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Combo emerges as bridge to transplant in rel/ref PTCL

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stockguard   Wednesday, 02/06/19 05:43:36 PM
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Combo emerges as bridge to transplant in rel/ref PTCL
Publish date: February 5, 2019

REPORTING FROM TCLF 2019

LA JOLLA, CALIF. – The combination of duvelisib and romidepsin is active and can provide a bridge to transplant in relapsed or refractory peripheral T-cell lymphoma (PTCL), according to researchers.

In a phase 1 trial, duvelisib plus romidepsin produced an overall response rate (ORR) of 59% in patients with PTCL. Sixteen patients achieved a response, nine had a complete response (CR), and six complete responders went on to transplant.

“So we think that you can achieve remission deep enough to then move on to a potentially curative approach,” said study investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

She and her colleagues evaluated romidepsin plus duvelisib, as well as bortezomib plus duvelisib, in a phase 1 trial (NCT02783625) of patients with relapsed or refractory PTCL or cutaneous T-cell lymphoma (CTCL).

Dr. Mehta-Shah presented the results at the annual T-cell Lymphoma Forum.

She reported results in 80 patients­ – 51 with PTCL and 29 with CTCL. The patients’ median age was 64 years (range, 28-83), and 57% of the study population were men. Patients had received a median of 3 (range, 1-16) prior therapies, and 16% had received a prior transplant.

Treatment
Dr. Mehta-Shah noted that patients and providers could choose whether patients would receive romidepsin or bortezomib.

Patients in the romidepsin arm received romidepsin at 10 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Patients in the bortezomib arm received bortezomib at 1 mg/m2 on days 1, 4, 8, and 11 of each cycle.

Duvelisib dosing was escalated, so patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily.

In the bortezomib arm, there was one dose-limiting toxicity – grade 3 neutropenia – in a patient who received duvelisib at the 25-mg dose. There were no dose-limiting toxicities in the romidepsin arm.

The researchers determined that the maximum tolerated dose (MTD) of duvelisib was 75 mg twice daily in the romidepsin arm and 25 mg twice daily in the bortezomib arm.

Lead-in phase
The study also had a lead-in phase during which patients could receive single-agent duvelisib.

“Because the original phase 1 study of duvelisib did not collect as many prospective tumor biopsies or on-treatment biopsies, we built into this study a lead-in phase so that we could characterize on-treatment biopsies to better understand mechanisms of response or resistance,” Dr. Mehta-Shah said.

Patients and providers could choose to be part of the lead-in phase, she noted. Patients who did not achieve a CR during this phase went on to receive either combination therapy, which was predetermined before the monotherapy began.

There were 14 patients who received duvelisib monotherapy at 75 mg twice daily. Four of them achieved a CR, and three had a partial response (PR). Ten patients went on to receive romidepsin as well. One of them achieved a CR, and three had a PR.

There were 12 patients who received duvelisib monotherapy at 25 mg twice daily. Three of them achieved a CR, and two had a PR. Nine patients went on to receive bortezomib as well. This combination produced one CR and two PRs.

Efficacy with romidepsin
Among all evaluable PTCL patients in the romidepsin arm, the ORR was 59% (16/27), and the CR rate was 33% (9/27).

Responses occurred in seven patients with PTCL not otherwise specified (NOS), six with angioimmunoblastic T-cell lymphoma (AITL), one with hepatosplenic T-cell lymphoma, one with aggressive epidermotropic CD8+ T-cell lymphoma, and one with primary cutaneous PTCL.

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CRs occurred in five patients with AITL and four with PTCL-NOS. Six patients who achieved a CR went on to transplant.

Among evaluable CTCL patients in the romidepsin arm, the ORR was 45% (5/11), and there were no CRs. Responses occurred in three patients with mycosis fungoides and two with Sézary syndrome.

The median progression-free survival was 5.41 months in CTCL patients and 6.72 months in PTCL patients.

Efficacy with bortezomib
Among evaluable PTCL patients in the bortezomib arm, the ORR was 44% (7/16), and the CR rate was 25% (4/16).

Responses occurred in three patients with AITL and four with PTCL-NOS. CRs occurred in two patients with each subtype.

Among evaluable CTCL patients in the bortezomib arm, the ORR was 27% (4/15), and there were no CRs. Responses occurred in one patient with mycosis fungoides and three with Sézary syndrome. One CTCL patient went on to transplant.

The median progression-free survival was 4.56 months among CTCL patients and 4.39 months in PTCL patients.

Safety
Dr. Mehta-Shah said both combinations were considered safe and well tolerated. However, there was a grade 5 adverse event (AE) – Stevens-Johnson syndrome – that occurred in the bortezomib arm and was considered possibly related to treatment.

Grade 3/4 AEs observed in the 31 patients treated at the MTD in the romidepsin arm were transaminase increase (n = 7), diarrhea (n = 6), hyponatremia (n = 4), neutrophil count decrease (n = 10), and platelet count decrease (n = 3).

Grade 3/4 AEs observed in the 23 patients treated at the MTD in the bortezomib arm were transaminase increase (n = 2) and neutrophil count decrease (n = 5).

Grade 3/4 transaminitis seemed to be more common among patients who received duvelisib alone during the lead-in phase, Dr. Mehta-Shah said.

Among patients treated at the MTD in the romidepsin arm, grade 3/4 transaminitis occurred in four patients treated during the lead-in phase and three who began receiving romidepsin and duvelisib together. In the bortezomib arm, grade 3/4 transaminitis occurred in two patients treated at the MTD, both of whom received duvelisib alone during the lead-in phase.

Based on these results, Dr. Mehta-Shah and her colleagues are planning to expand the romidepsin arm to an additional 25 patients. By testing the combination in more patients, the researchers hope to better understand the occurrence of transaminitis and assess the durability of response.

This study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.

The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

jensmith@mdedge.com

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