The FDA has lifted the clinical hold placed on the phase 1 PSMA-101-001 study of the CAR T-cell therapy P-PSMA-101 in patients with metastatic castration-resistant prostate cancer.
The FDA has lifted the clinical hold placed on the phase 1 PSMA-101-001 study (NCT04249947) of the CAR T-cell therapy P-PSMA-101 in patients with metastatic castration-resistant prostate cancer (mCRPC), according to Poseida Therapeutics, Inc, the drug developer.1
The company announced plans to resume the trial immediately, noting that they have agreed to make amendments to the protocol in an effort to increase patient compliance and safety. Some of these modifications are with regard to study inclusion and exclusion criteria, as well as frequency of monitoring and laboratory testing.
In August 2020, the regulatory agency made the decision to place a clinical hold on the trial examining P-PSMA-101 after a notification of a patient death had been issued by the company.2 The patient, who had reportedly progressed on many anticancer agents prior to receiving the CAR T-cell therapy in late July 2020, had normal laboratory results after the first week of treatment; the patient did not showcase any clinical symptoms suggestive of an adverse effect, according to the company.
Despite this, the patient missed his follow-up visits that were scheduled for day 10 and day 14 following treatment with the product. During that time span, he reportedly presented with symptoms that resulted in hospitalization. On day 19, the patient experienced hepatic failure and died.
At the time of the report, the cause of the hepatic failure had not been confirmed, although the patient experienced symptoms that proved to be consistent with macrophage activation syndrome (MAS). It is known, however, that MAS can be caused by other events beyond treatment with CAR T-cell therapy, such as autoimmune disease or infection.
Moreover, the patient developed blurred vision and was diagnosed with uveitis, according to the company. The toxicity was determined to potentially be linked with P-PSMA-101 per investigator assessment, although the company announced that they would be looking into this further.
No other participants enrolled to the study experienced severe toxicities of reduced vision, uveitis, MAS, or hepatic failure. Moreover, no patients reported cytokine release syndrome or neurotoxicity with the product.
Designed to target prostate-specific membrane antigen, P-PSMA-101 was developed using Poseida’s piggyBac DNA Modification System, which produces agents with a high percentage of stem cell memory cells.3 These cells are able to reconstruct T-cell subsets, such as effecter T cells, which play a key role in eliminating cancer cells. Additionally, the higher composition of stem cell memory cells is hypothesized to be able to potentially overcome challenges associated with earlier-generation CAR T-cell therapies, according to the company.
The open-label, multicenter, dose-escalating phase 1 trial was designed to identify the optimal dose of the CAR T-cell product for safe administration in patients with mCRPC.4 Patients had to have metastatic disease that continued to grow despite prior treatment for advanced CRPC in order to participate. Moreover, they had to have recovered from any serious toxicities that occurred from previous treatment. If they had acceptable organ function with predetermined parameters and an ECOG performance status ranging from 0 to 1, they were eligible for inclusion.5
However, if patients had unacceptable venous access and/or contraindications to leukapheresis or they had an active second malignancy beyond mCRPC, active autoimmune disease, a history of significant central nervous system disease, or an active systemic infection, they could not participate. If they had received anticancer medications within 2 weeks of conditioning chemotherapy, immunosuppressive treatment within 2 weeks of initiating leukapheresis, or systemic corticosteroid therapy in that time, they were not permitted.
The primary end point of the trial is safety, establishing the maximum-tolerated dose, and efficacy. In the trial, patients were given either single or multiple doses of P-PSMA-101; the first participant received treatment with the CAR T-cell product on May 20, 2020.