Clinical Trials /

Atezolizumab With or Without Cobimetinib in Treating Patients With Metastatic Bile Duct Cancer That Cannot Be Removed by Surgery or Gallbladder Cancer

NCT03201458

Description:

This randomized phase II trial studies how well atezolizumab with or without cobimetinib works in treating patients with bile duct cancer that has spread to other places in the body and cannot be removed by surgery or gallbladder cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib may work better at treating patients with bile duct and gallbladder cancer.

Related Conditions:
  • Cholangiocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab With or Without Cobimetinib in Treating Patients With Metastatic Bile Duct Cancer That Cannot Be Removed by Surgery
  • Official Title: A Randomized Phase 2 Study of Atezolizumab in Combination With Cobimetinib Versus Atezolizumab Monotherapy in Participants With Unresectable Cholangiocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01127
  • SECONDARY ID: NCI-2017-01127
  • SECONDARY ID: ETCTN10139
  • SECONDARY ID: 10139
  • SECONDARY ID: 10139
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT03201458

Conditions

  • Non-Resectable Cholangiocarcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm A (atezolizumab)
CobimetinibCotellic, GDC-0973, MEK Inhibitor GDC-0973, XL518Arm B (atezolizumab, cobimetinib)

Purpose

This randomized phase II trial studies how well atezolizumab with or without cobimetinib works in treating patients with bile duct cancer that has spread to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib may work better at treating patients with bile duct cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the progression free survival (PFS) of patients receiving atezolizumab
      monotherapy and cobimetinib in combination with atezolizumab for unresectable
      cholangiocarcinoma.

      SECONDARY OBJECTIVES:

      I. To assess the overall survival (OS) of patients receiving cobimetinib in combination with
      atezolizumab and atezolizumab monotherapy for unresectable cholangiocarcinoma.

      II. To determine the objective response rate (ORR), defined as complete plus partial
      response, of cobimetinib in combination with atezolizumab and atezolizumab monotherapy in
      patients with unresectable cholangiocarcinoma.

      III. To assess the safety and tolerability of cobimetinib in combination with atezolizumab
      and atezolizumab monotherapy in patients with unresectable cholangiocarcinoma.

      IV. To determine the relationship between PD-L1 expression in tumor at baseline and on
      treatment, and response to treatment.

      TERTIARY OBJECTIVES:

      I. To determine the effect of cobimetinib on CD8+ T cell infiltration in tumor. II. To
      determine the effect of cobimetinib on T cell subpopulations systemically and in tumor,
      PD-1/PD-L1 expression on tumor, and MHC 1/2 expression.

      III. To determine the effect of cobimetinib on markers of immune exhaustion and pro-apoptotic
      factors in CD8+ effector T cells.

      IV. To explore the effect of cobimetinib on local and systemic immune activation pathways and
      immune suppressive pathways through expression profiling.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15.
      Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 and cobimetinib
      orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (atezolizumab)ExperimentalPatients receive atezolizumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
Arm B (atezolizumab, cobimetinib)ExperimentalPatients receive atezolizumab IV over 30-60 minutes on days 1 and 15 and cobimetinib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Cobimetinib

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed cholangiocarcinoma, having received at least 1 prior line of
             systemic therapy, and received no more than 2 prior lines of therapy in the metastatic
             setting

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
             conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
             scan, magnetic resonance imaging (MRI), or calipers by clinical exam; assessment must
             be completed within 4 weeks of randomization

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)

          -  Life expectancy of greater than 2 months

          -  Leukocytes >= 2,500/mcL, within 2 weeks of randomization

          -  Absolute neutrophil count >= 1,500/mcL, within 2 weeks of randomization

          -  Platelets >= 75,000/mcL, within 2 weeks of randomization

          -  Hemoglobin >= 8 g/dL, within 2 weeks of randomization

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
             with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled),
             within 2 weeks of randomization

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x ULN, within 2 weeks of randomization

          -  Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault OR creatinine < 1.5 x
             ULN, within 2 weeks of randomization

