Researchers at Roswell Park Comprehensive Cancer Center have launched a randomized, phase 2 clinical trial that they hope will improve both survival and quality of life for patients with recurrent ovarian, fallopian tube or primary peritoneal cancer with malignant effusion. The study is exclusive to Roswell Park, where it was developed.

Emese Zsiros, MD, PhD, FACOG, Chair of the Department of Gynecologic Oncology, serves as principal investigator of the clinical trial, “APL-2 and Pembrolizumab Versus APL-2, Pembrolizumab and Bevacizumab Versus Bevacizumab Alone for the Treatment of Recurrent Ovarian, Fallopian tube, or Primary Peritoneal Cancer and Malignant Effusion” (NCT04919629). Brahm Segal, MD, Chair of the Department of Internal Medicine, Chief of Infectious Diseases and Member in the Department of Immunology at Roswell Park, will lead the trial’s immunologic studies.

The study will evaluate a new application for pegcetacoplan (APL-2), a complement C3 inhibitor that is FDA-approved for the treatment of paroxysmal nocturnal hemoglobinuria, a rare blood disease, but has not yet been evaluated for the treatment of cancer. APL-2 is a synthetic peptide that binds to and inhibits C3, a protein that is part of the immune system’s complement system and generally plays a beneficial role in defending against infections.

Research led by Dr. Segal’s laboratory showed that neutrophils recruited to the tumor microenvironment (TME) can acquire a suppressor role and inhibit the T-cell responses crucial for durable antitumor immunity. The team further observed that the TME has high levels of complement activation and that inhibiting complement stifled the neutrophils’ suppressive function and revived T-cell responses.

This body of research led the research team to hypothesize that APL-2 could decrease the accumulation of those neutrophils in tumor tissue and reduce their ability to inhibit T cells, thereby boosting the effectiveness of immune checkpoint inhibitors. That theory will be tested during the clinical trial by using APL-2 in combination with the immune checkpoint inhibitor pembrolizumab (brand name Keytruda) — another first.

“The tumor microenvironment of ovarian cancer is highly immunosuppressive, and identifying mechanisms of immunosuppression and ways to target them should improve therapeutic response,” says Dr. Zsiros.

“The principle that neutrophils and complement can impair T-cell responses in the TME isn’t unique to ovarian cancer, and we hope that knowledge gained from this trial will be applicable to other cancers,” adds Dr. Segal.

At the same time, the team hopes APL-2 will improve patients’ quality of life by shutting down the generation of anaphylatoxins, complement peptides that make blood vessels more permeable and contribute to malignant ascites and malignant pleural effusion.

Malignant ascites affects nearly 50% of women with stage 3 or stage 4 ovarian cancer and is associated with treatment resistance and poor prognosis. The condition can severely impact the patient’s quality of life. Standard-of-care treatment involves the antiangiogenic agent bevacizumab (brand name Avastin), either alone or in combination with chemotherapy, and repeated paracentesis. Malignant pleural effusion, which affects about a third of ovarian cancer patients during their illness, also is treated with paracentesis.

The clinical trial will enroll 40 evaluable patients, who must have received at least one prior line of platinum-based chemotherapy. Patients will be randomized to one of three cohorts: APL-2 plus pembrolizumab, APL-2 plus pembrolizumab and bevacizumab, or the standard of care — bevacizumab alone.

The study is supported with a five-year, $3.3 million multiple-principal-investigator Research Project Grant awarded to Drs. Zsiros and Segal to pursue multiple projects that focus on reining in the complement system to provide durable antitumor immunity and make immunotherapy more effective in patients with recurrent epithelial ovarian cancer.