A dose-optimization trial compared efficacy and toxicity outcomes for two daily dose regimens of duvelisib in patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL). The study was presented at the American Society of Hematology Annual Meeting.
Lead study author Steven Horwitz, MD, answered some questions about the study in an interview with DocWire News.
DocWire News: What prompted you to undertake this study?
Dr. Horwitz: We have conducted early studies suggesting quite good activity of duvelisib as a single agent in a range of subtypes of T-cell lymphoma. The Primo study, which will include over 100 patients will be sufficiently powered to give a much more precise estimate of the activity in peripheral t cell lymphomas. Based on the size of the study, we are hopeful that we might also gain some insight into whether there are differences in subtype specific activity. However, prior to initiating the main cohort we needed to first try to identify an optimal dose. That “dose optimization cohort” is the subject of our presentation here.
DW: What are the key takeaways from the study?
Dr. Horwitz: Relapsed or refractory Peripheral T-Cell Lymphoma (R/R PTCL) remains a disease of significant unmet medical need.
Duvelisib is an oral dual inhibitor of PI3K-δ and PI3K-γ approved for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies, relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies, and is being developed for the treatment of additional hematologic malignancies including R/R PTCL.
The PRIMO study is an ongoing, multi-center, open-label, registration-directed Phase 2 study evaluating duvelisib in patients with R/R PTCL that is expected to enroll approximately 120 patients. The study includes both a dose optimization phase and an expansion phase.
Results from a Phase 1 study suggest duvelisib monotherapy has activity in R/R PTCL. The objective of the Phase 2 PRIMO study is to first identify the optimal dose of duvelisib and then examine its efficacy, safety, and tolerability at the optimal dose.
In the dose optimization portion of the study, patients were randomized to receive duvelisib 25mg twice daily (cohort 1) or duvelisib 75mg twice daily continuously (cohort 2) until disease progression or unacceptable toxicity. The primary endpoint of the study was investigator-assessed overall response rate (ORR), and secondary endpoints included duration of response (DOR) and safety.
The investigator-assessed ORR in the ITT population was 35% in cohort 1 (n=20) and 54% in cohort 2 (n=13), with a complete response rate (CR) of 25% and 31% in cohort 1 and cohort 2, respectively. The ORR assessed by a blinded independent review, also in the ITT population, was 40% and 62% for cohort 1 and cohort 2, respectively. Nearly all of the responses were identified on first assessment. The most common (≥4 patients) Grade ≥3 adverse events (AEs) in all patients receiving duvelisib were neutropenia, thrombocytopenia, diarrhea, rash/maculopapular, lymphocytopenia, pneumonia and sepsis. Serious AEs occurring in >2 patients were colitis, diarrhea, abdominal pain, pyrexia, sepsis, pneumonia, hyponatremia, rash/maculopapular, dyspnea, and respiratory failure. Overall, 12% of patients receiving duvelisib discontinued due to an AE.
It appears that while there were responses, including complete responses at both the 25mg twice daily and duvelisib 75mg twice daily cohorts, more patients had early progression in the 25mg twice daily cohort. The analysis of drug levels (pk) in cycle 1 suggest that higher levels of drug in the blood seen in the 75mg twice daily may correlate with better early disease control. Due to this finding, patients in the rest of the study will start with 75 mg twice daily dosing but then have their dose reduced to hopefully minimize any long-term side effects.
DW: Did any of the study’s findings surprise you?
Dr. Horwitz: No significant surprises. The overall responses and side effects are quite similar to what we saw in earlier studies. The only mild surprise was in earlier small studies we had not seen rapid early progression at the 25 mg twice daily dosing.
DW: What limitations did the study have?
Dr. Horwitz: The dose optimization phase included a relatively small number of patients.
DW: Do you have any future research plans pertaining to this area?
Dr. Horwitz: The expansion phase of this registration-directed study is currently underway in the United States and is opening in Germany, UK, Italy, and Japan.