Capecitabine and Bevacizumab With or Without Atezolizumab in Treating Patients With Refractory Metastatic Colorectal Cancer
Condition: Metastatic Colorectal Carcinoma; Recurrent Colorectal Carcinoma; Refractory Colorectal Carcinoma; Stage IV Colorectal Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7
MeSH terms: Carcinoma; Colorectal Neoplasms
Intervention: Atezolizumab; Bevacizumab; Capecitabine; Laboratory Biomarker Analysis; Placebo
Intervention description: Given IV; Given IV; Given PO; Correlative studies; Given IV
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Atezolizumab; Capecitabine; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 133.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well capecitabine and bevacizumab with or without
      atezolizumab work in treating patients with colorectal cancer that is not responding to
      treatment and has spread to other places. Immunotherapy with monoclonal antibodies, such as
      atezolizumab and bevacizumab, may help the body?s immune system attack the cancer, and may
      interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy,
      such as capecitabine, work in different ways to stop the growth of tumor cells, either by
      killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving
      atezolizumab with capecitabine and bevacizumab may be a better way in treating colorectal
      cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed colorectal cancer that is either clinically or histologically
             proven to be metastatic and has progressed on regimens containing a fluoropyrimidine
             (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, bevacizumab and an
             anti-EGFR antibody (if tumor is RAS wild-type), or where the treatment was not
             tolerated or contraindicated

          -  Measurable disease; Note: previously irradiated sites can be included if there is
             documented disease progression in that site

          -  Capecitabine and bevacizumab considered appropriate treatment for the patient

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

          -  Absolute neutrophil count >= 1,500/uL (obtained =< 7 days prior to randomization)

          -  Platelets >= 100,000/uL (obtained =< 7 days prior to randomization)

          -  Total bilirubin =< 1.5 X upper limit of normal (ULN) (obtained =< 7 days prior to
             randomization); patients with known Gilbert?s syndrome who have serum bilirubin =< 3 X
             ULN may enroll

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 X ULN; < 3 X
             ULN if known hepatic metastases (obtained =< 7 days prior to randomization)

          -  Hemoglobin >= 9 g/dL continuation of erythropoietin products is permitted (obtained =<
             7 days prior to randomization); hemoglobin must be stable >= 9 g/dL >= 14 days without
             blood transfusion to maintain hemoglobin level

          -  Calculated creatinine clearance must be >= 50 ml/min using the Cockcroft-Gault formula
             or a 24 hour urine (obtained =< 7 days prior to randomization)

          -  The following laboratory values obtained =< 14 days prior to randomization

               -  Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized
                  ratio (INR) =< 1.5 X ULN if not anticoagulated; within local institutional
                  guidelines per local physician if anticoagulated

          -  Negative pregnancy test done =< 7 days prior to randomization, for women of
             childbearing potential only

          -  Provide informed written consent

          -  Willingness to return to enrolling institution for follow-up (during the active
             monitoring phase of the study)

          -  Willingness to provide tissue and blood samples for correlative research purposes

          -  Life expectancy of >= 3 months

        Exclusion Criteria:

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Women of child-bearing potential must agree to use two forms of adequate
                  contraception from time of initial consent, for the duration of study
                  participation, and for >= 6 months after the last dose of study drug; medically
                  acceptable contraceptives include: (1) surgical sterilization (such as a tubal
                  ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth
                  control pills, patches, implants or injections), (3) barrier methods (such as a
                  condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD);
                  contraceptive measures such as Plan B, sold for emergency use after unprotected
                  sex, are not acceptable methods for routine use; postmenopausal woman must have
                  been amenorrheic for at least 2 years to be considered of non-childbearing
                  potential; sexually active men must use at least one form of adequate
                  contraception from time of initial consent, for the duration of study
                  participation, and for >= 6 months after the last dose of study drug

          -  Chemotherapy, biologic anti-cancer therapy, or central field radiation therapy =< 28
             days prior to randomization; Note: local or stereotactic radiation =< 14 days prior to
             randomization

          -  Any investigational agent =< 28 days or 5 half-lives prior to randomization (whichever
             is longer)

          -  Prior treatment with atezolizumab or another PD-L1/PD-1 therapy

          -  History of allergic reactions attributed to therapeutic antibodies; Note: patients
             with reactions to chimeric antibodies may be permitted on a case by case basis with
             approval by study chair by contacting the data manager

          -  Known untreated central nervous system (CNS) metastases; Note: patients with radiated
             or resected lesions are permitted, provided the lesions are fully treated and
             inactive, patients are asymptomatic, and no steroids have been administered for this
             purpose =< 30 days prior to randomization

          -  Inadequately controlled hypertension (defined as average systolic blood pressure > 150
             mmHg and/or diastolic blood pressure > 100 mmHg)

          -  History of hypertensive crisis or hypertensive encephalopathy

          -  New York Heart Association (NYHA) grade II or greater congestive heart failure

          -  History of myocardial infarction, unstable angina, cardiac or other vascular stenting,
             angioplasty, or surgery =< 12 months prior to randomization

          -  Active coronary heart disease evidenced as angina or requiring medications to prevent
             angina

          -  History of stroke or transient ischemic attack, or other arterial thrombosis =< 12
             months prior to randomization

          -  Symptomatic peripheral vascular disease

          -  Any other significant vascular disease (e.g., aortic aneurysm, aortic dissection, or
             carotid stenosis that requires medical or surgical intervention, including angioplasty
             or stenting)

