Investigators Look to Add Duvelisib to Treatment Arsenal of Rare T-Cell Lymphoma Subtype

Since the September 2018 FDA approval of duvelisib (Copiktra) in relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, investigators have been working to bring the agent to a broader population of patients with hematologic malignancies, including those with rare T-cell lymphoma subtypes for whom there are few available therapies.1 Thus, the upcoming phase 3 TERZO trial (NCT06522737) will evaluate duvelisib in patients with nodal T-cell lymphoma with follicular helper T phenotype, a subtype of peripheral T-cell lymphoma (PTCL).2

Duvelisib is an inhibitor of the PI3K-δ and PI3K-γ isoforms.2 Beyond the 2018 FDA indication, the oral agent is approved in the European Union (EU) and United Kingdom (UK) for patients with relapsed/refractory CLL as well as refractory follicular lymphoma, both following 2 prior lines of systemic therapy. No other agent beyond brentuximab vedotin (Adcetris) is approved for the treatment of patients with relapsed/refractory PTCL––and only in anaplastic large cell lymphoma––in the EU or UK, and approvals for single agents for PTCL in the US, besides brentuximab vedotin, were supported by findings from single-arm studies. In January 2023, the European Commission granted orphan drug designation to duvelisib for the treatment of patients with PTCL.3

“The preclinical data supporting the mechanism of action and the potential efficacy of duvelisib in hematologic malignancies, including PTCL, are quite strong,” Christopher P. Fox, PhD, clinical professor in Hematology, Faculty of Medicine and Health Sciences, University of Nottingham, England, said in an interview with Oncology Live. “There is a wealth of evidence that inhibiting PI3K and its subunits can have anticancer activity. Both in cell lines and animal models, there are persuasive data that duvelisib by inhibiting the δ and γ subunits exerts a significant anticancer effect through a number of mechanisms.”

PRIMO Data Provide Rationale for Further Development of Duvelisib

Duvelisib was previously evaluated in patients with relapsed/refractory PTCL in the phase 2 PRIMO study (NCT03372057).4 The open-label, single-arm trial enrolled patients from the US, EU, UK, and Japan with measurable disease per Lugano 2014 criteria, an ECOG performance status of 2 or less, and no prior history of allogeneic stem cell transplant or PI3K inhibitor treatment. Eligible patients also needed to have received at least 2 cycles of at least 1 prior standard regimen and have a CD4 lymphocyte count of at least 50/mm3.

In the dose-expansion phase, patients received duvelisib at a dose of 75 mg twice daily for 2 cycles. Those who experienced a response or stable disease then received the agent at a dose of 25 mg twice daily.

Disease response assessment was performed at screening, at cycle 2, and then at every 2 subsequent cycles. The primary end point was overall response rate (ORR) per independent review committee (IRC). Secondary end points included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety, and pharmacokinetics. Pharmacodynamics and biomarkers were assessed as exploratory end points.

Findings from the dose-expansion phase of PRIMO presented during the 66th American Society of Hematology Annual Meeting and Exposition in San Diego, California, showed that patients who received duvelisib (n = 123) achieved an ORR of 48%, including a 33.3% complete response (CR) rate. The median DOR was 7.89 months (95% CI, 6.41-20.96), the median duration of CR was 7.89 months (95% CI, 6.41-22.74), and the median time to response was 1.77 months (range, 0.5-3.7).

At a median follow-up of 6.24 months for PFS, the median value was 3.45 months (95% CI, 1.84-3.94). At a median follow-up of 35.45 months, the median OS was 12.35 months (95% CI, 8.38-22.70).

“We [also] observed good median dose intensity of duvelisib in PRIMO,” Fox noted. “The dose scheduling was designed to have a higher dose of 75mg twice a day for the first 2 cycles of treatment to maximize tumor control, before dropping to 25 mg twice a day during cycle 3 and beyond. The rationale was to mitigate against the later toxicities, the immune-mediated toxicities, that we are familiar with [when using] duvelisib and the PI3K class of agents.”

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 97.6% of patients. Common any-grade TEAEs reported in at least 15% of patients included increased alanine aminotransferase (ALT; 37.4%), increased aspartate aminotransferase (AST; 35.8%), and decreased neutrophil count (33.3%). Grade 3 or higher TEAEs that occurred in at least 5% of patients included increased ALT (21.1%), decreased neutrophil count (17.9%), and increased AST (17.1%).

Overall, 100% of patients withdrew from the study. Reasons for withdrawal included disease progression (40.7%), adverse effects (AEs; 22.0%), other reasons (15.4%), clinical deterioration due to disease progression (8.9%), death (8.1%), termination of study by sponsor (2.4%), withdrawal of consent (1.6%), and study drug interruption beyond 42 days due to duvelisib-related toxicity (0.8%). TEAEs that led to dose hold (44.7%), reduction (9.8%), and discontinuation (33.3%) were all reported.

