A Trial of Perioperative CV301 Vaccination in Combination With Nivolumab and Systemic Chemotherapy for Metastatic CRC

Study Overview
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Brief Summary
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This is a multi-center Phase II randomized study. We plan to enroll 78 patients with biopsy-proven hepatic-limited metastatic colorectal cancer deemed resectable after multi-disciplinary discussion. Eligible patients must have confirmed isolated liver metastases by radiographic imaging of the investigators' choosing. Imaging must include the chest, abdomen, and pelvis regardless of imaging modality chosen. Patients will be randomized to either the control arm or the experimental arm. The control arm will receive mFOLFOX6 every 2 weeks for 4 cycles concurrently with Nivolumab. The experimental arm will first be treated with 2 vaccinations of MVA-BN-CV301 given two weeks apart (Days -28, -14) concurrently with Nivolumab followed by 4 vaccinations of FPV-CV301 given two weeks apart concurrently with mFOLFOX6 and Nivolumab, which will again be administered every 2 weeks for 4 cycles (FPV-CV301, mFOLFOX6 and Nivolumab) After Cycle 4, patients will be re-evaluated for surgical resection by re-staging CT chest, abdomen and pelvis (C/A/P). Patients still considered resectable will undergo surgical resection with the goal of complete resection. Patients who cannot be completely resected will continue to be followed on study, and an additional appropriate candidate will be randomized to the corresponding arm. We will collect peripheral blood and tumor tissue at the time of surgical resection, if applicable, or by re-biopsy if resection is not possible. Post-operative therapy will begin when patients are deemed ready by their surgical oncologist team. Patients in the control arm will then undergo another 8 cycles of mFOLFOX6 with Nivolumab administered concurrently. Nivolumab will then be administered every four weeks. The experimental arm will receive the same post-operative regimen but including FPV-CV301 boosters given concurrently with mFOLFOX6 and Nivolumab. FPV-CV301 will then be administered every 12 weeks, and Nivolumab every 4 weeks. We will collect peripheral blood for evaluation of correlates upon the completion of therapy. The vaccination approach of initial immunization during the neoadjuvant period followed by FPV-CV301 boosters for two years postoperatively was chosen to optimize the induction of a long-lasting tumor-specific host response. Neoadjuvant vaccination will also allow for analysis of the tumor microenvironment in resection specimens. Post-therapy patients will be under surveillance per NCCN guidelines with repeat CEA every 3 months for 2 years followed by every 6 months for 1 year (total 3 years), repeat CT of the C/A/P every 3 months for 2 years followed by every 6 months for up to 1 year (total 3 years), and colonoscopy at one year with repetition based on findings at the time of the procedure.

Official Title
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A Phase II Trial of Perioperative CV301 Vaccination in Combination With Nivolumab and Systemic Chemotherapy for Resectable Hepatic-Limited Metastatic Colorectal Cancer HCRN: GI16-288

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: mFOLFOX6
* Biological: MVA-BN-CV301
* Biological: FPV-CV301
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Age ≥ 18 years at the time of consent. ECOG Performance Status of ≤ 2 and/or sufficient to undergo both perioperative systemic chemotherapy and hepatic surgery as determined by surgical and medical oncology evaluations. Histologically confirmed hepatic-limited metastatic colorectal cancer. Genomic testing results are required. FoundationOne platform is preferred, however results from an equivalent genomic platform may be used after discussion with the sponsor investigator. Completely resectable disease as determined by the guidelines below and surgical oncology evaluation. Patients with bilobar disease that requires resection and ablation are allowed provided the surgical oncologist can render the patient NED (no evidence of disease) at the conclusion of the operation. Synchronous primary colorectal and metastatic hepatic tumors are eligible, provided all disease can be resected in a single operation. NOTE: Subjects who had surgery for their primary tumor prior to registration to this trial are still eligible. Additionally: No radiographic evidence of involvement of: extrahepatic bile ducts, main portal vein or celiac/retroperitoneal