Atezolizumab With or Without Cobimetinib in Treating Patients With Metastatic Bile Duct Cancer That Cannot Be Removed by Surgery or Gallbladder Cancer
Condition: Gallbladder Carcinoma; Metastatic Cholangiocarcinoma; Stage III Intrahepatic Cholangiocarcinoma AJCC v8; Stage IV Intrahepatic Cholangiocarcinoma AJCC v8; Unresectable Cholangiocarcinoma
MeSH terms: Cholangiocarcinoma
Intervention: Atezolizumab; Biopsy; Biospecimen Collection; Cobimetinib; Computed Tomography; Magnetic Resonance Imaging
Intervention description: Given IV; Undergo tumor biopsy; Undergo collection of blood samples; Given PO; Undergo CT; Undergo MRI
Intervention MeSH terms: Atezolizumab; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 86.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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
      (metastatic) and cannot be removed by surgery (unresectable) 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 is used in patients whose cancer has a mutated (changed) form of a gene
      called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking
      the action of an abnormal protein that signals cancer cells to multiply. This helps slow or
      stop the spread of cancer cells. Giving atezolizumab with cobimetinib may work better at
      treating patients with bile duct and gallbladder cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Pathologically confirmed metastatic or unresectable cholangiocarcinoma or gallbladder
             carcinoma (GBC), having received at least 1 prior line of systemic therapy, and
             received no more than 2 prior lines of therapy in the metastatic setting (disease
             recurrence =< 6 months from the last dose of adjuvant therapy in resected patients
             will be considered the first line of therapy)

               -  Includes intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma
                  (EHC), and gallbladder carcinoma (GBC), but not ampulla of vater cancers

          -  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 CT scan, MRI, or calipers
             by clinical exam; assessment must be completed within 4 weeks of randomization

          -  Age >= 18 years. Because no dosing or adverse event data are currently available on
             the use of cobimetinib in combination with atezolizumab in patients < 18 years of age,
             children are excluded from this study

          -  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)

          -  Administration of atezolizumab and cobimetinib may have an adverse effect on pregnancy
             and poses a risk to the human fetus, including embryo-lethality; 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 to =< grade 1 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 strong inhibitors or
             inducers of CYP3A4 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 (CHF),
             unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
             that would limit compliance with study requirements

               -  Symptomatic CHF is defined as New York Heart Association (NYHA) CHF class II or
                  higher disease

          -  Pregnant women are excluded from this study because both atezolizumab and cobimetinib
             are expected to cause fetal harm if used during pregnancy; because there is an unknown
             but potential risk for adverse events in nursing infants secondary to treatment of the
             mother with cobimetinib or atezolizumab, breastfeeding should be discontinued if the
             mother is treated with either therapy; these potential risks may also apply to other
             agents used in this study

          -  Inability or unwillingness to swallow pills

          -  History of malabsorption syndrome or other condition that would interfere with enteral
             absorption

          -  Clinically significant ascites, defined as ascites that is symptomatic or has resulted
             in a paracentesis in the past 3 months