AdventHealth Cancer Institute is Among the First in the World to Offer a New Phase II Clinical Trial of a Novel, Customized Precision Immunotherapy for Patients with High-risk Muscle-invasive Urothelial Carcinoma

Under the leadership of principal investigator Guru Sonpavde, MD, AdventHealth Cancer Institute (AHCI) is among the first sites in the world and the only in Florida to offer a new, global Phase II clinical trial to evaluate the efficacy and safety of pembrolizumab plus V940 (mRNA-4157) in patients with high-risk, muscle-invasive urothelial carcinoma (MIUC) of the bladder and upper urinary tract following radical resection. V940 is a novel, customized immunotherapy that consists of mRNA that encodes up to 34 neoantigens (new mutated proteins) found specifically in an individual patient’s tumor. The mRNA is customized after molecular DNA and RNA analysis of the tumor and blood from each patient. A precision immunotherapy, the mRNA product is designed to activate the immune system to target these neoantigens. Dr. Sonpavde helped design the trial and serves on the Steering Committee.

About 50% of MIUC patients experience recurrence of their cancer after surgery. The purpose of this new international study is to assess the safety and efficacy of V940 in combination with pembrolizumab (MK-3475) compared to pembrolizumab combined with placebo as an adjuvant (post-operative) treatment for participants with pathologic high-risk MIUC after radical resection. Pembrolizumab is a monoclonal antibody that targets the PD-1 receptor on T cells and is FDA-approved for patients with advanced/chemotherapy-refractory metastatic urothelial carcinoma. AMBASSADOR A031501, a recent Phase III found that pembrolizumab improved disease-free survival (DFS) for high-risk MIUC patients. Dr. Sonpavde was involved in the AMBASSADOR A031501 trial as a key investigator and author.

The primary hypothesis of the AHCI's new clinical trial is that V940 in combination with pembrolizumab will further enhance disease-free survival for these patients after surgery. All study participants will receive 200 mg of pembrolizumab via intravenous (IV) infusion every 6 weeks for up to 9 cycles. The treatment arms will also receive V940 or placebo injections intramuscularly once every 3 weeks for 9 doses to activate the immune cells against the cancer. Preliminary results of KEYNOTE-942, a Phase II trial of this same treatment combination in melanoma patients following surgery, increased recurrence-free survival by 44%.

“We’re trying to improve the cure rate for patients with high-risk, muscle-invasive cancers of the bladder and upper urinary tract by killing the microscopic cancer cells that remain after resection,” explains Dr. Sonpavde.

Targeting Cancer Through a Precision Medicine Approach

Over time, tumors develop numerous mutations. When these mutations are translated into proteins, they can produce neoantigens. Studies have demonstrated that T cells can recognize and target these neoantigens, generating an anti-tumor response.

An individualized mRNA therapy, V940 can encode up to 34 neoantigens and will be personalized for each study participant through the following process:

• Perform next-generation sequencing of the patient’s tumor and blood.
• Conduct whole-exome sequencing of the tumor to assess mutations and of the blood to establish the human leukocyte antigen type.
• Create a transcriptome of the tumor by RNA sequencing.
• Input the whole-exome sequencing and human leukocyte antigen typing data into an automated mRNA-4157 bioinformatics system to establish the amino acid sequences of up to 34 selected neoantigens.
• Reincorporate the top amino acid candidate into an optimized mRNA-4157 sequence (long, continuous mRNA molecule).

“V940 represents precision oncology at its best,” shares Dr. Sonpavde. “It is a customized immunotherapy designed to activate the immune system specifically against new proteins found only in the cancer of the specific patient. We’re hopeful this innovative approach will improve patient outcomes and are excited to help lead such a significant research study right here in Central Florida.”