European Commission Grants Orphan Drug Designation to Nana-val for Peripheral T-cell Lymphoma

The European Commission has granted an orphan drug designation to nanatinostat and valganciclovir (Nana-val) for use as a potential therapeutic option in patients with peripheral T-cell lymphoma (PTCL), according to an announcement from Viracta Therapeutics, Inc.¹

Nanatinostat is selective for certain isoforms of class I HDACs, which is a key component of producing viral genes that are epigenetically silenced in Epstein-Barr virus (EBV)–associated malignancies. The agent is under investigation in combination with valganciclovir, an antiviral agent, in those with several subtypes of relapsed or refractory EBV-positive lymphoma as part of the phase 2 NAVAL-1 basket trial (NCT05011058).²

“This orphan drug designation acknowledges the high unmet medical need of this patient population as well as the potential of the Nana-val to offer therapeutic benefit to patients with recurrent PTCL,” Lisa Rojkjaer, MD, chief medical officer of Viracta Therapeutics, Inc., stated in a press release. “Patients with PTCL have few effective treatment options, particularly those with relapsed or refractory disease. Of note, EBV is frequently associated with PTCL, and reportedly confers a worse overall survival for patients.”

A phase 1/2 trial (NCT03397706) enrolled patients with histologically confirmed EBV-positive lymphomas who had relapsed or refractory to at least 1 previous systemic therapy and who were at least 18 years of age.³ Patients were required to have an absolute neutrophil count of at least 1.0 x 10⁹/L, a platelet count of at least 50 x 10⁹/L, and have no curative options available to them.

Participants were enrolled to 5 dose-escalation cohorts to identify the recommended phase 2 dose (RP2D) of Nana-val for phase 2 expansion. In the phase 2 portion of the research, participants received the RP2D identified as 20 mg of nanatinostat daily for 4 days per week plus 900 mg of valganciclovir daily as part of 28-day cycles. Treatment was continued until progressive disease or withdrawal.

The primary end points of the trial were safety and RP2D for the phase 1b portion of the trial, and overall response rate (ORR) for the phase 2 portion of the research. Key secondary end points comprised pharmacokinetics, duration of response (DOR), time to response, progression-free survival (PFS), and overall survival (OS).

By June 18, 2021, a total of 55 patients were enrolled to the trial; 25 patients comprised the phase 1b portion and 30 patients comprised the phase 2 portion. Among those enrolled, patients had diffuse large B-cell lymphoma (DLBCL; n = 7), extranodal natural killer (NK)/T-cell disease (n = 9), PTCL not otherwise specified (n = 5), angioimmunoblastic T-cell lymphoma (n = 6), cutaneous T-cell disease (n = 1), Hodgkin lymphoma (n = 1), other B-cell lymphoma (n = 3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD; n = 13).

The median age of patients was 60 years (range, 19-84), and most patients were male (n = 35). The median number of previous therapies received was 2 (range, 1-11), with 76% of patients having received at least 2 previous therapies. Seventy-eight percent of patients were refractory to the most recent previous therapy received and 84% had exhausted all standard treatments.

Data from the study showed that among evaluable patients (n = 43), the ORR achieved with the regimen was 40% per investigator assessment, which included a complete response (CR) rate of 19%. In those with T/NK-NHL (n = 15), all of whom were refractory to the last therapy they received, the ORR with Nana-val was 60% and the CR rate was 27%. In the 6 patients with DLBCL, the ORR achieved with the combination was 67% and the CR rate was 33%. In the 13 patients with IA-LPD, the ORR with Nana-val was 30% and the CR rate was 20%.

Among all responders, the median DOR was 10.4 months. Of the 17 responders, 8 continued to respond to treatment for at least 6 months.

Regarding safety, the most frequently experienced treatment-emergent toxicities included nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3 or 4 treatment-emergent effects that occurred in more than 10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%).

“Following the conclusion of our phase 1b/2 study, we are now continuing the evaluation of Nana-val in patients with relapsed/refractory EBV-positive lymphoma in our global phase 2 NAVAL-1 trial, which is actively enrolling at sites across Europe, North America, and Southeast Asia,” Rojkjaer added in the press release.

The phase 2 trial is enrolling patients with EBV-positive, relapsed/refractory lymphoma who have previously received at least 2 previous systemic therapies.² Patients were required to have measurable disease per Lugano 2007 criteria, an ECOG performance status of 0 to 2, and acceptable bone marrow function.

They could not have available therapy and they could not be candidates for high-dose chemotherapy with allogeneic or autologous stem cell transplantation or CAR T-cell therapy. Other exclusion criteria included the presence or history of central nervous system involvement by lymphoma, having received systemic anticancer therapy or CAR T in 21 days, antibody agents within 28 days, and daily corticosteroids within the week prior to day 1 of cycle 1, among others.

On the trial, participants will receive nanatinostat at 20 mg daily on days 1 through 4 weekly in combination with valganciclovir at 900 mg once daily.

The primary outcome measure for NAVAL-1 was ORR, and secondary end points included DOR, time to next anti-lymphoma treatment, PFS, time to progression, OS, incidence and severity of treatment-emergent toxicities, and pharmacokinetic measures.

NAVAL-1 was initiated in June 2021.⁴

“The initiation of NAVAL-1 is an important milestone for Viracta, and we are thrilled to have this pivotal trial open for enrollment,” Ivor Royston, MD, president and chief executive officer of Viracta, stated in a press release issued at the time. “We believe we are uniquely positioned with our all-oral therapeutic approach, together with our novel trial design, to expand the impact and broaden the reach to patients with various lymphoma subtypes in key geographies around the world.”

References

1. Viracta Therapeutics announces orphan drug designation granted by the European Commission for Nana-val for the treatment of peripheral T-cell lymphoma. News release. Viracta Therapeutics, Inc. September 7, 2022. Accessed September 7, 2022. https://prn.to/3x7Msc9
2. An open-label, phase 2 trial of nanatinostat in combination with valganciclovir in patients with Epstein-Barr virus-positive (EBV+) relapsed/refractory lymphomas (NAVAL-1). ClinicalTrials.gov. Updated August 11, 2022. Accessed September 7, 2022. https://clinicaltrials.gov/ct2/show/NCT05011058
3. Haverkos BM, Alpdogan O, Baiocchi R, et al. Nanatinostat (Nstat) and valganciclovir (VGCV) in relapsed/refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphomas: final results from the phase 1b/2 VT3996-201 study. Blood. 2021;138(suppl 1):623. doi:10.1182/blood-2021-152603
4. Viracta Therapeutics announces the initiation of NAVAL-1, a global pivotal trial for the treatment of relapsed/refractory Epstein-Barr virus-positive lymphoma. News release. Viracta Therapeutics, Inc. June 1, 2021. Accessed September 7, 2022. https://bit.ly/3x5cOM5