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Ofra-Vec for the Treatment of Platinum-Resistant Ovarian Cancer

The FDA has granted Fast Track designation for ofra-vec (ofranergene obadenovec or VB-111) in combination with paclitaxel for the treatment of platinum-resistant ovarian cancer. It is an investigational anti-cancer, gene-based agent in development to treat a wide range of solid tumors.

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The lead clinical program for ofra-vec is the OVAL Phase III registration-enabling trial in recurrent platinum-resistant ovarian cancer patients. Researchers recently completed patient enrollment of 409 patients in this global trial being conducted at centers in the United States, Europe, Israel, and Japan. In addition, the Independent Data Safety Monitoring Committee unanimously recommended to continue the trial as planned, following review of unblinded data from 370 randomized patients.


OVAL (VB-111-701/GOG-3018) is an international, Phase III, randomized, pivotal registration-enabling clinical trial comparing a combination of ofra-vec and paclitaxel to placebo plus paclitaxel in adult patients with recurrent platinum-resistant ovarian cancer. The OVAL trial has two primary endpoints: progression-free survival (PFS) and overall survival (OS). Successfully meeting either primary endpoint has the potential to support a Biologics License Application (BLA). Meeting the PFS endpoint, with a top-line readout anticipated in the second half of 2022 could accelerate BLA submission by approximately 2 years, subject to discussions with the FDA. A top-line readout of the OS primary endpoint is anticipated in 2023. The clinical trial is being conducted in collaboration with the GOG Foundation, Inc., an independent international non-profit organization with the purpose of promoting excellence in the field of gynecologic malignancies.


Ofra-vec is a unique biologic agent designed to use a dual mechanism to target solid tumors. Its mechanism combines the blockade of tumor vasculature with an anti-tumor immune response and is administered as an IV infusion once every 6-8 weeks. It has been observed in past clinical research to be generally well-tolerated in >300 cancer patients and demonstrated activity signals in an "all comers" Phase I trial, as well as in three tumor-specific Phase II trials.


The FDA granted ofra-vec orphan designation for the treatment of malignant glioma and Fast Track designation for the treatment of rGBM and platinum-resistant ovarian cancer. It demonstrated proof-of-concept and survival benefit in Phase II clinical trials in radioiodine-refractory thyroid cancer and platinum-resistant ovarian cancer.


Fast Track Designation for ONC-392 Monotherapy in PD(L)1-Resistant NSCLC

The FDA granted Fast Track designation to ONC-392, a next-generation anti-CTLA-4 monoclonal antibody that preserves the CTLA-4 immune checkpoint function, as a single agent for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have had disease progression on prior anti-PD-(L)1 therapy.


The ONC-392 program may be eligible for more frequent meetings with the FDA to discuss the drug's development plan ensuring collection of appropriate data needed to support approval, and more frequent written communications with the FDA regarding topics such as the design of the proposed clinical trials. Fast Track programs also have eligibility for rolling review, as well as eligibility for Accelerated Approval and Priority Review if relevant criteria are met.


ONC-392 is currently in Phase I clinical testing to evaluate safety, pharmacokinetics, and efficacy as monotherapy and in combination with anti-PD-1 standard of care in advanced solid tumors and NSCLC (PRESERVE-001). In recently completed Parts A and B of the study, researchers observed promising clinical activity of ONC-392 in PD(L)1-resistant cancer, including NSCLC.


The trial is conducted to assess the safety, pharmacokinetics, and efficacy of ONC-392 as a single agent in advanced solid tumors and in combination with anti-PD(L)1 standard of care in NSCLC and other solid tumors. The study consists of three linked parts: Part A is a dose-finding rapid titration study of ONC-392 as a single agent in patients with advanced solid tumors of various histologies to define the recommended Phase II dose for ONC-392 monotherapy (RP2D-M); Part B is dose-finding for combination with standard dose of pembrolizumab (Part B) to define the recommended Phase II dose for ONC-392 combination therapy (RP2D-C); and Part C comprises expansion cohorts of ONC-392 in monotherapy and in combination therapy with pembrolizumab to determine safety and initial efficacy.


Fam-Trastuzumab Deruxtecan-Nxki for Previously Treated HER2-Mutant Metastatic NSCLC

The FDA accepted a supplemental Biologics License Application (sBLA) of HER2-directed antibody-drug conjugate fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy. The application has also been granted Priority Review.


The Priority Review follows Breakthrough Therapy Designation by the FDA for fam-trastuzumab deruxtecan-nxki in this cancer type in May 2020. The sBLA is based on data from the registrational DESTINY-Lung01 Phase II trial published in The New England Journal of Medicine, and is supported by the Phase I trial (DS8201-A-J101) published in Cancer Discovery.


Primary results from previously treated patients with HER2-mutations (cohort 2) of DESTINY-Lung01 demonstrated a confirmed objective response rate (ORR) of 54.9 percent (95%: 44.2-65.4) in patients treated with fam-trastuzumab deruxtecan-nxki (6.4mg/kg) as assessed by independent central review. One (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed. A confirmed disease control rate (DCR) of 92.3 percent was seen with a reduction in tumor size observed in most patients. After a median follow-up of 13.1 months, the median duration of response (DoR) for fam-trastuzumab deruxtecan-nxki was 9.3 months. The median progression-free survival (PFS) was 8.2 months, and the median overall survival (OS) was 17.8 months.


The safety profile of the most common adverse events with fam-trastuzumab deruxtecan-nxki in DESTINY-Lung01 was consistent with previous clinical trials with no new safety concerns identified.


Fam-trastuzumab deruxtecan-nxki is being further assessed in a comprehensive clinical development program evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung, and colorectal cancers.


GCC19CART for R/R Metastatic Colorectal Cancer

The FDA granted Fast Track Designation to GCC19CART, a solid tumor therapy candidate in treating patients with relapsed and refractory metastatic colorectal cancer (R/R mCRC). It is the lead solid tumor candidate from the CoupledCAR technology platform, which has been specifically designed to target and eliminate cancer cells expressing guanylyl cyclase C (GCC), a marker for colorectal cancer. The designation for GCC19CART was based on its potential to address the unmet need for patients with R/R mCRC who have failed standard therapies.


R/R mCRC is a disease with a large unmet medical need. Once a patient fails multiple lines of standard-of-care treatments as defined by the National Comprehensive Cancer Network, there are very few effective options. The currently approved third-line treatments in the U.S. provide an overall response rate (ORR) of 1-1.6 percent and overall median survival of 6.4-7.1 months. Researchers plan to initiate a Phase I study designed to evaluate the safety, tolerability, and activity of GCC19CART in patients with R/R mCRC in the U.S. in mid-2022.