Background:
- Immune based approaches in GI cancers have unfortunately- with the notable exception of
immune checkpoint inhibition in microsatellite instable (MSI-H) disease and gastric
cancer-been largely unsuccessful. The reasons for this are unclear but no doubt relate
to the fact that in advanced disease GI cancer appears to be less immunogenic, as
evidenced by the lack of infiltrating lymphocytes with advancing T stage as well as an
immunosuppressive tumor micro environment.
- VB-111 is an anti-angiogenic agent comprising of a nonreplicating E1 deleted adenovirus
type 5 which contains a modified murine preproendothelin (PPE) promoter and Fas-chimera
transgene
- VB-111 has been tested and shows promise in glioblastoma, ovarian and thyroid tumors
- Nivolumab is a human monoclonal antibody directed against PD-1.
- The aim of this study is to study the effects of VB-111 in colorectal cancer (CRC) and
to evaluate whether the antitumor immunity induced by VB-111 therapy can be enhanced by
PD-1 inhibition.
Objectives:
- To determine the safety and tolerability of VB-111 in combination with nivolumab in
patients with refractory, metastatic CRC
- To determine Best Overall Response (BOR) (partial response (PR) + complete response
(CR)) according to Response Evaluation Criteria (RECIST v1.1) of combined treatment of
VB-111 and nivolumab in patients with refractory, metastatic CRC.
Eligibility:
- Histopathological confirmation of colorectal cancer metastatic to the liver
- Patients must have progressed on > 2 lines of standard of care chemotherapy for
colorectal cancer or been intolerant of chemotherapy or refused prior chemotherapy.
- Patients tumors must be documented to be microsatellite stable (MSS).
- Patients must have at least 1 focus of metastatic disease that is amenable to pre-and
on-treatment biopsies and be willing to undergo this.
- All patients enrolled will be required to have measurable disease by RECIST v 1.1
criteria.
Design:
- The proposed study is a phase II study of VB-111 in combination with immune checkpoint
inhibition (nivolumab) in patients with metastatic CRC
- Treatment will be delivered in cycles consisting of 2 weeks with VB-111 given every 6
weeks and nivolumab given every 2-week until progression or unacceptable toxicity.
- Disease status evaluation will be done every 8 (+/- 1) weeks after the start of study
therapy.
- INCLUSION CRITERIA:
- Patients must have histopathological confirmation of colorectal cancer.
- Patients must have radiologically confirmed liver metastasis.
- Patients must:
- have progressed on > 2 lines of standard of care chemotherapy for colorectal
cancer
OR
--been intolerant of standard of care chemotherapy for colorectal cancer
OR
- refused prior standard of care chemotherapy for colorectal cancer.
- Patients who have a known KRAS wild type tumor must have progressed, been
intolerant of or refused anti-EGFR based treatment.
- Patients tumors must be documented to be microsatellite stable (MSS).
- Patients must have at least 1 focus of metastatic disease that is amenable to
pre- and on-treatment biopsies and be willing to undergo this. Ideally, the
biopsied lesion should not be one of the target measurable lesions, although this
can be up to the discretion of the investigators
- Patients must have measurable disease by RECIST v 1.1 criteria.
- Age greater than or equal to 18 years. Because no dosing or adverse event data
are currently available on the use of nivolumab in combination with VB-111 in
patients < 18 years of age, children are excluded from this study, but will be
eligible for future pediatric trials.
- ECOG performance status 0-1
- Adequate hematological function defined by:
- white blood cell (WBC) count greater than or equal to 3 (SqrRoot) 10(9)/L
- absolute neutrophil count (ANC) greater than or equal to 1.5 (SqrRoot) 10(9)/L
- lymphocyte count greater than or equal to 0.5 (SqrRoot) 10(9)/L
- platelet count greater than or equal to 100 (SqrRoot) 10(9)/L
- Hgb greater than or equal to 9 g/ dL (more than 48 hours post-completion of blood
transfusion)
- PT and PTT (seconds) < 1.2 x ULN. Patients who are anticoagulated do not need to
meet criteria for PT and PTT
- INR < 1.2 x ULN. Patients who are anticoagulated do not need to meet criteria for
INR.
