Addition of NG-641 to Nivolumab Under Exploration in Epithelial Tumors

Epithelial Tumors

The combination of the novel adenoviral vector NG-641 and nivolumab (Opdivo) is being investigated in patients in the phase 1a/b NEBULA trial (NCT05043714) in patients with previously treated metastatic or advanced epithelial tumors to assess if the combination can re-program immunosuppressive tumor microenvironments to allow these tumors to respond to immunotherapy.

The open-label, dose-escalating NEBULA trial is examining the safety and preliminary efficacy of the adenoviral vector. Details of the ongoing trial were presented in a poster at the 2022 AACR Annual Meeting.¹

NG-641 is a next-generation blood-stable and transgene-armed T-SIGn adenoviral vector. T-SIGn vectors allow for intravenous administration for selective infection of cancer cells as well as replication at tumor sites. Activated immune cells from the therapy support functional anti-tumor responses.

The agent expresses 4 immunostimulatory transgenes and works by crosslinking T cells to fibroblast activating-protein–positive cancer-associated fibroblasts, which activates the immune system. Additionally, CXCL9 and CXCL10 induce T-cell migration and interferon-α2 enhances T-cell activation and induces the killing of cancer cells by tumor antigen–specific T cells.

Already, NG-641 has shown encouraging preliminary safety and tolerability results in the ongoing phase 1a dose-escalation STAR trial (NCT04053283), which is a first-in-human study for the gene therapy.

When used in combination with nivolumab in the NEBULA study, the regimen is expected to result in complementary mechanisms of action.

Patients with metastatic or advanced epithelial cancers who have received prior anti–PD-1/PD-L1 therapy, have measurable disease, an ECOG performance status, adequate lung reserve, and adequate organ and bone marrow function are eligible to enroll in the trial. The included tumor types are urothelial carcinoma, squamous cell carcinoma of the head and neck, microsatellite instability–high or mismatch repair deficient cancers, non–small cell lung cancer, uterine or endometrial cancer, cervical cancer, esophageal cancer, gastric cancer, triple-negative breast cancer, cutaneous squamous cell carcinoma, hepatocellular carcinoma, and tumor mutational burden–high tumors.

Those with active infections, viral disease, autoimmune disease, acute kidney injury, renal impairment, or interstitial lung disease as well as patients with risk factors for bleeding or clotting events, bowel obstruction, or tumor flare are ineligible to participate in the trial.

A total of 30 patients are expected to be enrolled in the phase 1a portion of the trial, which consists of 5 escalating dose levels in a Bayesian Optimal Interval design. Phase 1b is the dose-expansion stage of the trial, which will consist of tumor-specific cohorts.

Dose level –1 is an intravenous infusion of NG-641 at 6 x 10¹¹ virus particles (vp) given on days 1, 3, and 5; dose level 1 is 1 x 10¹² vp of NG-641 on days 1, 3, and 5; dose level 2 is 1 x 10¹² vp on day 1 followed by 3 x 10¹² vp on days 3 and 5; dose level 3 is 1 x 10¹² vp on day 1 followed by 6 x 10¹² vp on days 3 and 5; and dose level 4 is 1 x 10¹² vp on day 1 followed by 1 x 10¹³ vp on days 3 and 5. Across all dose levels, nivolumab will be administered at 480 mg on day 15 of the 4-week cycle.

The primary end point of the NEBULA trial is safety and tolerability as well as the recommended dose of the regimen. The secondary end point is preliminary antitumor activity. Additionally, pharmacokinetics, immunogenicity, and pharmacodynamics will be assessed using tumor tissue and blood samples.

Enrollment to the first cohort is currently ongoing in the United States at the UCLA Medical Center and in the United Kingdom at The Clatterbridge Cancer Centre, Oxford University Hospitals.

Reference

1. Lillie T, Parkes E, Ottensmeier C, et al. A multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA). Presented at: AACR Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Abstract CT214.