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A Phase 1b Study of Atezolizumab in Combination With Vemurafenib or Vemurafenib Plus Cobimetinib in Participants With BRAFV600-Mutation Positive Metastatic Melanoma

NCT01656642

Description:

This is an open-label, multicenter, Phase Ib, dose-escalation and cohort-expansion study of atezolizumab (anti-programmed death-ligand 1 [PD-L1] antibody) in combination with vemurafenib or vemurafenib plus cobimetinib in participants with BRAFV600-mutation positive metastatic melanoma. Enrolled participants may continue treatment until they are no longer experiencing clinical benefit as assessed by the investigator and in alignment with the protocol.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

A <span class="go-doc-concept go-doc-intervention">Phase 1b</span> Study of <span class="go-doc-concept go-doc-intervention">Atezolizumab</span> in Combination With Vemurafenib or Vemurafenib Plus <span class="go-doc-concept go-doc-intervention">Cobimetinib</span> in Participants With BRAFV600-<span class="go-doc-concept go-doc-keyword">Mutation</span> Positive Metastatic <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: A Phase 1b Study of Atezolizumab in Combination With Vemurafenib or Vemurafenib Plus Cobimetinib in Participants With BRAFV600-Mutation Positive Metastatic Melanoma
  • Official Title: A Phase Ib, Open-Label Study of The Safety and Pharmacology of Atezolizumab (Anti PD-L1 Antibody) Administered in Combination With Vemurafenib or Vemurafenib Plus Cobimetinib in Patients With BRAFV600-Mutation Positive Metastatic Melanoma
  • Clinical Trial IDs

    NCT ID: NCT01656642

    ORG ID: GP28384

    NCI ID: 2012-002738-35

    Trial Conditions

    Malignant Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Atezolizumab MPDL3280A, an engineered anti-PD-L1 antibody C1: Ate+ Vem - No Run-in, C2: Ate + Vem (56 Day Run-in), C3: Ate + Vem (28 Day Run-in), C4: Ate + Vem + Cob (28 Day Run-in), ECA: Ate + Vem + Cob (Mandatory Biopsy PD), ECB: Ate + Vem + Cob (Mandatory Biopsy), ECC: Ate + Vem + Cob (No Mandatory Biopsy)
    Cobimetinib GDC-0973; XL518, Cotellic C4: Ate + Vem + Cob (28 Day Run-in), ECA: Ate + Vem + Cob (Mandatory Biopsy PD), ECB: Ate + Vem + Cob (Mandatory Biopsy), ECC: Ate + Vem + Cob (No Mandatory Biopsy)
    Vemurafenib Zelboraf C1: Ate+ Vem - No Run-in, C2: Ate + Vem (56 Day Run-in), C3: Ate + Vem (28 Day Run-in), C4: Ate + Vem + Cob (28 Day Run-in), ECA: Ate + Vem + Cob (Mandatory Biopsy PD), ECB: Ate + Vem + Cob (Mandatory Biopsy), ECC: Ate + Vem + Cob (No Mandatory Biopsy)

    Trial Purpose

    This is an open-label, multicenter, Phase Ib, dose-escalation and cohort-expansion study of
    atezolizumab (anti-PD-L1 antibody) in combination with vemurafenib or vemurafenib plus
    cobimetinib in participants with BRAFV600-mutation positive metastatic melanoma. Enrolled
    participants may continue treatment until they are no longer experiencing clinical benefit
    as assessed by the investigator and in alignment with the protocol.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    C1: Ate+ Vem - No Run-in Experimental Cohort 1 (C1): Participants will receive atezolizumab (Ate) 1200 milligrams (mg) every 3 weeks (q3w) along with vemurafenib (Vem) 750 mg QD for 21 days in each cycle followed by 7 days off treatment (28-day cycle). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent occurs. Atezolizumab, Vemurafenib
    C2: Ate + Vem (56 Day Run-in) Experimental Run-in period (56 days): participants will receive vemurafenib 960 mg orally twice daily from day 1 to 49 and vemurafenib 720 mg orally twice daily from day 50 to 56. Combination treatment period: Participants will receive fixed dose of atezolizumab 1200 mg IV q3w in combination with vemurafenib 720 mg orally twice daily in 21 days cycle. Atezolizumab, Vemurafenib
    C3: Ate + Vem (28 Day Run-in) Experimental Run-in period (28 days): participants will receive vemurafenib 960 mg orally twice daily for 21 days, then vemurafenib 720 mg orally twice daily for 7 days. Combination treatment period: Participants will receive fixed dose of atezolizumab 1200 mg IV q3w in combination with vemurafenib 720 mg orally twice daily in 21 days cycle. Atezolizumab, Vemurafenib
    C4: Ate + Vem + Cob (28 Day Run-in) Experimental Run-in period (28 days): participants will receive vemurafenib 960 mg orally twice daily for 21 days, then vemurafenib 720 mg orally twice daily for 7 days in combination with cobimetinib (Cob) 60 mg IV once daily, 21 days on/7 days off schedule (21/7). Combination treatment period: Participants will receive fixed dose of atezolizumab 800 mg IV q2w in combination with vemurafenib 720 mg orally twice daily and cobimetinib 60 mg orally once daily 21/7 in 28 days cycle. Atezolizumab, Cobimetinib, Vemurafenib
    ECA: Ate + Vem + Cob (Mandatory Biopsy PD) Experimental Expansion cohort A (ECA): Approximately 10 participants who experienced disease progression (PD) after receiving prior checkpoint inhibitor therapy will be enrolled and treated with atezolizumab + vemurafenib + cobimetinib. Serial biopsy tissue sample collections of accessible lesions will be mandatory for all participants enrolled in this cohort. The doses will be decided based on the results of Cohorts 1-4. Atezolizumab, Cobimetinib, Vemurafenib
    ECB: Ate + Vem + Cob (Mandatory Biopsy) Experimental Approximately 20 participants will be enrolled and treated with atezolizumab + vemurafenib + cobimetinib. Serial biopsy tissue sample collections of accessible lesions will be mandatory for all participants. The doses will be decided based on the results of Cohorts 1-4. Atezolizumab, Cobimetinib, Vemurafenib
    ECC: Ate + Vem + Cob (No Mandatory Biopsy) Experimental Approximately 10 participants who experienced disease progression after receiving prior checkpoint inhibitor therapy will be enrolled and treated with atezolizumab + vemurafenib + cobimetinib. Serial biopsy tissue sample collections will be optional for all participants enrolled in this cohort. The doses will be decided based on the results of Cohorts 1-4. Atezolizumab, Cobimetinib, Vemurafenib