“We saw an AE profile with duvelisib [that was] consistent with what we have seen with other PI3K inhibitors, but with a lower frequency of the severe immune-mediated toxicities,” Fox said. “The data so far are supportive of taking this dose schedule into the phase 3 [trial] and then we’ll be able to compare [duvelisib] in a randomized fashion vs standard chemotherapy effects and make a clearer judgement as to whether the PI3K inhibitor is putting patients more at risk of these immune-mediated events than we would see with standard therapy.”

Study authors concluded that findings from PRIMO confirmed duvelisib as a promising agent for patients with relapsed/refractory PTCL. Supported by these findings, investigators initiated TERZO to further evaluate the agent in relapsed/refractory nodal T-cell lymphoma with follicular helper T phenotype.

TERZO Study Design

TERZO is a multicenter, open-label study that will evaluate duvelisib compared with investigator’s choice of gemcitabine or bendamustine in adult patients with relapsed/refractory nodal T-cell lymphoma with follicular helper T phenotype (Figure).2,5 Eligible patients need to have measurable disease per Lugano 2014 criteria for T-cell lymphoma and have received at least 1 prior cytotoxic therapy for T-cell lymphoma. Patients with cutaneous-only disease, those who underwent prior allogeneic transplant or autologous transplant within 60 days of the first dose of study drug, those with prior treatment with a PI3K inhibitor, or those who received gemcitabine or bendamustine within 60 days prior to the first dose of study drug will not be eligible.

“For patients with relapsed/refractory PTCL, many countries and centers would regard a clinical trial as the standard of care, given that the outcomes for patients with conventional treatments are so poor,” Fox said. “Clinical trials are always attractive to patients with PTCL. Barriers to recruitment will come down to patient- and center-related factors. Patients may not be able to travel to a center that has the trial open, and some centers may choose to preferentially use stem cell transplantation, but that’s typically in a minority of patients.”

Eligible patients will be randomly assigned 1:1 to receive duvelisib or investigator’s choice of gemcitabine or bendamustine. Patients in the investigational arm will receive duvelisib at a dose of 75 mg twice daily for the first two 28-day cycles, then at a dose of 25 mg twice daily for cycle 3 and beyond. Patients in the control arm will receive intravenous (IV) gemcitabine at a dose of 1200 mg/m2 on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles or IV bendamustine at a dose range of 90 mg/m2 to 120 mg/m2 on day 1 and day 2 of each 21-day cycle for up to 6 cycles.

The primary end point is IRC-assessed PFS. Secondary end points include OS, investigator-assessed PFS, IRC-assessed ORR, IRC-assessed CR rate, IRC-assessed DOR, IRC-assessed PFS in patients who proceeded to stem cell transplantation, safety, and quality of life.

TERZO is expected to enroll approximately 124 patients at sites in the EU and UK. The study has not started recruiting participants. The estimated start is March 2025, and the estimated primary completion is February 2028.

“If [findings from] TERZO are positive and we see statistically significant superiority of duvelisib in terms of PFS for patients with relapsed/refractory, angioimmunoblastic or T-follicular helper subtype PTCL, this would be a practice-changing study if the toxicity profile is deemed to be acceptable,” Fox said. “TERZO is a study with regulatory intent to get an approval through its design and statistical assumptions. PFS superiority would be very meaningful and hopefully lead to an approval. [This study] would be a first step towards a biologically-targeted intervention prolonging PFS in the relapsed/refractory setting.”

References

1. Duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). FDA. September 24, 2018. Accessed January 31, 2025. bit.ly/3WIBpTs
2. Cwynarski K, Domenech ED, Sidransky D, Bentur OS, Zinzani PL. A multicenter, open-label, phase 3, randomized controlled trial of duvelisib versus investigator’s choice of gemcitabine or bendamustine in patients with relapsed/refractory nodal T cell lymphoma with T follicular helper phenotype. Blood. 2024;144(suppl 1):3074.1. doi:10.1182/blood-2024-203290
3. Secura Bio, Inc. receives orphan drug designation in Europe for duvelisib for the treatment of patients with peripheral T-cell lymphoma. News release. Secura Bio Inc. January 9, 2023. Accessed January 31, 2025. bit.ly/3CAJind
4. Mehta-Shah N, Zinzani PL, Jacobsen ED, et al. Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma: final results from the phase 2 PRIMO trial. Blood. 2024;144(suppl 1):3061. doi:10.1182/blood-2024-203577
5. A study of duvelisib versus gemcitabine or bendamustine in participants with relapsed/refractory nodal T cell lymphoma with T follicular helper (TFH) phenotype (TERZO). ClinicalTrials.gov. Updated February 4, 2025. Accessed February 4, 2025. https://clinicaltrials.gov/study/NCT06522737