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

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ClinicalTrials.gov Identifier: NCT03547999
Recruitment Status : Recruiting
First Posted : June 6, 2018
Last Update Posted : July 13, 2018
Sponsor:
Collaborators:
Bavarian Nordic
Hoosier Cancer Research Network
Bristol-Myers Squibb
Information provided by (Responsible Party):
Darren Carpizo, MD, Hoosier Cancer Research Network

Brief Summary:

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 who are eligible for and consent to enroll onto this trial will be randomized to either the control arm or the experimental arm. Patients in the control arm (Arm A) will receive mFOLFOX6 and Nivolumab every 2 weeks for 4 cycles starting from Day 0. The experimental arm (Arm B) will first be treated with two doses of Nivolumab and MVA-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 Days 0, 14, 28, 42). The treatment order for Arm A is nivolumab followed by mFOLFOX6. For Arm B the order of administration is nivolumab followed by the vaccination at least one hour prior to mFOLFOX6. A window of +2 days between administration of nivolumab ± vaccination and mFOLFOX6 is allowed. This window will accommodate subjects that receive their chemotherapy locally.

After neoadjuvant therapy, patients will be re-evaluated for surgical resection with re-staging CT of the C/A/P. 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. Synchronous primary colorectal and metastatic hepatic tumors are eligible, provided all disease can be resected in a single operation. Patients deemed unresectable will be managed according to their individual cancer center's disease group management team and will continue to receive both CV301 and nivolumab as described below in the post-operative treatment schedule. In the event that administration of CV301 and/or Nivolumab is impacting the delivery or tolerability of standard of care therapy, patients will be removed from protocol therapy.

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 (Day 0, 14, 28, 42, 56, 70, 84, 98) followed by Nivolumab every 4 weeks completing therapy at week 110. Patients in the experimental arm will receive 8 cycles of mFOLFOX6 in addition to Nivolumab (Day 0,14,28,42, 56, 70, 84, 98) and FVP-CV301 boosters with the first two given 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. In both arms, Nivolumab will be administered on the day that systemic chemotherapy resumes for 8 cycles. The treatment order for Arm A is nivolumab followed by mFOLFOX6. For Arm B the order of administration is nivolumab followed by the vaccination at least one hour prior to mFOLFOX6. A window of +2 days between administration of nivolumab ± vaccination and mFOLFOX6 will be allowed. This window will accommodate subjects that receive their chemotherapy locally.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: mFOLFOX6 Biological: MVA-BN-CV301 Biological: FPV-CV301 Drug: Nivolumab Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open-Label
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 26, 2018
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Active Comparator: Arm A - Control
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
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.

Drug: Nivolumab
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.
Other Name: Opdivo

Experimental: Arm B - Experimental
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
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.

Biological: MVA-BN-CV301
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.
Other Names:
  • Modified Vaccinia Ankara
  • CV301

Biological: FPV-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.
Other Name: Fowl Pox Virus

Drug: Nivolumab
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.
Other Name: Opdivo




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 5 years ]
    Compare OS in both Arms. OS is defined by the date of metastasectomy to date of death from any cause.


Secondary Outcome Measures :
  1. Recurrence free survival (RFS) [ Time Frame: 3 years ]
    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.

  2. Evaluate Overall Response Rate (ORR) [ Time Frame: 3 years ]
    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. Evaluate the proportion of patients amenable to complete resection/ablation [ Time Frame: 3 years ]
    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

  4. Evaluate the perioperative surgical outcomes [ Time Frame: 3 years ]
    Assess complications between the experimental and control groups

  5. Evaluate the perioperative surgical outcomes [ Time Frame: 3 years ]
    Assess severity scores between the experimental and control groups

  6. Overall Survival (OS) [ Time Frame: 3 years ]
    Compare OS between treatment groups OS is defined by the date of metastasectomy to date of death from any cause

  7. Pathologic Complete Response [ Time Frame: 3 years ]
    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

  8. Progression Free Survival (PFS) [ Time Frame: 3 years ]
    In patients who experience a recurrence after protocol therapy, compare the progression free survival post-recurrence between the experimental and control groups.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 in which at least one metastatic tumor is large enough to provide tissue for 5 core biopsies. 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.
  • FoundationOne testing results will be requested if previously performed. If FoundationOne testing has not been done, tissue should be submitted for testing per standard of care.
  • 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. 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 measured by CT and 3D CT volumetry as deemed by the individual site surgical oncologists.
  • Patients must be treatment naïve with respect to their stage IV colorectal cancer. History of prior surgery for management of a primary colorectal cancer is allowed as long as the surgery was completed at least six months prior to study enrollment and the patient did not receive adjuvant systemic chemotherapy containing oxaliplatin. If the patient received adjuvant systemic chemotherapy with oxaliplatin, therapy must have completed at least 12 months prior to study enrollment.
  • Hematological:

    • Platelet Count ≥ 100,000 mm^2
    • 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
  • 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 males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 5 months (FOCBP) and 7 months (males) after treatment discontinuation if they are randomized to the control only arm. If they randomize to the experimental arm they must use 2 forms of effective methods of contraception from the time of informed consent and throughout their lifetime. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.
  • 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 one or more of the mismatch repair genes.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03547999


Contacts
Contact: Darren Carpizo, MD, PhD 732-235-7701 carpizdr@cinj.rutgers.edu
Contact: Donna Sullivan 317-634-5842 ext 40 dsullivan@hoosiercancer.org

Locations
United States, New Jersey
Rutgers Cacner Institute of New Jersey Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Tracie Saunders    732-235-8861    tks13@cinj.rutgers.edu   
Principal Investigator: Darren Carpizo, MD,PhD         
Sponsors and Collaborators
Darren Carpizo, MD
Bavarian Nordic
Hoosier Cancer Research Network
Bristol-Myers Squibb
Investigators
Principal Investigator: Darren R. Carpizo, M.D. Rutgers Cancer Institute of New Jersey

Additional Information:
Responsible Party: Darren Carpizo, MD, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT03547999     History of Changes
Other Study ID Numbers: HCRN GI16-288
First Posted: June 6, 2018    Key Record Dates
Last Update Posted: July 13, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Darren Carpizo, MD, Hoosier Cancer Research Network:
CV301 Vaccination
mFOLFOX6
Fowlpox (FP)-CV301
nivolumab
MVA-BN-CV301

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Vaccines
Antibodies, Monoclonal
Nivolumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents