A Randomized, Phase IIB, Multicenter, Trial of Oral Azacytidine Plus Romidepsin versus Investigator's Choice in Patients with Relapse or Refractory Periperal T-cell lymphoma (PTCL).

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Project Abstract CHOP-based regimens, the present standard of care for peripheral T-cell lymphoma (PTCL), were established in aggressive B-cell malignancies and extrapolated to the PTCL. As a result, the median survival of patients with PTCL is only 1 to 3 years, with a median 5-year survival of only 20-25%. Major challenges to develop PTCL- specific treatment relate to their rarity and heterogeneity. Specifically, the annual incident rate ratio of all PTCLs is 1.3673 per 100,000 among all races on average and their prevalence rate is 5.30 per 100,000. The extreme heterogeneity is affirmed by the fact that the WHO recognizes 30 distinct subtypes of the disease. Many lines of data now suggest that the PTCL exhibit a unique vulnerability to epigenetic modifiers. In order to identify potentially new standards for the disease, we will conduct a randomized, phase IIB, multicenter trial of Oral Azacytidine (AZA) plus Romidepsin (ROMI) versus Investigator’s Choice (IC) including romidepsin, belinostat, pralatrexate and gemcitabine in patients with Relapse or Refractory (R/R) PTCL. We anticipate generating sufficient data that will inform a ‘go-no-go’ decision regarding a full scale randomized Phase 3. To date, several agents have gained FDA accelerated approval for the treatment of R/R PTCL. Based on these examples, the logic for a potential regulatory study design is as follows: the patient population is “patients with PTCL who have received one prior systemic therapy.” This patient population was studied in all precedent examples of accelerated approvals (pralatrexate, romidepsin, belinostat). While the term PTCL encompasses multiple T-cell lymphoma histology’s, the FDA has permitted registration trials to be conducted in this category of T-cell lymphoma malignancies due to the rarity of the disease. We will adopt the traditional endpoint of progression free survival (PFS), used for regular approvals of new agents in R/R lymphomas (B- and T-lymphomas), in contrast to response rate or CR rate used for accelerated approvals. Lastly, the control arm is an investigator choice that includes appropriate and clinically meaningful drugs for this trial. Finally, the correlative samples obtained from patients on trial will determine how the genetic features of the disease influence clinical outcome and will clarify the immunologic effects induced by the combination. We believe this study will transform how we think about future treatment paradigms, and improve the outcomes of patients with PTCL.