Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in People With Previously Untreated Metastatic Colorectal Cancer QUILT-2.004
Condition: Colorectal Tumors; Colorectal Neoplasms; Colorectal Carcinoma; Colorectal Adenocarcinoma; Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Avelumab; Ad-CEA vaccine; Bevacizumab; 5-Fluorouracil (FU); Leucovorin; Oxaliplatin; Capecitabine; 5-Fluorouracil (FU)
Intervention description: 10 mg/kg intravenous (IV) over 30-60 min on Day 1; Subcutaneous injection in the thigh prior to Avelumab on Day 1 of cycles 1, 2 3, 5, 7, 9; every 6 cycles thereafter.; 5mg/kg intravenous (IV) over 30-90 min on day 1 (Arm A) or 2 (Arm B). Part of the standard of care therapy.; 400mg/m^2 (only Arm A) intravenous (IV) bolus on day 1. Part of the standard of care therapy.; 400mg/m^2 intravenous (IV) over 2 hours on day 1 (Arm A) or Day 2 (Arm B). Part of the standard of care therapy.; 85mg/m^2 (Arm A) or 68mg/m^2 (Arm B) intravenous (IV) over 2 hours on day 1 (Arm A) or Day 2 (Arm B). Part of the standard of care therapy.; 625 mg/m^2 twice a day by mouth. Part of the standard of care therapy.; 2400 mg/m^2 (Arm A and B) intravenous (IV) over 46 hours (+/-2 hours) to start on Day 1 (ARM A) or Day 2 (Arm B). Part of the standard of care therapy.
Intervention MeSH terms: Leucovorin; Bevacizumab; Avelumab; Capecitabine; Fluorouracil; Oxaliplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Anti-PDL1 Antibody; Therapeutic Cancer Vaccine; Mismatch Repair Deficiency; Progression Free Survival; Adenovirus Based, CEA-Targeting Vaccine

Summary:

      Background:

      Colorectal cancer is a common cancer in the Unites States (U.S.) It causes the second most
      cancer-related deaths. The drug avelumab and vaccine Ad-CEA together help the immune system
      fight cancer.

      Objective:

      To test if avelumab and Ad-CEA plus standard therapy treats colorectal cancer that has spread
      to other sites better than standard therapy alone.

      Eligibility:

      People ages 18 and older with untreated colorectal cancer that has spread in the body

      Design:

      Participants will be screened with:

      Test to see if their cancer has a certain deficiency

      Blood, urine, and heart tests

      Scans

      Medical history

      Physical exam

      Tumor sample. This can be from a previous procedure.

      A small group of participants will get Ad-CEA and avelumab plus standard therapy. This is
      leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab
      for up to 24 weeks then capecitabine plus bevacizumab.

      The others will have treatment in 2-week cycles. They will be Arm A or B:

      Arm A: FOLFOX and bevacizumab by intravenous (IV) days 1 and 2 for 12 cycles. After that,
      capecitabine by mouth twice a day and bevacizumab by IV on day 1.

      Arm B: Ad-CEA injection every 2-12 weeks. Avelumab by IV on day 1 of each cycle. FOLFOX and
      bevacizumab by IV days 2 and 3 for 12 cycles. Then, capecitabine by mouth twice a day and
      bevacizumab through IV on day 2.

      Participants will repeat screening tests during the study.

      Participants will be treated until their disease gets worse or they have bad side effects.
      Arm A participants can join Arm B. They will have a visit 4 5 weeks after they stop therapy.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Subjects must have previously untreated metastatic or unresectable colorectal cancer
             and have no contraindications to treatment with the standard of care regimen as
             determined by the investigator. Prior adjuvant therapy for surgically resectable
             disease (including oligometastatic disease) is acceptable (including immunotherapy)
             but must have been completed at least 6 months prior to enrollment.

          -  Patients should not be eligible for potentially curative surgical intervention in the
             case of oligometastatic disease at the time of enrollment or must have actively
             refused after explicit discussion of potential benefit of this intervention with
             multidisciplinary team.

          -  Histologically confirmed colorectal cancer

          -  Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
             (RECIST) criteria.

          -  Age greater than or equal to 18 years. Because safety data is not known with this
             agent in patients less than 18 years old, children are excluded from this study.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

          -  Patients must have normal organ and marrow function as defined below:

               -  Creatinine clearance (per Institutional standard or 24-hour urine) greater than
                  or equal to 30 mL/min.