lymph nodes. Adequate predicted functional liver remnant (FLR) as deemed by the individual site surgical oncologists. Patients with synchronous metastatic disease are allowed provided their primary tumor can be completely resected at the time of metastasectomy. Neoadjuvant pelvic radiotherapy for rectal cancer is not permitted Patients must be treatment naïve with respect to their stage IV colorectal cancer. History of prior adjuvant systemic chemotherapy containing oxaliplatin is allowed as long as as it has been greater than 12 months from completion of oxaliplatin to study enrollment. NOTE: Neoadjuvant pelvic chemoradiotherapy as part of the management of synchronous metastatic rectal cancer is allowed, provided chemoradiation was completed prior to enrollment on study. Hematological: Platelet Count ≥ 100,000 mm^3 Absolute Neutrophil Count (ANC) ≥1500 µ/L Hemoglobin (Hgb) ≥ 9 g/dL Renal: o Creatinine < 1.5 x ULN OR Calculated Creatinine Clearance ≥ 60 mL/min Hepatic: Total Bilirubin ≤ 1.5 × upper limit of normal (ULN)^2 Aspartate aminotransferase (AST) ≤ 5 × ULN; given presence of liver metastases Alanine aminotransferase (ALT) ≤ 5 × ULN; given presence of liver metastases Alkaline Phosphatase < 2.5 x ULN INR, PT, or APTT ≤ 1.5x ULN unless participant is receiving anticoagulant therapy, in which case they must be on a stable dose Females of childbearing potential must have a negative serum pregnancy test within 24 hours of study drug. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months without another cause, or a documented serum follicle stimulating hormone (FSH) ≥ 35 mIU/mL. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Females of childbearing potential and male participants must be willing to abstain from heterosexual intercourse or to use contraception as outlined in the protocol. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Exclusion Criteria: Patients with mutations in or deficient expression of one or more of the mismatch repair genes listed: MSH2, MSH3, MSH6, MLH1, PMS1, PMS2. Active infection requiring systemic therapy. Pregnant or breastfeeding. Second primary malignancy. Clear exceptions are 1) patient had a second primary malignancy but has been treated and disease free for at least 3 years and, 2) in situ carcinoma (e.g. in situ carcinoma of the cervix). Patients with chronic lymphocytic leukemia will be allowed if their blood counts are within acceptable hematologic parameters and if they are not currently requiring cytotoxic or biologic anticancer treatment (supportive treatment such as IVIG is permitted). Metastatic disease not limited to the liver. Disease not amenable to complete resection, not resectable within the confines of a single surgery, or where resection would result in inadequate functional liver remnant. Prior surgery or systemic therapy for colorectal cancer within 6 months or 12 months if systemic chemotherapy included oxaliplatin of study enrollment. Immunodeficient patients including but not limited to patients with HIV/AIDS and chronic Hepatitis B and C. Patient with clinically significant cardiomyopathy, coronary disease, heart failure New York Heart Association (NYHA) class III or IV, or cerebrovascular accident (CVA) within 1 year of study enrollment (CV301). Subjects with known severe allergy to eggs, egg products, or aminoglycoside antibiotics (for example, gentamicin or tobramycin) (CV301). Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Participants with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g. Hormone replacement after adrenal crisis) Excluding patients with serious or uncontrolled medical disorders Treatment with botanical preparations (e.g. herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment. History of allergy or hypersensitivity to study drug components. History of allogenic stem cell or solid organ transplant.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A - Control<br>mFOLFOX6 and Nivolumab every 2 weeks for 4 cycles. After neoadjuvant therapy, patients will be re-evaluated for surgical resection. Patients still considered resectable will undergo surgical resection with the goal of completely treating all of their disease by either resection and/or ablation. Patients with bilobar disease must have all of their disease treated in a single operation. Once patients in the post-operative period are deemed ready to begin therapy, patients in the control arm will then undergo another 8 cycles of mFOLFOX6 in addition to Nivolumab. After this, Nivolumab will be given every 4 weeks completing therapy at week 110. | Drug: mFOLFOX6<br>* The control arm (Arm A) and experimental arm (Arm B) will receive mFOLFOX6 every 2 weeks for 4 cycles. Once patients in the post-operative period are deemed ready to begin therapy, patients in the control arm will then undergo another 8 cycles of mFOLFOX6.<br>Drug: Nivolumab<br>* Nivolumab at a dose of 240 mg as a 30 minute IV infusion every 2 weeks until progression. Arm B will receive Nivolumab starting with the vaccinations. Arm A will begin the Nivolumab with the initiation mFOLFOX.<br>* Other names: Opdivo;|
