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

Multiple Myeloma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03312530
• Other study ID #: BO39813
• Secondary ID: 2017-000830-68
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 13, 2017
• Est. completion date: May 18, 2021

Study information

• Verified date: February 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 49
• Est. completion date: May 18, 2021
• Est. primary completion date: May 18, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

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

Locations

Country	Name	City	State
Czechia	Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika	Brno
Czechia	Fakultni nemocnice Ostrava; Klinika hematoonkologie	Ostrava
Czechia	Univerzita Karlova v Praze a Vseobecna fakultni nemocnice v Praze - 1; Lekarska Fakulta - I	Prague 2
Denmark	Rigshospitalet; Hæmatologisk Klinik	København Ø
Denmark	Odense Universitetshospital	Odense C
France	CHU - Hôtel Dieu hematolgie clinique	Nantes
France	Hôpital Saint-Louis	Paris
France	CHU Lyon - Centre Hospitalier Lyon Sud	Pierre-Benite (Lyon)
France	IGR	Villejuif
Germany	UNI-Klinikum Heidelberg Medizinische Klinik Innere Medizin V	Heidelberg
Germany	Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik	Mainz
Germany	Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II	Tübingen
Germany	Universtitätsklinikum Ulm; Klinik für Innere Medizin III	Ulm
Netherlands	Amsterdam UMC Location AMC	Amsterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Norway	Førde sentralsjukehus	Førde
Norway	Oslo University Hospital HF, Rikshospitalet	Oslo
Poland	Medical University School; Dept. of Haematology	Lodz
Poland	Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu	Pozna?
Poland	Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology	Warszawa
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Univ 12 de Octubre	Madrid
Spain	Hospital Universitario de la Princesa	Madrid
Spain	Clínica Universidad de Navarra	Pamplona	Navarra
Sweden	Skånes Universitetssjukhus	Lund

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Czechia,  Denmark,  France,  Germany,  Netherlands,  Norway,  Poland,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Randomization up to end of study (up to approximately 3 years, 7 months)
Primary	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.	From randomization to the first occurrence of a response as defined above (up to approximately 3 years, 7 months)
Secondary	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).	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)
Secondary	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.	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)
Secondary	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.	Time from the first observation of partial response (PR) or better to the time of disease progression (up to approximately 3 years, 7 months)
Secondary	Overall Survival (OS)	OS was defined as the time from randomization until death from any cause.	From randomization until death from any cause (up to approximately 3 years, 7 months)
Secondary	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	Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary	Maximum Observed Plasma Concentration (Cmax) of Cobimetinib	Cmax is the maximum observed plasma concentration at steady state.	Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary	Time to Reach Cmax (Tmax) of Cobimetinib	Tmax is the time to reach Cmax.	Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary	AUClast of Venetoclax	AUClast=area under the plasma concentration-time curve (samples collected to 8hr postdose on C1D15)	Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary	Cmax of Venetoclax	Cmax is the maximum observed plasma concentration at steady state.	Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary	Tmax of Venetoclax	Tmax is the time to reach Cmax.	Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary	Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab		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)