2-4 hours(hrs) post-dose on Day 1 of Cycle 1; predose(within 1 hr),2-4 hrs post-dose on Day 15 of Cycle 1; Arm B and C: 2-4 hrs post-dose on Day 1 of Cycle 1; pre-dose(within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1(cycle length: 28 days) ]
  6. Maximum Observed Plasma Concentration (Cmax) of Cobimetinib [ Time Frame: Arm A: 2-4 hrs post-dose on Day 1 of Cycle 1; predose (within 1 hr), 2-4 hrs post-dose on Day 15 of Cycle 1; Arm B and C: 2-4 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]
  7. Time to Reach Cmax (Tmax) of Cobimetinib [ Time Frame: Arm A: 2-4 hrs post-dose on Day 1 of Cycle 1; predose (within 1 hr), 2-4 hrs post-dose on Day 15 of Cycle 1; Arm B and C: 2-4 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]
  8. AUC of Venetoclax [ Time Frame: 6 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1; pre-dose (within 1 hr) on Day 1 of Cycles 2, 3 (cycle length: 28 days) ]
  9. Cmax of Venetoclax [ Time Frame: 6 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1; pre-dose (within 1 hr) on Day 1 of Cycles 2, 3 (cycle length: 28 days) ]
  10. Tmax of Venetoclax [ Time Frame: 6 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1; pre-dose (within 1 hr) on Day 1 of Cycles 2, 3 (cycle length: 28 days) ]
  11. Cmax of Atezolizumab [ Time Frame: Pre-infusion (0 hr), 0.5 hr post-infusion (infusion duration: 1 hr) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycle 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 24 months) ]
  12. Minimum Observed Serum Concentration (Cmin) of Atezolizumab [ Time Frame: Pre-infusion (0 hr), 0.5 hr post-infusion (infusion duration: 1 hr) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycle 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 24 months) ]
  13. Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab [ Time Frame: Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 24 months) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Life expectancy of at least 12 weeks
  • Documented multiple myeloma
  • Received 3 to 5 prior lines of therapy for multiple myeloma, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD)
  • Achieved a response (minimal response [MR] or better) to at least one prior regimen
  • Documented evidence of progressive disease (as defined by the IMWG criteria) on or after their last prior therapy, or participants who were intolerant to their last prior therapy
  • Toxicities resulting from previous therapy (including peripheral neuropathy) that must be resolved or stabilized to Grade 1

Exclusion Criteria:

  • Anti-myeloma treatment within 14 days or 5 pharmacokinetic (PK) half-lives of the treatment, whichever is longer, before the date of randomization
  • Completion of autologous stem cell transplant within 100 days prior to the date of randomization
  • Prior allogeneic stem cell transplant as well as prior solid organ transplant
  • Spinal cord compression not definitively treated with surgery and/or radiation
  • Prior treatment with MEK inhibitors, B-cell lymphoma-2 (Bcl-2) inhibitors, or immune checkpoint inhibitor therapies including anti-cytotoxic T-lymphocyte associated protein-4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1) or anti-programmed death-ligand 1 (anti-PD-L1)
  • Treatment with systemic immunostimulatory agents within 28 days or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
  • Treatment with systemic immunosuppressive medication within 14 days prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study
  • Prior radiation therapy within 14 days prior to study enrollment and/or persistence of radiation-related adverse effects
  • History or evidence of retinal pathology on ophthalmic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
  • Left ventricular ejection fraction (LVEF) below institutional lower limit of normal
  • History of clinically significant cardiovascular dysfunction
  • Any previous venous thromboembolism greater than (>) Grade 3 within 12 months of study enrollment
  • History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins (for participants in Arm C only)
  • History of other malignancy that could affect compliance with the protocol or interpretation of results
  • Active or history of autoimmune disease or immune deficiency
  • History of malabsorption or other condition that would interfere with absorption of study drugs
  • Active tuberculosis
  • Severe infection within 28 days prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Treatment with therapeutic oral or IV antibiotics within 14 days prior to initiation of study treatment
  • Positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] and/or total hepatitis B core antibody [HBcAb]) or hepatitis C virus (HCV) antibody
  • Known history of human immunodeficiency virus (HIV) seropositivity
  • Treatment with a live, attenuated influenza vaccine (e.g., FluMist) within 28 days prior to Cycle 1 Day 1, at any time during the study, and for at least 5 months after the last dose of study drug (for participants in Arm C only)
  • Received strong cytochrome P-3A (CYP3A) inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers, and moderate CYP3A inducers within 7 days prior to the initiation of study treatment

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): NCT03312530


Contacts
Contact: Reference Study ID Number: BO39813 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
Czechia
Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika Not yet recruiting
Brno, Czechia, 625 00
Fakultni nemocnice Ostrava; Klinika hematoonkologie Recruiting
Ostrava, Czechia, 708 52
Univerzita Karlova v Praze a Vseobecna fakultni nemocnice v Praze - 1; Lekarska Fakulta - I Recruiting
Prague 2, Czechia, 128 08
Denmark
Righospitalet, Haematologisk Klinik Recruiting
Kobenhavn, Denmark, 2100
Odense Universitetshospital Recruiting
Odense C, Denmark, 5000
France
CHU - Hôtel Dieu hematolgie clinique Recruiting
Nantes, France, 44093
Hôpital Saint-Louis Recruiting
Paris, France, 75475
CHU Lyon - Centre Hospitalier Lyon Sud Not yet recruiting
Pierre-Benite (Lyon), France, 69495
IGR Not yet recruiting
Villejuif, France, 94800
Germany
UNI-Klinikum Heidelberg Medizinische Klinik Innere Medizin V Recruiting
Heidelberg, Germany, 69120
Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik Not yet recruiting
Mainz, Germany, 55131
Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II Recruiting
Tübingen, Germany, 72076
Universtitätsklinikum Ulm; Klinik für Innere Medizin III Recruiting
Ulm, Germany, 89081
Netherlands
Academisch Medisch Centrum Not yet recruiting
Amsterdam, Netherlands, 1105 AZ
Universitair Medisch Centrum Utrecht Not yet recruiting
Utrecht, Netherlands, 3584 CX
Norway
Førde sentralsjukehus Recruiting
Førde, Norway, 6800
Oslo University Hospital HF, Rikshospitalet Recruiting
Oslo, Norway, 0424
Poland
Medical University School; Dept. of Haematology Recruiting
Lodz, Poland, 93-510
Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu Not yet recruiting
Poznań, Poland, 60-569
Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology Recruiting
Warszawa, Poland, 02-781
Gornoslaskie Centrum Medyczne Not yet recruiting
Wrocław, Poland, 50-367
Spain
Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia Recruiting
Badalona, Barcelona, Spain, 08915
Clínica Universidad de Navarra Recruiting
Pamplona, Navarra, Spain, 31620
Hospital Clinic de Barcelona Recruiting
Barcelona, Spain, 08036
Hospital Universitario de la Princesa Not yet recruiting
Madrid, Spain, 28006
Hospital Univ 12 de Octubre Recruiting
Madrid, Spain, 28041
Sweden
Sahlgrenska University Hospital Recruiting
Göteborg, Sweden, 413 45
Skånes Universitetssjukhus, Lund Recruiting
Lund, Sweden, 221 85
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03312530     History of Changes
Other Study ID Numbers: BO39813
2017-000830-68 ( EudraCT Number )
First Posted: October 17, 2017    Key Record Dates
Last Update Posted: May 11, 2018
Last Verified: May 2018

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

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Atezolizumab
Venetoclax
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs