ORLANDO, Fla. – Kura Oncology Inc., encouraged by new data on tipifarnib and positive feedback from the FDA, said Sunday that next year it will initiate a single-arm, phase II registration-directed trial of the candidate in angioimmunoblastic T-cell lymphoma (AITL), a rare and often aggressive form of peripheral T-cell lymphoma (PTCL). As designed, the trial may be adequate to support an NDA seeking accelerated approval, the San Diego-based company said.
AITL is an aggressive form of T-cell lymphoma frequently characterized by high levels of CXCL12 expression. Looking back at data from the ongoing phase II study, Kura's head of development and chief medical officer, Antonio Gualberto, told BioWorld that "we noticed that when CXCL12 was high, the patients responded." But the retrospective observation, which one needs to allow could have been a fluke, now needs to be confirmed prospectively, he said at the 61st American Society of Hematology annual meeting. That's what the pivotal trial will do.
Seeking to enroll 128 patients with AITL and AITL-like histologies who are relapsed or refractory to at least one prior systemic cytotoxic therapy, the new study will feature two primary objectives, though meeting just one could support approval. Investigators will first look at efficacy in terms of objective response rate (ORR) in all patients enrolled. Second, they'll look at efficacy in terms of ORR in patients who carry killer-cell immunoglobulin-like receptor 3DL2 variants, a biomarker found during sequencing of patient biopsies from an ongoing phase II study to be associated with a relatively higher number of complete responses.
Updated interim data from the ongoing phase II trial were presented at ASH. Results showed that, among 20 patients with AITL who were evaluable for efficacy, five achieved a complete response (CR) and five achieved a partial response (PR), for an ORR of 50% on an evaluable basis and 38% on an intent-to-treat basis. In addition, three patients experienced disease stabilization. The report builds on an initial readout of the study in June.
Based on such data, Gualberto said, his team got a positive opinion from the FDA indicating that a small trial could support registration for either the whole AITL population or just those who carry killer-cell immunoglobulin-like receptor 3DL2 variants. "Chances are that either both or one of them will become positive very quickly," he said.
Tipifarnib is a farnesyl transferase in-licensed from Janssen in December 2014. Since then, Kura has built a substantial patent estate around it and around farnesyl transferase inhibition generally, company CEO and President Troy Wilson told BioWorld. "Our patents are broad enough now that a couple of them read on any farnesyl transferase inhibitor," he said. The molecule has been tested in more than 5,000 patients, with publications going as far back as 2011 that show it inhibiting pathways important to the growth of B cells and T cells.
Thomas Witzig, a hematologist at Mayo Clinic and a principal investigator in the ongoing phase II study, is now encouraging Kura's team to look at applying tipifarnib in the broader population of PTCL patients, the related disease cutaneous T-cell lymphoma, diffuse large B-cell lymphoma and acute myeloid leukemia.
"Our dream for the molecule," said Wilson, "is that we can move from disease to disease now using this molecular understanding to very thoughtfully move across these different indications for patients."