Notably, the trial is assessing intravenous administration of PRGN-3005 against intraperitoneal administration in 2 separate cohorts.
Precigen’s PRGN-3005 UltraCAR-T, an investigational MUC16-directed chimeric antigen receptor T-cell (CAR-T) therapy intended for the treatment of patients with platinum-resistant ovarian cancer, is currently being assessed in a phase 1/1b clinical trial (NCT03907527).1
The trial, and the CAR-T itself, incorporate features intended to overcome the barriers that held back the success of CAR-T approaches in this indication that have previously been pursued by other companies and institutions. In observance of Ovarian Cancer Awareness Month, held annually in September, CGTLive™ is taking a closer look at this renewed effort to apply cell therapy in this difficult indication.
Led by study director Amy R. Lankford, PhD, the head of Clinical Operations at Precigen, the trial is following an open-label, dose escalation and dose expansion design. Notably, the trial is assessing intravenous (IV) administration of PRGN-3005 against intraperitoneal (IP) administration in 2 separate cohorts, in order to evaluate whether regional administration of the CAR-T is more effective than IV administration, which is typically used for CAR-T products directed against hematological malignancies. PRGN-3005 targets MUC16, an antigen found on almost all advanced ovarian tumors, and is engineered to express a cytokine intended to improve persistence of the CAR T-cells. The autologous cell therapy is also able to be manufactured unusually quickly, with the study utilizing an “overnight” manufacturing process that administers the CAR-T to patients the day after ex vivo nonviral gene transfer.2 The trial has an estimated primary completion date of December 15, 2023, and an estimated completion date of November 15, 2028.
“[Other] CAR T-cell products in the ovarian cancer space have been tested and haven't seemed to be that effective,” Mary “Nora” Disis, MD, director of University of Washington Medicine’s Cancer Vaccine institute and one of the trial’s lead investigators, said in a June 2023 interview with CGTLive™’s sister publication OncLive®. “They were done with first-generation technologies and 1 of the major problems was that they really didn't persist in the body, and so they really didn't have much of an antitumor effect. I think with strategies such as this that are engineering agents to help those CART-cell products persist we'll start seeing clinical efficacy with these products in ovarian cancer.”
The study is taking place at the University of Washington and Fred Hutchinson Cancer Research Center and according to the clinicaltrials.gov page, which was last updated on January 9, 2023, recruitment is ongoing. The trial is expected to enroll 71 participants in total. In addition to including patients with advanced platinum-resistant, recurrent, or refractory ovarian carcinoma, the trial is also recruiting patients with advanced platinum-resistant, recurrent, or refractory fallopian tube carcinoma and primary peritoneal carcinoma.
Primary end points for the trial include the incidence of adverse events in the 12 months following infusion and the maximum tolerated dose of the CAR-T in the 28 days following infusion. The secondary end points include the evidence of antitumor activity measured via Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) in the 5 years following treatment and the number of PRGN-3005 T-Cells within patients’ bodies as measured in the 12 months following infusion.
The trial is open to women aged 18 and older with one of the aforementioned solid tumor indications who have experienced disease progression after standard of care therapy or who are unable to be treated with any available therapies with known clinical benefit. Furthermore, participants are required to be 14 days out from cytotoxic chemotherapy at the time of cell collection and (with exceptions existing) 28 days out from receiving systemic steroids at the time of enrollment. Patients are also required to have laboratory values indicating adequate organ function and an Eastern Cooperative Oncology Group performance status score of 2 or less, to have recovered from major acute infections and/or surgical procedures, and to be free of any concurrent medical condition that precludes protocol treatment. Patients’ disease must be able to be accurately measured according to RECIST 1.1 criteria in at least 1 dimension as greater than or equal to 1.0 cm or greater than 1.5 cm lymph node.
On the other hand, the study is excluding from participation patients with conditions including symptomatic restrictive cardiomyopathy, unstable angina or symptomatic coronary artery disease within 4 months prior to enrollment, New York Heart Association functional class III-IV heart failure on active treatment, symptomatic pericardial effusion, clinically significant hypotension, pulmonary hypertension, pulmonary fibrosis, restrictive lung disease, active autoimmune disease requiring immunosuppressive therapy or uncontrolled with treatment, known or treated brain metastases, and active seizure disorder. Patients with cancer antigen 125 levels less than or equal to the upper limit of normal during screening; a history of HIV, West Nile virus, Zika virus, or active hepatitis B/C infections; those who have received another investigational agent within the past 28 days; those who are pregnant or breastfeeding; and those with a baseline oxygen saturation on room air of less than 92%, forced expiratory volume in 1 second of less than or equal to 50%, or diffusion capacity of the lung for carbon monoxide (corrected) of less than 40% will also be excluded from participation. Patients who have had a second malignancy in the past 5 years will also be excluded, with exceptions existing for basal carcinoma of the skin, squamous carcinoma of the skin, and in situ cervical dysplasia for which curative therapy was received.
Recently, at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois, interim data from the clinical trial was presented.1,2 The results indicated that PRGN-3005 was well-tolerated with reductions in tumor burden observed. In the interview with OncLive, Disis summarized the key findings:
“...Many CAR T-cell therapies are associated with very severe cytokine release syndrome (CRS). We fortunately did not see that here; we saw CRS, but it was quite mild, so the safety of the infusions was really quite favorable. The second thing the study was looking at was whether the T-cells did persist—and they did. They persisted for weeks and weeks after infusion. We're still collecting the data, but the T-cells seem to persist for a very long time. The third thing that we looked at was how to deliver the CAR T-cells. Ovarian cancer is generally an intraabdominal tumor so we looked at intraperitoneal delivery, intravenous delivery, and then intravenous delivery with chemotherapy to lymphodeplete T-cells because we know that that lymphodepletion can make the CAR T-cells expand even more in the body. Then the final thing is we followed the patients for some type of response rate and in the arm that received the intravenous CAR T-cells with the lymphodepletion, over two-thirds of the patients showed some impact in disease reduction.”