Abstract
DYNAMO: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma
Introduction: Indolent non-Hodgkin lymphoma (iNHL) is characterized by a relapsing clinical course with shorter responses to therapy after each relapse. Duvelisib is an oral dual inhibitor of PI3K-d,γ in development for the treatment of hematologic malignancies, including previously-treated iNHL. Data from a Phase 1 study of duvelisib indicate the potential for duvelisib to be an effective treatment for previously-treated iNHL, with an acceptable safety profile. DYNAMO is a Phase 2 study designed to evaluate the safety and efficacy of duvelisib in a previously-treated, refractory iNHL population.
Methods: DYNAMO is an ongoing, open-label, single-arm, safety and efficacy study that includes adult patients (pts) diagnosed with follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or marginal zone lymphoma (MZL) whose disease is refractory to rituximab and to a chemotherapy regimen (containing an alkylator or purine analogue) or radioimmunotherapy. Pts received duvelisib 25 mg twice daily (BID) in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study is overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), time to response (TTR), adverse events (AEs), and changes in safety laboratory values. Pneumocystis jirovecii pneumonia (PJP) prophylaxis was mandated for all patients. Here we present the results from the final analysis, with a data cut-off of 07 April 2016.
Results: 129 iNHL pts received at least 1 dose of duvelisib, including 83 pts with FL, 28 with SLL, and 18 with MZL. The median duration of exposure was 6 months (range 0.4 - 23.8). The median age was 65 years, and 68% were male. The median time from initial diagnosis to the first dose of duvelisib was 4.5 years, and from last anticancer therapy was 3.5 months. Pts had received a median of 3 prior regimens (range 1 - 18), with 40% having received ≥ 4 regimens. 77% of patients had disease refractory to ≥ 2 regimens and 96% were refractory to their most recent regimen. 64% of patients previously received bendamustine, 80% of whom were refractory.
The ORR was 46% (all PRs, 95% CI 37 - 55), with a median DoR of 9.9 months (95% CI 4.5 - 10.3). The median TTR was 1.9 months (range 1.4 - 11.7). With a median follow-up of 11.5 months, the median PFS was 8.4 months (95% CI 5.8 - 11.3) with a 60% estimated probability of being alive and event-free at 6 months, and the median OS was 18.4 months (95% CI 15.7 - NE) with an estimated probability of survival of 74% at 12 months. 83% of pts experienced a reduction in tumor burden following treatment with duvelisib. The response rate across the disease subtypes was: 41% FL, 68% SLL, and 33% MZL (see Table).
AEs were predominantly Grade 1-2. The most common ≥ Grade 3 AEs were transient cytopenias (neutropenia [28%], anemia [12%], and thrombocytopenia [13%]), and diarrhea (15%). 63% of pts had dose modifications (interruptions or reductions) due to AEs and 17% of pts discontinued due to an AE. AEs leading to duvelisib discontinuation in ≥ 2 pts included pneumonitis (n = 3), pneumonia (n = 2), and rash generalized (n = 2). Six pts had an AE with an outcome of death, four assessed as related to duvelisib (suspected viral infection, septic shock, and 2 severe cutaneous reactions [TEN and DRESS]). The incidence of ≥ Grade 3 infection was 20%. The incidence of pneumocystis was 0.8% (1 patient) and the incidence of CMV was 2.3% (3 subjects), none of which were fatal.
Conclusions: In the Phase 2 DYNAMO study, duvelisib achieved meaningful clinical activity in a heavily pretreated and highly refractory iNHL population. The safety profile was acceptable, with the majority of AEs low grade (≤ Grade 2) and the majority of pts able to remain on duvelisib. These results suggest duvelisib has a favorable benefit-risk profile in this patient population and further development is ongoing.
Table 1 Table 1.
Disclosures
Flinn: Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Miller:Infinity: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Assouline:BMS: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani:Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Pettitt:Roche: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Infinity: Research Funding. Tournilhac:Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Honoraria, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Honoraria, Research Funding. Crump:Roche: Consultancy; Seattle Genetics: Consultancy; Janssen-Ortho: Consultancy; Celgene: Consultancy. Santabarbara:Infinity: Consultancy. Shi:Infinity: Employment. Steelman:Infinity: Employment. Wagner-Johnston:Pharmacyclics: Speakers Bureau.
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