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Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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.

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.

mFOLFOX6

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.

MVA-BN-CV301

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.

FPV-CV301

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.

Patrick Boland, M.D.

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.

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

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

Compare OS in both Arms. OS is defined by the date of metastasectomy to date of recurrence or death from any cause.

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.

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.

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

Assess complications and severity scores between the experimental and control groups

Compare OS between treatment groups OS is defined by the date of metastasectomy to date of death from any cause

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

In patients who experience a recurrence after protocol therapy, compare the progression free survival post-recurrence between the experimental and control groups.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Trial of Perioperative CV301 Vaccination in Combination With Nivolumab and Systemic Chemotherapy for Metastatic CRC	NCT03547999	Metastatic Colo...	mFOLFOX6 MVA-BN-CV301 FPV-CV301 Nivolumab	18 Years -	Hoosier Cancer Research Network
A Trial of Perioperative CV301 Vaccination in Combination With Nivolumab and Systemic Chemotherapy for Metastatic CRC	NCT03547999	Metastatic Colo...	mFOLFOX6 MVA-BN-CV301 FPV-CV301 Nivolumab	18 Years -	Hoosier Cancer Research Network

Spots Global Cancer Trial Database for cv301 vaccination