          -  International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
             =< 1.5 x ULN (this applies only to patients who do not receive therapeutic
             anticoagulation; patients receiving therapeutic anticoagulation, such as
             low-molecular-weight heparin or warfarin, should be on a stable dose), within 2 weeks
             of randomization

          -  Women of childbearing potential must agree to use either two adequate barrier methods
             or a barrier method plus a hormonal method of contraception to prevent pregnancy, or
             to abstain from heterosexual activity (complete abstinence) prior to study entry, for
             the duration of study participation, and for 5 months (150 days) after the last dose
             of study agent; should a woman become pregnant or suspect she is pregnant while she or
             her partner is participating in this study, she should inform her treating physician
             immediately; male patients must agree to use an adequate method of contraception, or
             to abstain from heterosexual activity (complete abstinence), prior to study entry, for
             the duration of study participation, and for 5 months (150 days) after the last dose
             of study agent

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Patients positive for human immunodeficiency virus (HIV) are allowed on study, but
             HIV-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART)

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  polymerase chain reaction (PCR)-based tests

          -  Oxygen saturation >= 92% on room air

        Exclusion Criteria:

          -  Received chemotherapy or radiotherapy within 3 weeks prior to randomization or those
             who have not recovered from adverse events (other than alopecia) due to agents
             administered more than 3 weeks earlier; herbal therapy intended as anticancer therapy
             must be discontinued at least 1 week prior to randomization; for patients who received
             prior immunotherapy (eg anti-CTLA-4), at least five drug half-lives must have passed
             before the patient may enroll on this study; however, the following therapies are
             allowed:

               -  Hormone-replacement therapy or oral contraceptives

               -  Palliative radiotherapy for bone metastases >= 2 weeks prior to randomization

          -  Prior treatment with a MEK inhibitor or ERK inhibitor

          -  Prior treatment with any anti-PD-1 or anti-PD-L1 antibody, prior allogeneic bone
             marrow transplantation, or prior solid organ transplantation

          -  Treatment with any investigational agent within 4 weeks prior to cycle 1, day 1, or
             five drug half-lives (whichever is longer)

          -  Treatment with systemic immunosuppressive medications (including, but not limited to,
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) within 6 weeks prior to cycle 1 day 1;

               -  Patients who have received acute, low dose, systemic immunosuppressant
                  medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

               -  The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
                  for patients with orthostatic hypotension or adrenocortical insufficiency is
                  allowed

          -  Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS
             metastases, with the following exceptions:

               -  Patients with asymptomatic treated CNS metastases may be enrolled, provided all
                  the criteria listed above are met as well as the following:

                    -  Radiographic demonstration of clinical stability upon the completion of CNS
                       directed therapy and no evidence of interim progression between the
                       completion of CNS directed therapy and the screening radiographic study

                    -  No stereotactic radiation or whole-brain radiation within 28 days prior to
                       randomization

                    -  Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
                       and >= 2 weeks from discontinuation of corticosteroids

          -  Has a known concurrent malignancy that is expected to require active treatment within
             two years, or may interfere with the interpretation of the efficacy and safety
             outcomes of this study in the opinion of the treating investigator; superficial
             bladder cancer, non-melanoma skin cancers, or low grade prostate cancer not requiring
             therapy should not exclude participation in this trial

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  Allergy or hypersensitivity to components of the cobimetinib formulations

          -  History of congenital long QT syndrome or corrected QT interval (QTc) > 450 msec
             within 2 weeks of randomization

          -  Left ventricular ejection fraction (LVEF) below institutional lower limit of normal
             (LLN) or below 50%, whichever is lower, as determined by echocardiogram or multi-gated
             acquisition (MUGA) scan within 4 weeks of randomization

          -  Patients who meet any of the following exclusion criteria related to ocular disease
             will be excluded from study entry:

               -  Known risk factors for ocular toxicity, consisting of any of the following:

                    -  History of serous retinopathy

                    -  History of retinal vein occlusion (RVO)