          -  Any previous National Cancer Institute (NCI) Common Terminology Criteria for Adverse
             Events (CTCAE) grade 4 venous thromboembolism

          -  Clinically-significant evidence of bleeding diathesis or coagulopathy as so judged by
             the treating physician

          -  History of active gastrointestinal (GI) bleeding or other major bleeding =< 12 months
             prior to randomization; Note: patients who do not have resolution of the predisposing
             risk factor (e.g., resection of a bleeding tumor, treatment and endoscopic
             documentation of a resolved ulcer) will also be excluded

          -  Major surgical procedure, open biopsy, or significant traumatic injury =< 56 days
             prior to randomization

          -  Anticipation of need for major surgical procedure =< 6 months after randomization

          -  Minor surgical procedure =< 7 days prior to randomization; exception: insertion of an
             indwelling catheter or percutaneous needle biopsy =< 48 hours prior to randomization

          -  History of intra-abdominal abscess =< 6 months prior to randomization; Note: if the
             affected area was surgically resected, and there is no further risk to the area,
             patients may enroll

          -  History of abdominal or other significant fistula, gastrointestinal or other organ
             perforation; Note: if the affected area was surgically resected, and there is no
             further risk to the area, patients may enroll

          -  Serious, non-healing wound, ulcer, or bone fracture as so judged by the treating
             physician

          -  Known proteinuria defined by >= 2+ protein by urinalysis (UA) or >= 1 gram protein by
             24 hour urine collection; Note: Subjects that are >= 2+ or greater on dipstick but < 1
             g protein on 24 hour urine ARE eligible to participate

          -  Intolerance to bevacizumab defined as any NCI CTCAE grade 3 or grade 4 toxicity
             attributed to this agent that required discontinuation of bevacizumab (e.g., arterial
             thromboembolism [ATE], perforation, wound healing difficulty, proteinuria, reversible
             posterior leukoencephalopathy syndrome [RPLS]); Note: patients with prior grade 3
             bevacizumab-related hypertension may be permitted if hypertension was manageable with
             standard oral antihypertensives as so judged by the treating physician

          -  Known dihydropyrimidine dehydrogenase (DPD) deficiency

          -  Impairment of GI function or GI disease that may significantly alter capecitabine drug
             absorption

          -  Active inflammatory bowel disease

          -  History of diverticulitis, chronic ulcerative lower GI disease such as Crohn?s disease
             or ulcerative colitis, or other symptomatic lower GI conditions that might predispose
             to perforations

          -  History 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; Note: patients with a history of
             autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may
             be eligible for this study

          -  Active current infection or history of recurrent bacterial, viral, fungal,
             mycobacterial or other infections, including but not limited to tuberculosis and
             atypical mycobacterial disease, hepatitis B and C, herpes zoster, and human
             immunodeficiency virus (HIV), but excluding fungal infections of nail beds

          -  Vaccination with a live or attenuated vaccine =< 28 days prior to randomization; Note:
             other types of vaccines, including inactivated/killed, toxoid (inactivated toxoid),
             and subunit/conjugate are all permitted at any time

          -  Any reversible treatment-related toxicity that has not resolved to NCI CTCAE grade =<
             1 except neuropathy

          -  Other concurrent severe and/or uncontrolled medical disease, psychiatric illness, or
             social situation, which could compromise safety of treatment as so judged by the
             treating physician; Note: this includes but is not limited to: severely impaired lung
             function, uncontrolled diabetes (history of consistent blood glucose readings above
             300 mg/dL or less than 50 mg/dL), severe infection, severe malnutrition, ventricular
             arrhythmias, known active vasculitis of any cause, tumor invasion of any major blood
             vessel, chronic liver or renal disease, and active upper GI tract ulceration

          -  Unwilling to or unable to comply with the protocol

          -  Current or recent (=< 10 days prior to randomization) use of aspirin (> 325 mg/day),
             or clopidogrel (> 75 mg/day)

          -  Current or recent (=< 10 days prior to randomization) use of therapeutic oral or
             parenteral anticoagulants or thrombolytic agents for therapeutic purposes, unless the
             patient has been on a stable dose of anticoagulants for at least 2 weeks at the time
             of randomization; Note: the use of full-dose oral or parenteral anticoagulants is
             permitted as long as the INR or activated partial thromboplastin time (aPTT) is within
             therapeutic limits (according to the medical standard of the institution) and the
             patient has been on a stable dose of anticoagulants >= 14 days at the time of
             randomization; prophylactic use of anticoagulants is allowed

          -  History or recent diagnosis of demyelinating disease

          -  History of other carcinoma =< 3 years; exception: if risk of recurrence is known to be
             under 5% at time of randomization

          -  Current or recent (=< 90 days prior to randomization) endoluminal stent in the
             stomach, bowel, colon or rectum

          -  Colonoscopy, sigmoidoscopy, or proctoscopy =< 7 days prior to randomization

          -  Current or recent (=< 28 days prior to randomization) use of sorivudine, brivudine,
             and St. John?s wort

          -  Primary or secondary immunodeficiency (history of or currently active) unless related
             to primary disease under investigation

          -  Prior allogeneic bone marrow transplantation or prior solid organ transplantation

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) =< 14 days prior to randomization; exception:
             patients who have received acute, low-dose, systemic immunosuppressant medications
             (e.g. a one-time dose of dexamethasone for nausea) are eligible; the use of inhaled
             corticosteroids and mineral-corticoids (e.g. fludrocortisone) for patients with
             orthostatic hypotension or adrenocortical insufficiency is allowed