Duvelisib Hits Endpoint But Misses Expectations in Phase II iNHL Study

Adelene Perkins

Treatment with single-agent duvelisib (IPI-145) demonstrated an overall response rate (ORR) of 46% for patients with indolent non-Hodgkin lymphoma (iNHL), which successfully met the primary endpoint for the phase II DYNAMO study but not investor expectations, according to the developer of the PI3K-delta and -gamma inhibitor, Infinity Pharmaceuticals.

The phase II study enrolled 129 patients with iNHL, which included follicular lymphoma (n = 83), small lymphocytic leukemia (SLL; n = 28), and marginal zone lymphoma (MZL; n = 18). The ORRs in each of these groups, respectively, were 41%, 68%, and 33%. The majority of adverse events reported in the study were labeled as clinically manageable and reversible.

Despite meeting the primary endpoint of the study, the magnitude of benefit did not match Infinity's expectations. Based upon the results, the long-term outlook for the medication was adjusted, studies exploring duvelisib in combination with venetoclax were paused, and 21% of the organization's workforce was laid off as part of a research and development restructuring.

"While the DYNAMO study met its primary endpoint, we hoped that treatment with duvelisib as a monotherapy would have provided a larger clinical benefit for patients with advanced indolent non-Hodgkin lymphoma, a difficult-to-treat disease," Adelene Perkins, president and chief executive officer at Infinity, said in a statement. "We plan to seek feedback from the US Food and Drug Administration to determine our next steps with respect to duvelisib in indolent non-Hodgkin lymphoma."

Expectations for duvelisib in the DYNAMO study were set by the performance of the PI3K-delta inhibitor idelalisib (Zydelig), which was approved as a single-agent for patients with iNHL in July 2014. This approval was based on findings from a single-arm phase II study, in which single-agent idelalisib showed an ORR of 54% for patients with follicular lymphoma and 58% for those with SLL.

The open-label phase II DYNAMO study, which began enrolling in May 2013, included patients with iNHL who were refractory to rituximab and either chemotherapy or radioimmunotherapy. Continuous duvelisib was administered at 25 mg twice daily.

The most common grade ≥3 adverse events with duvelisib were neutropenia (28%), infection (20%), diarrhea (15%), thrombocytopenia (13%), and anemia (12%). Hepatotoxicity data were not released nor were data on other serious adverse events that are associated with idelalisib.

Secondary outcome measures of the phase II study included safety, duration of response, progression-free survival (PFS), and overall survival. Findings for these endpoints were not yet released and would be presented at an upcoming medical meeting, according to Infinity.

"We are still digesting these data, including an analysis of secondary endpoints and other prespecified analyses. With these data in hand, we plan to seek feedback from FDA. In the meantime, we continue to work on our NDA [New Drug Application] filing strategy, which includes the DYNAMO and DUO studies," Julian Adams, PhD, president, research and development, Infinity, said during a webcast following the announcement of the results.

The open-label phase III DUO study is comparing single-agent duvelisib with ofatumumab (Arzerra) in 300 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The study, which only included those deemed ineligible for treatment with a purine analog-based therapy, completed enrollment in November 2015.

"As we look at the future for duvelisib in iNHL we continue to believe that monotherapy is important but that combinations regimens offer the best chance to provide new hope for patients," said Adams.

In addition to trials assessing the drug as a single-agent, a number of studies are looking at the medication as part of a combination therapy. The phase Ib/II CONTEMPO trial is examining duvelisib with rituximab (Rituxan) or obinutuzumab (Gazyva) for patients with previously untreated CD20-positive follicular lymphoma. The ongoing study plans to enroll 120 patients (NCT02391545).

Additionally, the phase III BRAVURA trial is looking at duvelisib in combination with bendamustine and rituximab (BR) compared with BR alone for patients with previously treated NHL. The primary endpoint of this study, which plans to enroll 600 patients, is PFS. The study was initiated in December 2015 (NCT02576275).

The now paused phase I/II study exploring venetoclax (Venclexta) and duvelisib planned to enroll 174 patients with relapsed/refractory CLL, SLL, and other iNHL subtypes who had not yet received a BCL-2 or PI3K inhibitor. The phase I portion of the study was designed to assess the safety of the combination, with the phase II portion focused on clinical activity. The study was initiated through a collaborative agreement between Infinity and AbbVie (NCT02640833).

Findings from the DUO study for the primary endpoint of PFS are anticipated in the second half of 2016, according to Infinity. Findings from the DUO and DYNAMO trials were meant to support a regulatory filing for the PI3K inhibitor, as part of the DUETTS development program.