               -  Adequate hepatic function defined by a total bilirubin level less than or equal
                  to 1.5 the upper limit of normal range (ULN), an aspartate aminotransferase
                  (AST), level less than or equal to 2.5 ULN, and an alanine aminotransferase (ALT)
                  level less than or equal to 2.5 ULN or, for subjects with documented metastatic
                  disease to the liver, AST and ALT levels less than or equal to 5 ULN.

               -  Hematological eligibility parameters (within16 days of enrollment):

               -  Granulocyte count greater than or equal to 1,500/mm^3

               -  Platelet count greater than or equal to 100,000/mm^3

               -  Hemoglobin greater than or equal to 9 g/dL

          -  The effects of Ad-CEA vaccine and Avelumab on the developing human fetus are unknown.
             For this reason and because Ad-CEA vaccine and Avelumab as well as other therapeutic
             agents used in this trial are known to be teratogenic, women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry and for the duration of study
             participation and for a period of 4 months after the last treatment with avelumab or 6
             months after the last administration of bevacizumab, whichever occurs later. 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.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA:

          -  Metastatic or unresectable colorectal cancer with mismatch repair deficiency (MMR-D or
             microsatellite instability (MSI)-High).

          -  Concurrent treatment for cancer except agents specified within the treatment protocol.

          -  Prior surgery or gastrointestinal perforation within 28 days of enrollment.

          -  Persisting toxicity related to prior therapy (National Cancer Institute (NCI) Common
             Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade > 1); however, alopecia,
             sensory neuropathy Grade <=2, or other Grade <=2 AEs not constituting a safety risk
             based on investigator's judgment are acceptable.

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome.

          -  Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
             HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

          -  Any significant disease that, in the opinion of the investigator, may impair the
             patient's tolerance of study treatment.

          -  Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
             agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
             diseases not requiring immunosuppressive treatment are eligible.

          -  Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
             inhaled, topical steroids, or local steroid injection (e.g., intra-articular
             injection); b. Systemic corticosteroids at physiologic doses less than or equal to 10
             mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity
             reactions (e.g., computed tomography (CT) scan premedication).

          -  Patients who are receiving any other investigational agents within 28 days before
             start of study treatment.

          -  Prior organ transplantation including allogenic stem-cell transplantation.

          -  Subjects with active central nervous system (CNS) metastases causing clinical symptoms
             or metastases that require therapeutic intervention are excluded. Subjects with a
             history of treated CNS metastases (by surgery or radiation therapy) are not eligible
             unless they have fully recovered from treatment, demonstrated no progression for at
             least 2 months, and do not require continued steroid therapy. Subjects with CNS
             metastases incidentally detected during Screening which do not cause clinical symptoms
             and for which standard of care suggests no therapeutic intervention is needed are
             eligible.

          -  Active infection, requiring systemic therapy,

          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (< 3 months prior to enrollment), myocardial infarction (< 3 months
             prior to enrollment), unstable angina, congestive heart failure (greater than or equal
             to New York Heart Association Classification Class II), or uncontrolled arrhythmias.

          -  Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study.

          -  Pregnant women and breastfeeding mothers are excluded due to unknown impact on embryos
             or infants.

          -  Known alcohol or drug abuse.

          -  Known prior severe hypersensitivity to investigational product or any component in its
             formulations, including known severe hypersensitivity reactions to monoclonal
             antibodies (NCI CTCAE v4.03 Grade greater than or equal to 3).

          -  Patients with a known hypersensitivity/allergy to any of the standard of care agents
             used in this study or related compounds (e.g., platinum compounds) are excluded.

          -  Prior history of hypertensive emergency or hypertensive encephalopathy (for those
             expected to receive bevacizumab.

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture, including tumor
             related pathological fracture.

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation).

          -  Patients being treated with medications with drug-drug interactions with study agents
             will require evaluation by to determine if full doses of all study treatments can be
             given safely. Significant drug-drug interactions will need to be addressed prior to
             enrollment. Alternatively, the patient will not be eligible.

          -  Vaccination within 4 weeks of the first dose of avelumab and while on trials is
             prohibited except for administration of inactivated vaccines.