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 3 years, repeat CT of the C/A/P every 3
months for 2 years followed by every 6 months for up to 5 years, and colonoscopy at one year
with repetition based on findings at the time of the procedure.
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.