- Adequate hepatic function defined by:
- a total bilirubin level less than or equal to 1.5 x ULN,
- an AST level less than or equal to 2.5xULN in the absence of hepatic metastasis; or
less than or equal to 5 x ULN in the presence of hepatic metastases,
- an ALT level less than or equal to 2.5xULN in the absence of hepatic metastasis; or
less than or equal to 5 x ULN in the presence of hepatic metastases
-Adequate renal function defined by:
- Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be
used in place of CrCl) (A Creatinine clearance (CrCl) or eGFR should be calculated per
institutional standard.):
- < 1.5x institution upper limit of normal OR
greater than or equal to 50 mL/min/1.73 m(2) for participant with creatinine levels greater
than or equal to 1.5 X institutional ULN
- The effects of nivolumab and VB-111 on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use adequate
contraception prior to study entry and for the duration of study participation and up
to 5 months (women) and 7 months (men) after the last dose of the nivolumab or 2
months after the last dose of VB-111 whichever is the longer time period. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.
- Troponin level in normal range at the time of enrollment.
- Patient must be able to understand and willing to sign a written informed consent
document.
- Weight > 35kg
- Patients must be enrolled in tissue collection protocol 11C0112.
EXCLUSION CRITERIA:
- Patients who have had standard-of-care anti-cancer therapy or therapy with
investigational agents (e.g. chemotherapy, immunotherapy, endocrine therapy, targeted
therapy, biologic therapy, tumor embolization, monoclonal antibodies or other
investigation agents), large field radiotherapy, or major surgery within 4 weeks prior
to enrollment.
- Patients who have had anti-VEGF therapy within 4 weeks prior to enrollment.
- Patients currently on a corticosteroid dose greater than physiologic replacement
dosing defined as 10 mg of cortisone per day or its equivalent.
- Patients with known brain metastases because of their poor prognosis and because they
often develop progressive neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events.
- Patients with signs of liver failure, e.g. clinically significant ascites,
encephalopathy, or variceal bleeding within 6 months prior to enrollment.
- Prior major liver resection: remnant liver <50% of the initial liver volume. Patients
with a biliary stent can be included.
- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids. These include but are not limited to patients with
a history of immune related neurologic disease, multiple sclerosis, autoimmune
(demyelinating) neuropathy, Guillain-Barre syndrome or CIDP, myasthenia gravis;
systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma,
inflammatory bowel disease (IBD), Crohn s, ulcerative colitis, hepatitis; and patients
with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or
phospholipid syndrome. Such diseases should be excluded because of the risk of
recurrence or exacerbation of disease.
Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with
replacement hormones including physiologic corticosteroids are eligible. Patients with
rheumatoid arthritis and other arthropathies, Sjogren s syndrome and psoriasis controlled
with topical medication and patients with positive serology, such as antinuclear antibodies
(ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
involvement and potential need for systemic treatment but should otherwise be eligible.
- History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with
organizing pneumonia) or evidence of active pneumonitis on screening chest CT scan.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations (within timeframes identified in
the bullets below) that would limit compliance with study requirements.
- History of severe or unstable cerebrovascular disease.
- Pulse oximetry < 92% on room air
- Myocardial infarction within 6 months prior to enrollment
- History of myocarditis
- Sustained hypotension (<90/50 mmHg) or uncontrolled hypertension (>160/100 mmHg)
- Stroke within 6 months prior to enrollment.
- Patients with proliferative and/or vascular retinopathy.
- Significant vascular disorders (e.g. aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to enrollment.
- History of hemoptysis (> 1/2 teaspoon of bright red blood per episode) or active GI
bleeding within 6 months prior to enrollment.
- Evidence of a bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)
- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
enrollment.
- HIV-positive patients are excluded because HIV causes complicated immune deficiency
and study treatment can possess more risks for these patients.
- Prior autologous or allogenic hematopoietic stem cell transplant.
- Subjects with ascites.
- Patients with unhealed surgical wounds for more than 30 days.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab or VB-111.
- History of severe hypersensitivity reaction to any monoclonal antibody.
- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years prior to enrollment.
- Pregnant women are excluded from this study because nivolumab and VB-111 potential for
teratogenic or abortifacient effects are unknown. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with nivolumab and VB-111, breastfeeding should be discontinued if the mother
is treated with nivolumab and/or and VB-111.
