Phase II Trial of VB-111 in Combination With Nivolumab in Patients With Metastatic Colorectal Cancer (mCRC)
VB-111 in Combination With Nivolumab in People With Metastatic Colorectal Cancer (mCRC)
Sponsors
Source
National Institutes of Health Clinical Center (CC)
Oversight Info
Is Fda Regulated Drug
Yes
Is Fda Regulated Device
No
Brief Summary
Background:
Gastrointestinal cancer is one of the most common cancers worldwide. Researchers think an
unmet need exists to understand and improve treatment options. They want to see if a
combination of drugs can help people with metastatic colorectal cancer.
Objective:
To see if using a combination of VB-111 and nivolumab is safe and will cause colorectal
tumors to shrink.
Eligibility:
People ages 18 and older with microsatellite stable colorectal cancer that has spread to the
liver
Design:
Participants must consent to sample collection protocol 11C0112.
Participants will be screened with:
Blood tests
Scans
Tumor samples. If these are not available, participants will have a biopsy.
Before they start treatment and with every treatment cycle, participants will have:
Physical exams
Blood tests
Heart tests
Before they start treatment and every 4 cycles, participants will have CT or MRI scans. For
these, they will lie in a machine that takes pictures of the body. For the MRI, a soft
padding or coil will be placed around their head.
Participants will have biopsies before they start therapy. They will have them again after 2
6 weeks on study.
On day 1 of 14-day cycles, participants will get one or both study drugs by vein.
After they finish treatment, participants will have monthly visits for 3 months. They will
have a physical exam and blood tests.
If participants stop treatment for reasons other than their disease getting worse, they will
have scans about every 8 weeks. This will continue until their disease gets worse.
Participants will be contacted by phone or email every 6 months. This will continue for life.
...
Detailed Description
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.
Overall Status
Not yet recruiting
Start Date
2019-12-12
Completion Date
2022-12-31
Primary Completion Date
2022-12-31
Phase
Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
To determine the safety and tolerability of VB-111 in combination with immune checkpoint inhibition (anti-PD-1) in patients with refractory, metastatic CRC |
90 days after treatment |
To determine Best Overall Response (BOR) |
every 8 weeks |
Enrollment
27
Conditions
Intervention
Intervention Type
Biological
Intervention Name
Description
1E13 or 0.7E13 VP via IV infusion on Day 1 of cycle 1 and continue every 6 weeks
Arm Group Label
1/Arm 1
Intervention Type
Drug
Intervention Name
Description
240 mg of nivolumab via IV infusion on Day 1 of each cycle starting on cycle 2 and continue every 2 weeks
Arm Group Label
1/Arm 1
Eligibility
Criteria
- INCLUSION CRITERIA:
- Patients must have histopathological confirmation of colorectal cancer by the
Laboratory of Pathology of the NCI.
- 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, fibrinogen < 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
- 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.
Gender
All
Minimum Age
18 Years
Maximum Age
N/A
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
Tim F Greten, M.D. |
Principal Investigator |
National Cancer Institute (NCI) |
Overall Contact
Location
Facility |
Status |
Contact |
National Institutes of Health Clinical Center Bethesda Maryland 20892 United States |
Not yet recruiting |
Last Name: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office Phone: 888-624-1937 |
Location Countries
Country
United States
Verification Date
2019-11-13
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor
Keywords
Has Expanded Access
No
Condition Browse
Secondary Id
20-C-0022
Number Of Arms
1
Intervention Browse
Mesh Term
Nivolumab
Arm Group
Arm Group Label
1/Arm 1
Arm Group Type
Experimental
Description
VB-111 and nivolumab
Firstreceived Results Date
N/A
Firstreceived Results Disposition Date
N/A
Study Design Info
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Study First Submitted
November 15, 2019
Study First Submitted Qc
November 15, 2019
Study First Posted
November 18, 2019
Last Update Submitted
December 6, 2019
Last Update Submitted Qc
December 6, 2019
Last Update Posted
December 9, 2019
ClinicalTrials.gov processed this data on December 09, 2019
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.