Adaptimmune ($ADAP) has responded to the failure of its T-cell therapy to induce objective clinical responses in ovarian cancer patients by adding fludarabine--the drug linked to deaths in a Juno Therapeutics trial--to the preconditioning regimen. Investors reacted to the lack of efficacy and addition of fludarabine by driving down Adaptimune’s share price by 12%.
When Adaptimmune began the Phase I/IIa trial of its autologous T cells, it only used cyclophosphamide in the preconditioning stage. Adaptimmune hoped the one type of chemotherapy would be sufficient to prepare patients to respond well to infusions of its NY-ESO-1 transduced autologous T cells, but data from the trial suggest otherwise. With the regimen failing to induce a single objective clinical response, Adaptimmune has revised the protocol to include fludarabine.
“We hope that, as previously observed in synovial sarcoma, this lymphodepleting regimen will enable anti-tumor immune responses mediated by NY-ESO SPEAR T-cell therapy in these patients with advanced chemotherapy relapsed or refractory ovarian cancer,” Adaptimmune CMO Dr. Rafael Amado said in a statement. The experience of Adaptimmune and other research groups suggests fludarabine helps with the expansion and persistence of transduced cells.
Data from the synovial sarcoma study released over the weekend foreshadowed the need to add fludarabine to the ovarian cancer trial. In one cohort of the synovial sarcoma study, the preconditioning regimen was limited to cyclophosphamide. None of the 5 patients in that cohort experienced an objective response. The response rate in an arm that received fludarabine and cyclophosphamide topped 50%. That prompted Adaptimmune to stop enrollment in the fludarabine-free cohort.
Adaptimmune is hoping the addition of fludarabine to the preconditioning regimen in the ovarian cancer trial has a similarly notable effect on efficacy. The plan is to enroll 10 patients under the revised, fludarabine-featuring protocol.
If some of those patients experience clinical responses, it will cement the status of fludarabine as an essential component of preconditioning. But, with the cerebral edema and neurotoxicity deaths in Juno’s CAR-T trial providing a clear warning, companies will need to tread carefully as they look to identify the optimal regimens.