VB-111 in Combination With Nivolumab in People With Metastatic Colorectal Cancer (mCRC)

Patrocinador principal: National Cancer Institute (NCI)

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.

...

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.

• Metastatic Colorectal Cancer
• Colorectal Neoplasms
• Colorectal Carcinoma
• Colorectal Cancer With Hepatic Metastases
• Colorectal Tumors

Tipo de intervención: Biological

Nombre de intervención: VB-111

Descripción: 1E13 or 0.7E13 VP via IV infusion on Day 1 of cycle 1 and continue every 6 weeks

Etiqueta de grupo de brazo: 1/Arm 1

Tipo de intervención: Drug

Nombre de intervención: Nivolumab

Descripción: 240 mg of nivolumab via IV infusion on Day 1 of each cycle starting on cycle 2 and continue every 2 weeks

Etiqueta de grupo de brazo: 1/Arm 1

Criterios:

- 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.

Género: All

Edad mínima: 18 Years

Edad máxima: N/A

Voluntarios Saludables: No

Apellido: Tim F Greten, M.D.

Teléfono: (240) 760-6114

Email: [email protected]

United States

July 9, 2020

Tipo: Sponsor

• Nonreplicating adenovirus
• Antitumor Immunity
• PD-1 inhibition
• Immune Checkpoint Inhibition

• Colorectal Neoplasms

Etiqueta: 1/Arm 1

Tipo: Experimental

Descripción: VB-111 and nivolumab

Asignación: N/A

Modelo de intervención: Single Group Assignment

Propósito primario: Treatment

Enmascaramiento: None (Open Label)