On June 23, 2022 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision-oncology biopharmaceutical company, reported that the first patient has been enrolled in a multicenter phase 2 clinical trial evaluating its spleen tyrosine kinase (SYK) inhibitor mivavotinib (CB-659) in patients with relapsed/refractory non-germinal center B-cell like (non-GCB) diffuse large B-cell lymphoma (DLBCL), a DLBCL subpopulation that primarily comprises patients with activated B-cell like disease (ABC) (Press release, Calithera Biosciences, JUN 23, 2022, View Source [SID1234616206]).
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In a retrospective analysis of prior phase 1/2 studies in patients with DLBCL, patients with non-GCB DLBCL who received mivavotinib had a response rate of 53%, as compared to a response rate of 22% in patients with GCB DLBCL. Additionally, recent preclinical studies have shown enhanced SYK activity, and greater sensitivity to SYK inhibition, in DLBCL tumor-cell lines with mutations in MYD88 and CD79b genes. A significant fraction of patients with non-GCB DLBCL have tumors that harbor these mutations, and this subset of patients is known to have poorer outcomes with standard-of-care therapies.
"Mivavotinib has demonstrated potential to be a first-to-market approach for non-GCB DLBCL, including the genetic subset of patients harboring MYD88 and/or CD79 mutations," said Susan Molineaux, PhD, president and chief executive officer of Calithera. "This study will advance understanding of how our novel biomarker-driven approach could help address this high unmet therapeutic need, and we look forward to sharing data by the first quarter of 2023."
The phase 2 clinical trial (NCT05319028) is an open-label study of mivavotinib monotherapy in patients with relapsed/refractory non-GCB DLBCL. The main study objectives are to confirm previously seen single-agent activity in non-GCB DLBCL patients, evaluate activity according to MYD88/CD79b mutational status, and refine dose/schedule in this patient population. Approximately 50 non-GCB DLBCL patients, with or without MYD88/CD79b mutations, will be randomized 1:1 to one of two oral dose/schedule cohorts: a continuous dosing schedule (100 mg QD) or an induction dosing schedule (120 mg QD x 14 days, then 80 mg QD starting Day 15).
Centrally assessed ctDNA-based liquid next-generation sequencing (NGS) will be performed after randomization to ascertain MyD88/CD79b mutation status. The primary endpoints of the study are overall response rate as assessed by an independent radiology review committee and safety. Key secondary endpoints include duration of response, progression-free survival, and complete response.
Data from the trial could position Calithera to initiate a study with registrational intent in biomarker-specific DLBCL populations.