The use of fludarabine was fingered as a key culprit in the deaths of several patients taking Juno’s lead CAR-T therapy, but it’s an absolutely vital part of the preconditioning regimen being used to prepare patients for the wave of new cell therapies now in the clinic for cancer. And Adaptimmune $ADAP helped underscore just how critical it is today, saying that it’s readjusting its trial protocol for its T-cell therapy for ovarian cancer, adding fludarabine to the combination after failing to get any initial responses in patients without it.
Chief Medical Officer Rafael Amado put it this way:
“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.”
Shares of Adaptimmune dropped 12% Wednesday morning.
This flu/cy combo has emerged as a central feature in cell therapies. By using the combo on patients, investigators have seen clear signs that their cell therapies are better able to populate and durably attack cancer cells. But you have to get the mix of flu/cy plus the right dosage of your cell therapy balanced properly to avoid killing patients.
When Juno $JUNO tried it, their recipe of flu/cy combined with JCAR015 killed three patients by spurring cerebral edema. Another patient in a separate study also was killed by severe neurotoxicity, bringing the death count to 4. The FDA responded by placing the lead program on complete hold, then lifted the hold after Juno proposed pulling fludarabine from the mix.
That quick fix to get the hold lifted may have significantly reduced the threat of lethal toxicity, but Juno’s rival Kite $KITE has managed to forge ahead with its own balancing act of flu/cy combined with their lead CAR-T. And it seems clear that any therapies that don’t use flu/cy may be at a competitive disadvantage. At the time, Jefferies’ Biren Amin noted:
“Critically, we also know that a flu/cy regimen much higher than what Kite uses in their trials (roughly four times more cy for ALL patients) was involved in all four cerebral edema cases (at Juno).”
Adaptimmune now plans to add 10 more patients to its small Phase I/II study to see how they will respond to the new therapeutic regimen. The UK biotech – with R&D ops in Philadelphia – had to put one trial for myxoid round cell liposarcoma on partial hold on orders from the FDA in August, after regulators said they had some trial design questions to clear up before patients could be treated.
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