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Multiple MyelomaPhase 1/2NCT03312530

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

A Phase 1/2 study testing Cobimetinib, Venetoclax and Atezolizumab in people with Multiple Myeloma, run by Hoffmann-La Roche at 26 sites in 9 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Multiple Myeloma
What is being tested?
Cobimetinib, Venetoclax and Atezolizumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
49 participants
Where
26 sitesin 9 countries
Study dates
13 Nov 2017to 18 May 2021
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 24Show fewer
  • 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

Trial locations and contacts

26 sites in 9 countries.

26 sites in 9 countries

Spain5 sites

  • Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia

    Badalona, Barcelona, 08915

  • Hospital Clinic de Barcelona

    Barcelona, 08036

  • Hospital Universitario de la Princesa

    Madrid, 28006

  • Hospital Univ 12 de Octubre

    Madrid, 28041

  • Clínica Universidad de Navarra

    Pamplona, Navarre, 31620

Other trials in Spain

France4 sites

  • CHU - Hôtel Dieu hematolgie clinique

    Nantes, 44093

  • Hôpital Saint-Louis

    Paris, 75475

  • CHU Lyon - Centre Hospitalier Lyon Sud

    Pierre-Benite (Lyon), 69495

  • IGR

    Villejuif, 94800

Other trials in France

Germany4 sites

  • UNI-Klinikum Heidelberg Medizinische Klinik Innere Medizin V

    Heidelberg, 69120

  • Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik

    Mainz, 55131

  • Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II

    Tübingen, 72076

  • Universtitätsklinikum Ulm; Klinik für Innere Medizin III

    Ulm, 89081

Other trials in Germany

Czechia3 sites

  • Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika

    Brno, 625 00

  • Fakultni nemocnice Ostrava; Klinika hematoonkologie

    Ostrava, 708 52

  • Univerzita Karlova v Praze a Vseobecna fakultni nemocnice v Praze - 1; Lekarska Fakulta - I

    Prague, 128 08

Other trials in Czechia

Poland3 sites

  • Medical University School; Dept. of Haematology

    Lodz, 93-510

  • Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu

    Późna, 60-569

  • Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology

    Warsaw, 02-781

Other trials in Poland

Denmark2 sites

  • Rigshospitalet; Hæmatologisk Klinik

    København Ø, 2100

  • Odense Universitetshospital

    Odense C, 5000

Other trials in Denmark

Netherlands2 sites

  • Amsterdam UMC Location AMC

    Amsterdam, 1105 AZ

  • Universitair Medisch Centrum Utrecht

    Utrecht, 3584 CX

Other trials in Netherlands

Norway2 sites

  • Førde sentralsjukehus

    Førde, 6800

  • Oslo University Hospital HF, Rikshospitalet

    Oslo, 0424

Other trials in Norway

Sweden1 site

  • Skånes Universitetssjukhus

    Lund, 221 85

Other trials in Sweden

About this study

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

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).

Being tested
Cobimetinib, Venetoclax, Atezolizumab
Medical subject headings
Multiple Myeloma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CobimetinibDrug

    Also called Cotellic®

    Cobimetinib will be administered as per the schedule specified in the respective arm.

  • VenetoclaxDrug

    Also called GDC-0199, ABT-199

    Venetoclax will be administered as per the schedule specified in the respective arm.

  • AtezolizumabDrug

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

Study groups in NCT03312530
Study groupRoleWhat they receive
A: CobimetinibExperimentalParticipants 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.
Receives: Drug: Cobimetinib; Drug: Atezolizumab
B: Cobimetinib + VenetoclaxExperimentalParticipants 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.
Receives: Drug: Cobimetinib; Drug: Venetoclax
C: Cobimetinib + Venetoclax + AtezolizumabExperimentalParticipants 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.
Receives: Drug: Cobimetinib; Drug: Venetoclax; Drug: Atezolizumab
Safety Run-In: Cobimetinib + VenetoclaxExperimentalParticipants 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.
Receives: Drug: Cobimetinib; Drug: Venetoclax
Safety Run-In: Cobimetinib + Venetoclax + AtezolizumabExperimentalParticipants 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.
Receives: Drug: Cobimetinib; Drug: Venetoclax; Drug: Atezolizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With Adverse Events (AEs)

    An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the treatment. An AE was therefore any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. New or pre-existing conditions which worsened during the study were also considered AEs.

    Measured: Randomization up to end of study (up to approximately 3 years, 7 months)

  2. Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria

    ORR was defined as a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) and was analyzed in the safety evaluable population and in the biomarker-selected sub-populations of t(11;14) and RAS mutations.

    Measured: From randomization to the first occurrence of a response as defined above (up to approximately 3 years, 7 months)

Secondary outcomes (11)

  1. Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria

    Clinical benefit rate (CBR) was defined as a minimal response (MR) or better (PR,VGPR, CR, sCR).

    Measured: From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 3 years, 7 months)

  2. Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria

    PFS was defined as the time from randomization (for randomized participants) or first treatment date (for non-ranomized participants) to the first occurrence of disease progression or relapse as determined by the investigator using the IMWG criteria or death from any cause during the study, whichever occurred first.

    Measured: From enrollment or first treatment date to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 3 years, 7 months)

  3. Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria

    DOR was applicable to participants who achieved at least a PR, and was measured from the first observation of PR or better to the time of disease progression.

    Measured: Time from the first observation of partial response (PR) or better to the time of disease progression (up to approximately 3 years, 7 months)

  4. Overall Survival (OS)

    OS was defined as the time from randomization until death from any cause.

    Measured: From randomization until death from any cause (up to approximately 3 years, 7 months)

  5. Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib

    AUC0-24hr area under the plasma concentration-time curve from time 0 to 24 hrs

    Measured: 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

    Cmax is the maximum observed plasma concentration at steady state.

    Measured: 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

    Tmax is the time to reach Cmax.

    Measured: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

  8. AUClast of Venetoclax

    AUClast=area under the plasma concentration-time curve (samples collected to 8hr postdose on C1D15)

    Measured: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

  9. Cmax of Venetoclax

    Cmax is the maximum observed plasma concentration at steady state.

    Measured: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

  10. Tmax of Venetoclax

    Tmax is the time to reach Cmax.

    Measured: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

  11. Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab

    Measured: Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 3 years, 7 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Oct 2017
  2. Study start13 Nov 2017
  3. Primary completion18 May 2021
  4. Study completion18 May 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
49 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03312530
Sponsor's protocol ID
BO39813
Other IDs
2017-000830-68, 2017
Status last verified
Feb 2023
First submitted
12 Oct 2017
Last updated
28 Feb 2023
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Schjesvold F, Paiva B, Ribrag V, Rodriguez-Otero P, San-Miguel JF, Robak P, Hansson M, Onishi M, Hamidi H, Malhi V, Dail M, Javery A, Ku G, Raab MS. Cobimetinib Alone and Plus Venetoclax With/Without Atezolizumab in Patients With Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2023 Jan;23(1):e59-e70. doi: 10.1016/j.clml.2022.10.006. Epub 2022 Oct 22.

    PubMed 36450626

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Cobimetinib, Venetoclax and Atezolizumab in people with Multiple Myeloma, run by Hoffmann-La Roche at 26 sites in 9 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 26 sites in Spain, France, Germany, Czechia, Poland and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Adverse Events (AEs) (time frame: Randomization up to end of study (up to approximately 3 years, 7 months)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03312530, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2023; AzTrials last refreshed its copy on 6 Nov 2026.

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