Today, at the 2020 Annual Meeting of the American Hematology Society (ASH), the Weill Cornell Medicine T-cell lymphoma research team reported the outcome of the first phase 2 study evaluating the novel combination of oral azacitidine plus CHOP as initial treatment for patients with peripheral T-cell lymphoma (PTCL).
This multi-center phase 2 study, led by Dr. Jia Ruan, is the first of its kind to incorporate epigenetic priming with a hypomethylating agent in the frontline setting as a chemo-sensitizing strategy for PTCL.
The study enrolled 21 PTCL patients, with the majority of them (17 patients) having the diagnosis of angioimmunoblastic T-cell lymphoma, also known as PTCL with T-follicular helper phenotype (PTCL-TFH). This phenotype is known to have recurrent genetic mutations in epigenetic regulation, providing therapeutic targets for hypomethylating agents such as azacitidine. During study treatment, the patients received CHOP on day 1 of each cycle for 6 cycles, while oral azacitidine was given for 7 days prior to CHOP cycle 1, and for 14 days before CHOP cycles 2-6. The primary study objective was to see if the novel combination would improve complete response rates following 6 cycles of treatment.
The study treatment was well tolerated with expected side effects associated with CHOP chemotherapy. Eighteen patients were able to complete all 6 cycles of treatment without the need for chemotherapy dose reduction. Ten patients underwent successful stem cell transplant while in remission. Complete remission (CR) was achieved in 75% of clinical trial participants at the end of 6 cycles of treatment, exceeding the pre-determined efficacy threshold (60%) to declare the treatment as effective. Notably, within the subgroup of patients with the PTCL-TFH subtype, the treatment appears to work even better with a CR rate of 88%. The one-year progression-free survival (PFS) for all patients was 66%, and for the PTCL-TFH subgroup was 70%. The one-year overall survival (OS) for all patients was 81% and PTCL-TFH patients 94%. The research team is further analyzing sequencing biomarkers to correlate with response and survival.
This study provides the first demonstration that the addition of epigenetic hypomethylating agent oral azacitidine (CC486) to CHOP as initial therapy is safe, and highly effective to induce complete remission in PTCL. This combination will be further evaluated in the upcoming ALLIANCE/Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P with duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL.
The Fast Track Designation was introduced by the FDA in 1997 under the FDA Modernization Act. It was designed to speed up the development and review of drugs that treat serious conditions and fill an unmet medical need. Like all expedited designations, the Fast Track was designed to get new treatments into the hands of patients in need.
The Fast Track designation must be requested by the treatment’s sponsor. To determine whether a treatment warrants a Fast Track designation the FDA decides whether a drug shows promise in treating a serious condition or fills an unmet medical need. Determining whether a drug treats a condition that is “serious” is largely a subjective matter, but cancers including lymphoma are universally agreed upon to match the criteria of serious conditions. The factors the FDA will consider include the drug’s impact on survival, day-to-day functioning, and if left untreated, whether a less severe condition will turn into a more serious condition. An unmet medical need provides a treatment option to patients where no such option previously existed.
If other treatment options are already available then the treatment applying for the Fast Track designation must show superior effectiveness, avoid any major side effects found in currently available therapies, improve upon the diagnosis to show an improved outcome, or address an emerging or anticipated public health need.
Treatments that meet these criteria are eligible for more support from the FDA for their application process. If the relevant criteria is met they are also eligible for the accelerated approval and priority review designations.
Under the Prescription Drug User Act the FDA created a two-tiered system for review of new drug applications (NDA). The first tier of this system, known as Standard Review, is for treatments that offer a minor improvement over existing therapies, and sets the timeline to review at 10 months from receiving the NDA. The second tier, the Priority Review, is for drugs that offer major advances over existing therapies, or provide a treatment where none had previously existed, and reduces the approval timeframe of review to 6 months.
Significant improvements over pre-existing treatments include evidence of increased effectiveness in treatment, prevention, or diagnosis, reduction in treatment-limiting reactions, evidence of safety and effectiveness in a new patient population, and documented enhancement of patient compliance that is thought to lead to an improvement in serious outcomes.
Unlike other expedited approval programs with different levels of standards the Priority Review designation does not change the scientific or medical standards used for approval by the FDA. Instead more resources are devoted to expediting approval for the treatments that receive this designation because the FDA has decided chosen treatments serve a much greater need. To receive the Priority Review designation the FDA requires evidence of increased effectiveness in treatment prevention, or diagnosis of a condition.