    Eligibility Criteria

    Inclusion Criteria:

    - Histologic or cytologic documentation of metastatic or Stage IIIc unresectable
    melanoma, with BRAFV600 mutation as assessed by BRAF V600 Mutation Test. Origin of
    the primary tumor may be of skin, mucosal, or acral locations but not of uveal
    origin. Participants having an unknown primary tumor may be eligible if uveal
    melanoma can be ruled out

    - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

    - Adequate hematologic and end organ function

    - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version
    1.1

    - For women of childbearing potential, agreement to remain abstinent (refrain from
    heterosexual intercourse) or use 2 effective forms of contraceptive methods including
    at least 1 that results in a failure rate of less than (<) 1 percent (%) per year
    during the treatment period and for at least 6 months after the last dose of study
    drug

    - For men, agreement to remain abstinent (refrain from heterosexual intercourse) or use
    2 contraceptive measures, and agreement to refrain from donating sperm

    - Agreement to mandatory archival tissue or fresh biopsy

    - Agreement to the collection of serial fresh lesion samples (required, if feasible,
    for entry into Escalation Cohorts 4 and expansion cohorts and optional, but
    encouraged in Escalation Cohorts 2 & 3)

    Exclusion Criteria:

    - Receipt of prior systemic anti-cancer therapy for unresectable, locally advanced or
    metastatic melanoma

    - Receipt of prior immunomodulatory agents, including programmed death-1 (PD)-1 or
    programmed death-ligand 1 (PD-L1) targeted therapy or cytotoxic
    T-lymphocyte-associated antigen 4 (CTLA-4) targeted therapy, including ipilimumab
    (this exclusion criterion does not apply to patients enrolled in Expansion Cohort A)

    - Receipt of prior mitogen-activated protein kinase (MAPK) inhibitor pathway agents,
    including mitogen-activated protein kinase (MEK) kinase inhibitor and BRAF kinase
    inhibitor

    - Major surgical procedure within 28 days prior to Day 1 or anticipation of need for a
    major surgical procedure during the course of the study

    - Radiotherapy less than or equal to (<=) 7 days prior to Day 1

    - Adverse events from prior anti-cancer therapy that have not resolved to Grade <= 1
    except for alopecia

    - Any active malignancy (other than BRAF-mutated melanoma) or a previous malignancy
    within the past 3 years

    - For participants to be enrolled into the vemurafenib+cobimetinib+ atezolizumab
    cohorts: history of or evidence of retinal pathology on ophthalmologic examination
    that is considered a risk factor for neurosensory retinal detachment/central serous
    chorioretinopathy, retinal vein occlusion, or neovascular macular degeneration

    - Pregnant or breastfeeding women

    - Intake of St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme
    inducer) or grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor) within
    7 days prior to initiation of study treatment

    - Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells
    or any component of the atezolizumab formulation or known hypersensitivity to any
    component of cobimetinib or vemurafenib

    - Inability to comply with study and follow-up procedures

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Percentage of Participants With Dose Limiting Toxicities (DLT)

    Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Secondary Outcome Measures

    Area Under the Concentration-Time Curve (AUC) of Atezolizumab

    Maximum Serum Concentration (Cmax) of Atezolizumab

    Minimum Observed Serum Trough Concentration (Cmin) of Atezolizumab

    Maximum Plasma Concentration (Cmax) of Vemurafenib

    Minimum Observed Plasma Trough Concentration (Cmin) of Vemurafenib

    Maximum Plasma Concentration (Cmax) of Cobimetinib

    Minimum Observed Plasma Trough Concentration (Cmin) of Cobimetinib

    Percentage of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST)

    Percentage of Participants with Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST)

    Duration of Objective Response According to RECIST

    Overall Survival (OS) Duration

    Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST)

    Mean Atezolizumab Dose

    Percentage of Participants With Anti-Atezolizumab Antibodies

    Total Number of Atezolizumab Cycles

    Trial Keywords

    PD-L1

    PD-1

    PDL1

    antiPD-L1

    MPDL3280A

    Melanoma

    BRAF

    MPDL320A