| Experimental: Arm B - Experimental<br>Two doses of Nivolumab and MVA-BN-CV301 each given 2 weeks apart (Days -28, -14), followed by four doses of Nivolumab plus FPV-CV301 given 2 weeks apart concurrently with mFOLFOX6, which will again be administered every 2 weeks for 4 cycles (Nivolumab, FPV-CV301 and mFOLFOX6). After neoadjuvant therapy, patients will be re-evaluated for surgical resection. Patients still considered resectable will undergo surgical resection with the goal of completely treating all of their disease by either resection and/or ablation. Patients with bilobar disease must have all of their disease treated in a single operation. Patients in the experimental arm will receive 8 cycles of mFOLFOX6 in addition to Nivolumab and FVP-CV301 boosters with the first two given on Day 0 and 14 and then every 4 weeks. FVP-CV301 will then be administered every twelve weeks completing therapy at week 110. | Drug: mFOLFOX6<br>* The control arm (Arm A) and experimental arm (Arm B) will receive mFOLFOX6 every 2 weeks for 4 cycles. Once patients in the post-operative period are deemed ready to begin therapy, patients in the control arm will then undergo another 8 cycles of mFOLFOX6.<br>Biological: MVA-BN-CV301<br>* The experimental arm (Arm B) will receive MVA-BN-CV301 in 4 injections of 4 x 10(8) infectious units/0.5 mL given subcutaneously prior to the start of chemotherapy on days -28 and -14.<br>* Other names: CV301;Biological: FPV-CV301<br>* The experimental arm (Arm B) will receive FPV-CV301 in 1 dose of 1 x 10(9) infectious units/0.5 mL given subcutaneously concurrently with chemotherapy (at least an hour prior to chemotherapy) on days 0, 14, 28 and 42 pre-operatively, and FVP-CV301 boosters on day 0 and 14 and then every 4 weeks (day 42, 70, 98). After day 98, FVP-CV301 will then be administered every twelve weeks completing therapy at week 110.<br>* Other names: Fowl Pox Virus;Drug: Nivolumab<br>* Nivolumab at a dose of 240 mg as a 30 minute IV infusion every 2 weeks until progression. Arm B will receive Nivolumab starting with the vaccinations. Arm A will begin the Nivolumab with the initiation mFOLFOX.<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Compare OS in both Arms. OS is defined by the date of metastasectomy to date of recurrence or death from any cause. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence free survival (RFS) | Compare recurrence free survival between the experimental and control treatment groups. RFS is defined as the time from metastasectomy until progression by RECIST 1.1 or death from any cause. | 3 years | 
| Evaluate Best Overall Response Rate (ORR) | Evaluate the ORR (both by RECIST 1.1 and surgical pathology) between the experimental and control groups. ORR is defined as the sum of partial responses (PRs) and complete responses (CRs) by RECIST 1.1. | 3 years | 
| Evaluate the proportion of patients amenable to complete resection/ablation | Compare the proportion of patients amenable to complete resection/ablation between the experimental and control treatment groups in patients who experience a recurrence after surgery | 3 years | 
| Evaluate the perioperative surgical outcomes | Assess complications and severity scores between the experimental and control groups | 3 years | 
| Overall Survival (OS) | Compare OS between treatment groups OS is defined by the date of metastasectomy to date of death from any cause | 3 years | 
| Pathologic Complete Response | Compare the pathologic complete response rate to neoadjuvant therapy in resected tumor tissue between the experimental and control groups. Pathologic complete response is defined as no residual disease upon review of pathology | 3 years | 
| Progression Free Survival (PFS) | In patients who experience a recurrence after protocol therapy, compare the progression free survival post-recurrence between the experimental and control groups. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CV301 Vaccination, mFOLFOX6, Fowlpox (FP)-CV301, nivolumab, MVA-BN-CV301