A Trial of Perioperative CV301 Vaccination in Combination With Nivolumab and Systemic Chemotherapy for Metastatic CRC
| Status: | Recruiting |
|---|---|
| Conditions: | Colorectal Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/13/2019 |
| Start Date: | June 26, 2018 |
| End Date: | June 2023 |
| Contact: | Darren Carpizo, MD, PhD |
| Email: | carpizdr@cinj.rutgers.edu |
| Phone: | 732-235-7701 |
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
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.
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.
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. Preferable to
have at least one metastatic tumor large enough to provide tissue for 5 core biopsies
but if not feasible, additional metastatic lesions may be used to provide a total of 5
core samples. The biopsies should be obtained from the least number of lesions as
possible.
- 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 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 greater than 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
- 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 (FOCBP) 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
discontinuation of nivolumab. The two contraception methods can be comprised of two
barrier methods, or a barrier method plus a hormonal method. For subjects in the
vaccination Arm, if the vaccination is the last study drug administered the timeframe
for contraception is 4 months from last dose of vaccination.
- 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.
We found this trial at
2
sites
Duarte, California 91010
Principal Investigator: Laleh Melstrom, MD
Phone: 626-218-0961
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New Brunswick, New Jersey 08903
Principal Investigator: Darren Carpizo, MD,PhD
Phone: 732-235-8861
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