A Phase II Study to Evaluate Efficacy and Safety of P276-00 in Relapsed and/or Refractory Mantle Cell Lymphoma

Despite response rates of up to 97% with first-line standard or high-intensity chemotherapy, with or without stem-cell transplantation, most patients of mantle cell lymphoma (MCL)relapse.Prognosis of MCL after first relapse is very poor with median survival of around 1 to 2 years. Therefore, novel therapies are required for relapsed and/or refractory MCL.Overexpression of Cyclin D1 as a result of t(11;14)(q13;q32) translocation is the hallmark of MCL.It is postulated that Cyclin D1 may also have an oncogenic role independent of pRb in MCL.Therefore, inhibition of Cdk4-Cyclin D1 is a potentially promising target in MCL. P276-00 is a potent Cdk4-Cyclin D1 inhibitor worth exploring for its efficacy in MCL. Hence, this Phase II study is planned to examine the efficacy and safety of P276-00 in the treatment of patients with relapsed and/or refractory MCL. This is an open-label, single-arm, 2-stage trial. Approximately 35 patients are planned to be enrolled into the study to obtain a total of 25 efficacy evaluable patients (patients who complete at least 2 cycles of study treatment and have tumor measurements at the end of 2 cycles). A total of 15 efficacy evaluable patients are planned to be treated in Stage I of the study. If ≥1 response (CR or PR) of any duration or ≥2 stable disease (SD) for ≥4 cycles are seen in the Stage I, then the study will continue into Stage II, in which additional patients will be treated until there are 10 additional efficacy evaluable patients.The study is divided into 3 periods: Screening, Treatment, and Follow-up. During the Screening Period, patients will provide written informed consent and be evaluated for inclusion and exclusion criteria. During the Treatment Period, patients will be administered P276-00 as intravenous (iv) infusion on Days 1 to 5 of each 21-day cycle for a minimum of 6 cycles and a maximum of 12 cycles, or until progressive disease (PD) or unacceptable toxicity occurs. Safety and efficacy evaluations will be done on Days 1 to 5 and 11 of each cycle, and on Day 21 of every 2 cycles. Pharmacokinetic (PK) assessments will be done on Cycle 1, Day 1 (pre-dose and post-dose time points), and optional biomarker assessments will be done pre-dose within 4 weeks of Day 1 and post-dose on Day 4 or 5. The End-of-Last-Cycle Visit will occur at the end of Cycle 6, or if the patient continues study treatment beyond Cycle 6, it will occur at the end of the patient's last cycle; if the patient discontinues early, these assessments will be done as an Early Exit Visit. The Follow-up Visit will occur 4 weeks (±1 week) after the End-of-Last-Cycle Visit (or Early Exit Visit) for final safety assessments.Objective response rate is the primary end point for this study. Response evaluation will be performed using the International Working Group (IWG) revised response criteria for malignant lymphoma.