ASH 2019: PRIMO Study Evaluates Duvelisib in Relapsed or Refractory Peripheral T-Cell Lymphoma

Five abstracts highlighting data for duvelisib (Copiktra™; Verastem Oncology) have been selected for presentation at the upcoming annual meeting of the American Society of Hematology (ASH) taking place December 7-10, 2019, in Orlando, Florida.

Duvelisib is an oral inhibitor of PI3K with inhibitory activity predominantly against PI3K-δ and PI3K-γ isoforms expressed in normal and malignant B-cells.

The drug induces growth inhibition and reduced viability in cell lines derived from malignant B-cells and in primary CLL tumor cells. Duvelisib inhibits several key cell-signaling pathways, including B-cell receptor signaling and CXCR12-mediated chemotaxis of malignant B-cells. Additionally, duvelisib inhibits CXCL12-induced T cell migration and M-CSF and IL-4 driven M2 polarization of macrophages.

Key abstracts
One of the key abstracts to be presented during the ASH-meeting features clinical data from the dose optimization portion of the registration-directed Phase II PRIMO study evaluating duvelisib in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

The PRIMO study, an open-label, multicenter trial, is currently ongoing and is expected to enroll approximately 120 patients. In the dose optimization portion of the study, patients were randomized to receive duvelisib 25 mg twice daily with an option for dose escalation (cohort 1) or duvelisib 75 mg twice daily continuously (cohort 2) until disease progression or unacceptable toxicity (cycle=28 days).

The primary endpoint of the dose optimization portion is investigator-assessed overall response rate (ORR). Based on the efficacy and safety data to be reported at the meeting, the investigators have elected to investigate duvelisib starting at 75 mg twice daily for two cycles, followed by 25 mg twice daily, during the dose expansion portion of the study which is currently ongoing. [1]

“Identifying additional options for this aggressive type of T-cell lymphoma is critical. In the initial cohort of this trial, we identified that the dose of 75mg twice daily for two cycles helped to achieve more rapid tumor control in what are often aggressive diseases,” explained Steven M. Horwitz, MD, Memorial Sloan Kettering Cancer Center, and principal investigator of Phase II PRIMO study.

“We will assess if following the induction by 25mg twice daily dose we are able to maintain longer-term disease control and mitigate the potential for later onset toxicities in patients with relapsed or refractory PTCL,” he added.

“We look forward to sharing updated data from this ongoing study at ASH 2019,” Horwitz concluded.

Other presentations
Data to be presented during ASH also include the preliminary results from a Phase I study investigating duvelisib in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Results from previous studies suggested that PI3K-δ inhibition sensitizes CLL cells to ex vivo BCL-2 inhibition. [2] Based on these results, the researchers hypothesized that duvelisib in combination with venetoclax would lead to deep remissions that allow for an all oral, time-limited therapy.

During this meeting an analysis of cytogenetic and molecular markers associated with improved outcomes in the Phase III DUO study will also be presented. The DUO study examined the efficacy of duvelisib monotherapy versus ofatumumab (Arzerra®; Novartis) monotherapy in patients with relapsed or refractory CLL/SLL.

A description of the soon to be initiated TEMPO study, designed to investigating an intermittent dosing regimen of duvelisib in patients with indolent non-Hodgkin lymphoma. The study will evaluate the efficacy and safety of prescribed ‘drug holidays’ of duvelisib treatment.

Finally, reclinical data highlighting the effectiveness of duvelisib in combination with venetoclax (Venclexta®; AbbVie and Genentech) in Richter syndrome, also known as Richter’s Transformation, a rare complication of CLL/SLL) characterized by the sudden transformation of the CLL/SLL into a significantly more aggressive form of large cell lymphoma, will also be presented.

“We are pleased to share additional data on duvelisib across multiple areas of research that continues to expand our understanding of its potential benefit and utility for patients with certain types of blood cancers,” said Brian Stuglik, Chief Executive Officer of Verastem Oncology.

“The results of the dose optimization portion of the PRIMO study provide important guidance to support our ongoing evaluation of duvelisib for the treatment of relapsed or refractory PTCL,” Stuglik concluded.

Clinical trials
A Study of Duvelisib in Patients With Relapsed or Refractory Peripheral T Cell Lymphoma (PTCL) – NCT03372057
A Phase III Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL (DUO) – NCT02004522
A Phase II Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Subjects With Indolent Non-Hodgkin Lymphoma. (TEMPO) – NCT04038359

Reference
[1] Horwitz SM, Mehta-Shah N, Pro B, Jacobsen ED, Casulo C, Brammer JE, Haney J, et al. Dose Optimization of Duvelisib in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma from the Phase 2 Primo Trial: Selection of Regimen for the Dose-Expansion Phase. 2019 Annual meeting of the American Society of Hematology. Abstract: 1567. Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma [Abstract]
[2] Crombie JL, Tyekucheva S, Savell A, Francoeur K, Choiniere M, Montegaard J, Soumerai JD, Arnason JE, Fisher DC, Brown JR, and Davids MS. A Phase I Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL / SLL. 2019 Annual meeting of the American Society of Hematology. Abstract: 1763. Session: 642. CLL: Therapy, excluding Transplantation: Poster I Hematology Disease Topics & Pathways: Therapies, Combinations [Abstract]