                    -  Evidence of ongoing serous retinopathy or RVO at screening

          -  Patients receiving any medications or substances that are inhibitors or inducers of
             CYP450 enzymes are ineligible; these include St. John's wort or hyperforin (potent
             CYP3A4 enzyme inducer) and grapefruit juice (potent cytochrome P450 CYP3A4 enzyme
             inhibitor); such substances can significantly increase or decrease the serum level of
             cobimetinib; as part of the enrollment/informed consent procedures, the patient will
             be counseled on the risk of interactions with other agents, and what to do if new
             medications need to be prescribed or if the patient is considering a new
             over-the-counter medicine or herbal product

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease

               -  Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
                  [antibody to hepatitis B core antigen] antibody test) are eligible

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

          -  History or risk of autoimmune disease, including, but not limited to, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis

               -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
                  replacement hormone may be eligible

               -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
                  be eligible

               -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

                    -  Rash must cover less than 10% of body surface area (BSA)

                    -  Disease is well controlled at baseline and only requiring low potency
                       topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
                       flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

                    -  No acute exacerbations of underlying condition within the last 12 months
                       (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
                       retinoids, biologic agents, oral calcineurin inhibitors; high potency or
                       oral steroids)

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan; history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted

          -  Severe infections within 4 weeks prior to randomization, including, but not limited
             to, hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Signs or symptoms of infection within 2 weeks prior to randomization

          -  Received oral or intravenous (IV) antibiotics within 2 weeks prior to randomization;
             patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or chronic obstructive pulmonary disease) are eligible

          -  Major surgical procedure within 4 weeks prior to randomization or anticipation of need
             for a major surgical procedure during the course of the study

          -  Administration of a live, attenuated vaccine within 4 weeks before randomization or
             anticipation that such a live, attenuated vaccine will be required during the study
             and up to 5 months after the last dose of atezolizumab

               -  Influenza vaccination should be given during influenza season only (approximately
                  October to March); patients must not receive live, attenuated influenza vaccine
                  within 4 weeks prior to cycle 1, day 1 or at any time during the study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, active tuberculosis (TB), symptomatic congestive heart failure, unstable
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
             would limit compliance with study requirements

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with either therapy

          -  Inability or unwillingness to swallow pills

          -  History of malabsorption syndrome or other condition that would interfere with enteral
             absorption
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From date of randomization to time of progression or death, assessed up to 1 year
Safety Issue:
Description:PFS within each treatment arm will be summarized descriptively using Kaplan-Meier plots, and compared between groups, under the assumption of Cox proportional hazards, using the stratified log-rank test to account for tumor site.

Secondary Outcome Measures

Measure:Incidence of adverse events (AE)s assessed using National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 30 days after study treatment
Safety Issue:
Description:The incidence of AEs will be tabulated by subgroups of interest (e.g. grade 3 or higher, organ class, relationship to study drug). For analyses at the individual level, the highest grade and relationship to study drug will be assumed if multiple events have occurred. Toxicity will be tabulated by type and grade and will be summarized with descriptive statistics. Other safety data will be assessed in terms of physical examination, clinical chemistry, hematology, vital signs, and electrocardiography. Negative binomial regression and Cox proportional hazards models will be used to assess the rate of AE and time to first toxicity, respectively.
Measure:Objective response rate defined as the proportion of response evaluable subjects who have a complete response or partial response assessed by Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 1 year
Safety Issue:
Description:Response rates will be reported for each group along with exact confidence intervals, and an exact binomial test will be used to compare response rates across treatment groups.
Measure:Overall survival
Time Frame:From date of randomization to time of death, assessed up to 1 year
Safety Issue:
Description:Results will be summarized descriptively using Kaplan-Meier plots, and compared between groups, under the assumption of proportional hazards, using the stratified log-rank test to account for tumor site.
Measure:Change in CD8+ density within the tumor
Time Frame:Baseline up to 1 year
Safety Issue:
Description:Will be visualized using boxplots, and described using summary statistics including means and standard deviations presented with 95% confidence intervals. A student t-test or nonparametric Wilcoxon rank-sum test will be used to determine whether the increase in CD8+ T cells is greater in treatment arm B (combination cobimetinib plus atezolizumab) than in treatment arm A (atezolizumab monotherapy).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 8, 2018