Irinotecan and Cetuximab With or Without Bevacizumab in Treating Patients With RAS Wild-Type Locally Advanced or Metastatic Colorectal Cancer That Cannot Be Removed by Surgery
Condition: Colorectal Adenocarcinoma; RAS Wild Type; Stage IV Colorectal Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7
MeSH terms: Colorectal Neoplasms
Intervention: Bevacizumab; Cetuximab; Irinotecan; Laboratory Biomarker Analysis; Placebo
Intervention description: Given IV; Given IV; Given IV; Correlative studies; Given IV
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Cetuximab; Irinotecan; 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: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well irinotecan and cetuximab with or without
      bevacizumab work in treating patients with RAS wild-type colorectal cancer that has spread to
      other places in the body (locally advanced/metastatic) and cannot be removed by surgery.
      Irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell
      growth. Immunotherapy with monoclonal antibodies, such as cetuximab 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. Giving irinotecan and cetuximab with or without bevacizumab may work
      betting in treating patients with colorectal cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Metastatic or locally advanced (unresectable) colorectal cancer with histological
             confirmation of adenocarcinoma

          -  Measurable disease

          -  RAS wild-type tumor; Note: evidence of EGFR expression in the tumor is not required

          -  Previous failure of at least one fluoropyrimidine- and irinotecan-containing
             chemotherapy regimen for metastatic disease; Note: previous failure is defined as
             disease progression while receiving treatment or within 6 weeks after the last dose of
             irinotecan; failure for this assessment is defined as any enlargement of measurable or
             assessable lesion(s) or the development of any new lesion; a rising tumor marker alone
             is not sufficient to define failure; patients can have received irinotecan in any
             previous line of therapy

          -  Treatment with bevacizumab in at least one prior line of therapy for metastatic
             disease

          -  Negative serum or urine pregnancy test done =< 7 days prior to registration, for women
             of childbearing potential only

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1

          -  Total serum bilirubin =< institutional upper limit of normal (ULN) obtained =<14 days
             prior to randomization

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =<14 days prior to randomization

          -  Platelet count >= 100,000/mm^3 obtained =<14 days prior to randomization

          -  Hemoglobin >= 9.0 g/dL (hemoglobin may be supported by transfusion) obtained =<14 days
             prior to randomization

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5
             x ULN for subjects with liver involvement of their cancer) obtained =<14 days prior to
             randomization

          -  Creatinine within institutional limits of normal OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
             obtained =<14 days prior to randomization

          -  Urinary protein =< 1+ obtained =<14 days prior to randomization

               -  Patients discovered to have >= 2+ proteinuria must have a spot urine
                  protein:creatinine ratio (UPCR) < 1.0

          -  Partial thromboplastin time (PTT) =< 1 x institutional ULN and international
             normalized ratio (INR) =< 1.5 , unless participant is on full dose anticoagulation
             therapy obtained =<14 days prior to randomization; patients on full-dose
             anticoagulation are eligible if the following criteria are met:

               -  Patient has an in-range INR (usually 2-3) on a stable dose of warfarin or other
                  anticoagulant =< 14 days or is on a stable dose of low molecular weight heparin

               -  Patient has no active bleeding or pathological condition that carries a high risk
                  of bleeding (i.e., tumor involving major vessels or known varices)

               -  Patients receiving anti-platelet agents are eligible; in addition, patients who
                  are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are
                  eligible

          -  Life expectancy > 3 months

          -  Provide informed written consent

          -  Willing to provide blood samples for mandatory correlative and research purposes

          -  Willing to provide tissue and blood samples for mandatory banking purposes

          -  Any major surgery or open biopsy completed >= 4 weeks prior to randomization

          -  Any minor surgery or core biopsy completed >= 1 week prior to randomization and
             patient must have fully recovered from the procedure; Note: insertion of a vascular
             access device is not considered major or minor surgery

        Exclusion Criteria:

          -  Presence of a RAS mutation in exons 2, 3, or 4 of KRAS or NRAS (patients with
             mutations in exons 2, 3, or 4 of KRAS and/or NRAS are excluded)

          -  Prior treatment with cetuximab or panitumumab

          -  Prior intolerance to irinotecan and/or bevacizumab despite dose reduction

          -  Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous
             meningitis

          -  Active, uncontrolled infection, including hepatitis B, hepatitis C

          -  Concurrent anti-cancer therapy, including chemotherapy agents, targeted agents, or
             biological agents not otherwise specified in this protocol

          -  Anti-cancer therapy =< 14 days prior to randomization

          -  Prior radiotherapy to > 25% of bone marrow; Note: standard rectal cancer
             chemoradiation will not exclude subject from study protocol

          -  Radiation therapy =< 2 weeks prior to randomization

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Co-morbid systemic illnesses or other severe concurrent disease, history of any
             psychiatric or addictive disorder, or laboratory abnormality, which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Patients known to be human immunodeficiency virus (HIV) positive

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, symptomatic pulmonary fibrosis or interstitial pneumonitis, or psychiatric
             illness/social situations that, in the opinion of the investigator, may increase the
             risks associated with study participation or study treatment, or may interfere with
             the conduct of the study or the interpretation of the study results

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanoma
             skin cancer, prostatic intraepithelial neoplasia without evidence of prostate cancer,
             lobular carcinoma in situ in one breast, or carcinoma-in-situ of the cervix that has
             been treated

          -  History of prior malignancy for which patient is receiving other specific treatment
             for their cancer

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to irinotecan, cetuximab, and/or bevacizumab that led to discontinuation
             of those agents

          -  Significant history of bleeding events or pre-existing bleeding diathesis =< 6 months
             of randomization (unless the source of bleeding has been resected)

          -  History of gastrointestinal perforation =< 12 months prior to randomization

          -  Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled
             as indicated by baseline pattern of > 3 loose stools daily in subjects without a
             colostomy or ileostomy; subjects with a colostomy or ileostomy may be entered at
             investigator discretion

          -  Arterial thrombotic events =< 6 months prior to randomization; Note: this includes
             transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina or
             angina requiring surgical or medical intervention in the past 6 months, or myocardial
             infarction (MI)

          -  Clinically significant peripheral artery disease (e.g., claudication with < 1 block)
             or any other arterial thrombotic event

          -  Serious or non-healing wound, ulcer, or bone fracture

          -  History of hypertension not well-controlled (>= 160/90) even though on a regimen of
             anti-hypertensive therapy

          -  Evidence of Gilbert?s syndrome or known homozygosity for the UGT1A1*28 allele (special
             screening not required)