MCL-129: First-Line Ibrutinib Plus Venetoclax in MCL for Older Patients or Those with a TP53 Mutation: Ongoing Open-Label Arm of the PCYC-1143 Phase 3 SYMPATICO Study

Context: Ibrutinib, a once-daily inhibitor of Bruton tyrosine kinase (BTK), is approved in the US for patients with MCL with ≥1 prior therapy. Single-agent ibrutinib received accelerated approval for MCL after showing complete response (CR) rates of 19–21% and overall response rates of 68–72% (Dreyling Lancet 2016; Wang NEJM 2013). Venetoclax is a BCL2 inhibitor approved in the US for patients with CLL with ≥1 prior therapy and for patients with previously untreated AML. Single-agent venetoclax has also shown efficacy in MCL, with CR rates of 21% (Davids J Clin Oncol 2017). In preclinical models, ibrutinib + venetoclax showed synergistic antitumor activity via dual inhibition of the BTK and BCL2 pathways (Zhao Br J Haematol 2015). In the phase 2 AIM study, 71% of 24 patients with MCL treated with ibrutinib + venetoclax had a best response of CR. Notably, the CR rate was 50% in patients with TP53 mutations, a population considered chemo-insensitive; this included 1 previously untreated patient (Tam NEJM 2018). Objective: To evaluate ibrutinib + venetoclax in patients ≥65 years and patients Design: This new open-label arm of the ongoing phase 3 SYMPATICO study will be conducted in ∼75 previously untreated patients with MCL. This study is currently enrolling patients. Patients or other participants: Key inclusion criteria include age ≥65 years or 18–65 years with a TP53 mutation, pathologically confirmed treatment-naive MCL with ECOG performance status of 0–2, and measurable disease. Patients with the blastoid variant of MCL, history of CNS lymphoma, or prior treatment with a BTK or BCL-2 inhibitor are ineligible. Interventions: Patients will receive oral, once daily 560 mg ibrutinib + venetoclax in a 5-week ramp-up to 400 mg venetoclax. Patients receive ibrutinib + venetoclax for 104 weeks; afterwards, venetoclax is discontinued in all patients and single-agent ibrutinib continues until progressive disease or unacceptable toxicity. Main outcome measures: The primary objective is to evaluate the CR rate. Secondary objectives include additional efficacy evaluations, safety, and pharmacokinetics. Funding: Pharmacyclics LLC, an AbbVie Company.