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

Phase 2

Completed

• Conditions: Colorectal Cancer With Hepatic Metastases; Metastatic Colorectal Cancer; Colorectal Neoplasms; Colorectal Carcinoma; Colorectal Tumors
• Interventions: Biological: Vascular Biogenics (VB)-111; Drug: Nivolumab

• Registration Number: NCT04166383
• Lead Sponsor: National Cancer Institute (NCI)

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 Vascular Biogenics (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 computed tomography (CT) or magnetic resonance imaging (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 gastrointestinal (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.

* Vascular Biogenics (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 programmed cell death protein 1 (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 in Solid Tumors (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.

* Patient's 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.

Study Timeline

• Study First Submitted: 2019-11-15
• Study First Submitted QC: 2019-11-15
• Study First Posted: 2019-11-18
• Study Start: 2020-08-09
• Primary Completion: 2022-04-12
• Study Completion: 2022-12-31
• Results First Submitted: 2023-03-27
• Results First Submitted QC: 2023-05-12
• Results First Posted: 2023-06-09
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-13
• Last Update Posted: 2023-11-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 14

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1/Arm 1	Vascular Biogenics (VB)-111	Vascular Biogenics (VB)-111 and nivolumab
1/Arm 1	Nivolumab	Vascular Biogenics (VB)-111 and nivolumab

Primary Outcome Measures

Name	Time	Method
Number of Participants With Grade 1, Grade 2, Grade 3, Grade 4, and/or Grade 5 Adverse Events That Are Possibly, Probably and/or Definitely Related to Drug	90 days after treatment	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
Best Overall Response (BOR)	Follow up visits are planned to be performed at 60 (+/- 14 days) and 90 (+/- 14 days) days after treatment discontinuation to evaluate patient's safety, up to 6 months.	Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

Secondary Outcome Measures

Name	Time	Method
Median Overall Survival (OS)	The time between the first day of treatment to the day of death, an average of 6.9 months.	Overall survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median OS will be reported along with 95% confidence intervals. Overall survival is the time between the first day of treatment to the day of death.
Median Progression-free Survival (PFS)	The time between the first day of treatment to the day of disease progression, an average of 1.8 months.	Progression-free survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median PFS will be reported along with 95% confidence interval. PFS is defined as the time between the first day of treatment to the day of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
6-month Progression-free Survival (PFS)	6 months	6-month progression-free survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median PFS will be reported along with 95% confidence interval. PFS is defined as the time between the first day of treatment to the day of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States