Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in People With Previously Untreated Metastatic Colorectal Cancer QUILT-2.004

Study Overview
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Brief Summary
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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.

Detailed Description
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Background Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States and accounts for the second most cancer-related deaths. Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for its role in the maintenance of self-tolerance and prevention of autoimmunity. Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T cells is expected to reverse T cell suppression within tumors. These agents are dependent on underlying T cell activation against the tumor cell to be effective. Avelumab is a fully human immunoglobulin G 1 (IgG1) anti-PDL1 antibody that selectively binds to PD-L1 and competitively blocks its interaction with PD-1. In ongoing phase 1 trials of avelumab, the agent has been well tolerated and has shown clinical activity. Clinical trials with anti-PD-1/L1 agents in colorectal cancer have resulted in minimal activity in patients who do not have mismatch repair deficiency (MMR-D). Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to activate T cells against tumors. A novel adenovirus-based, carcinoembryonic antigen (CEA)-targeting vaccine has demonstrated cytolytic T cell responses in patients with metastatic colorectal cancer. Standard of care agents in first line metastatic colorectal cancer (CRC) have properties been associated with improved immune response via immunologic cell death and immunogenic modulation. Primary Objective -To determine if there is an improvement progression free survival among patients with metastatic colorectal cancer lacking a mismatch repair deficiency who are treated with standard of care + anti- PDL1 monoclonal antibody + Ad-CEA therapeutic cancer vaccine compared with standard of care alone. Eligibility Subject's age 18 and older with previously untreated pathologically confirmed metastatic or unresectable colorectal cancer; prior adjuvant therapy is acceptable. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Normal organ and bone marrow function. Subjects with active autoimmune diseases requiring treatment and subjects requiring system steroids (except for physiologic doses for steroid replacement) are not allowed. Tumor sample and whole blood sample must be available for proteomics, genomics and transcriptomics analyses. Subjects with metastatic or unresectable colorectal cancer with mismatch repair deficiency (MMR-D or microsatellite instability (MSI)-High) will not be eligible. Design This is a randomized, multicenter phase II clinical trial designed to evaluate the potential improvement in progression free survival (PFS) when Avelumab and Ad-CEA vaccine are used in combination with standard of care therapy in metastatic or unresectable colorectal cancer when compared with standard of care alone (FOLFOX-A). A lead in cohort, comprising the first 6 evaluable subjects enrolled, will be treated with avelumab + Ad- CEA vaccine + standard of care in order to assess the safety of the combination. If no more than 1 subject in the lead in cohort experiences a dose limiting toxicity attributable to the investigational new drug (IND) agents, 70 evaluable subjects will be randomized on a 1:1 basis to receive either Avelumab + Ad-CEA vaccine + standard of care (Arm B) or standard of care alone (Arm A). Standard of care therapy consists of 6 - 12 two-week cycles of bevacizumab + FOLFOX (5-FU, leucovorin, oxaliplatin) followed by two-week cycles of bevacizumab + capecitabine until disease progression. Subjects assigned to Arm A that have progressive disease will be offered Avelumab + Ad-CEA vaccine in combination with a standard chemotherapy regimen. Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods. The accrual ceiling for the study is set at 97.

Official Title
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A Randomized Phase II Trial of Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in Patients With Previously Untreated Metastatic or Unresectable Colorectal Cancer

Conditions
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Colorectal Tumors, Colorectal Neoplasms, Colorectal Carcinoma, Colorectal Adenocarcinoma, Colorectal Cancer

Intervention / Treatment
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* Drug: Avelumab
* Biological: Ad-CEA vaccine
* Drug: Bevacizumab
* Drug: 5-Fluorouracil (FU)
* Drug: Leucovorin
* Drug: Oxaliplatin
* Drug: Capecitabine
* Drug: 5-Fluorouracil (FU)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care (SOC) - Arm A<br>Participants will receive leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX)- + bevacizumab + for up to 12 2-week cycles followed by maintenance therapy with bevacizumab + capecitabine until disease progression. | Drug: Bevacizumab<br>* 5mg/kg intravenous (IV) over 30-90 min on day 1 (Arm A) or 2 (Arm B). Part of the standard of care therapy.<br>* Other names: Avastin;Drug: 5-Fluorouracil (FU)<br>* 400mg/m^2 (only Arm A) intravenous (IV) bolus on day 1. Part of the standard of care therapy.<br>* Other names: Tolak;Drug: Leucovorin<br>* 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.<br>* Other names: folinic acid;Drug: Oxaliplatin<br>* 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.<br>* Other names: Eloxatin;Drug: Capecitabine<br>* 625 mg/m^2 twice a day by mouth. Part of the standard of care therapy.<br>* Other names: Xeloda;Drug: 5-Fluorouracil (FU)<br>* 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.<br>* Other names: Tolak;|
| Experimental: Standard of Care (SOC) - Arm B + Lead in<br>Participants will receive leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX)- + bevacizumab + avelumab + Ad-CEA vaccine (given weeks 0,2,4,8,12,16 and then every 12 weeks) for up to 12 2-week cycles followed by maintenance therapy with bevacizumab + capecitabine + avelumab + Ad-CEA vaccine (following the every 12-week dosing schedule) until disease progression. | Drug: Avelumab<br>* 10 mg/kg intravenous (IV) over 30-60 min on Day 1<br>* Other names: Bavencio;Biological: Ad-CEA vaccine<br>* Subcutaneous injection in the thigh prior to Avelumab on Day 1 of cycles 1, 2 3, 5, 7, 9; every 6 cycles thereafter.<br>Drug: Bevacizumab<br>* 5mg/kg intravenous (IV) over 30-90 min on day 1 (Arm A) or 2 (Arm B). Part of the standard of care therapy.<br>* Other names: Avastin;Drug: 5-Fluorouracil (FU)<br>* 400mg/m^2 (only Arm A) intravenous (IV) bolus on day 1. Part of the standard of care therapy.<br>* Other names: Tolak;Drug: Leucovorin<br>* 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.<br>* Other names: folinic acid;Drug: Oxaliplatin<br>* 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.<br>* Other names: Eloxatin;Drug: Capecitabine<br>* 625 mg/m^2 twice a day by mouth. Part of the standard of care therapy.<br>* Other names: Xeloda;Drug: 5-Fluorouracil (FU)<br>* 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.<br>* Other names: Tolak;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival Between the Standard of Care (SOC) Arm A, and Standard of Care (SOC) Arm B + lead-in | Progression free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. | Up to 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Are Hospitalized Because of Adverse Events Attributed to Disease Progression | Participants hospitalized because of adverse events measured by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 attributed to disease progression. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. | Up to 51.5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progression Free Survival, Adenovirus Based, CEA-Targeting Vaccine, Therapeutic Cancer Vaccine, Mismatch Repair Deficiency, Anti-PDL1 Antibody