Safety and efficacy of VIP152, a CDK9 inhibitor, in patients with double-hit lymphoma (DHL).

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7538 Background: PTEFb/CDK9-mediated transcription of short-lived anti-apoptotic survival proteins and oncogenes like MCL-1 and MYC plays a critical role in a variety of cancers. VIP152 (formerly BAY 1251152), a potent and highly selective CDK9 inhibitor, has been evaluated in a Phase 1 dose-escalation study in patients with advanced cancer. The maximum tolerated dose was 30 mg once weekly administered in consecutive 21-day cycles, based on neutropenia as the dose-limiting toxicity (JCO 2018;36:2507; NCT02635672). DHL is defined as dual rearrangement of the MYC gene and either the BCL2 or BCL6 genes; the resulting overexpression of MYC and BCL2/BCL6 make it particularly difficult to treat. Patients with DHL have a poor prognosis and no standard of care. Considering the impact of CDK9 inhibition on MYC, an exploratory cohort of patients with DHL was added to the study. Methods: Patients with refractory or relapsed DHL were eligible. VIP152 was administered once weekly as a 30-minute IV infusion on Days 1, 8 and 15 of a 21-day cycle. Tumor response was assessed according to the revised Cheson criteria (2007). Results: To date a total of 7 patients have been enrolled and were evaluable at the time of data cutoff (24NOV2020). The patients were mostly men (6/7 pts, 86%) with a median (range) age of 70 (58-84) years. All patients received ≥2 prior therapies, including 2 patients with bone marrow transplant. Three of 7 patients (29%) had ≥3 prior therapies. The median time on treatment was 22 days (range 8-1361 days). The most common adverse events of any grade were: constipation, fatigue, nausea (each 3/7 pts, 43%) and abdominal pain, diarrhea, lymphocyte count decrease, neutrophil count decrease, skin infection, tumor pain, and vomiting (each 2/7 pts, 29%). Most were Grade 1 and Grade 2. The Grade 3 adverse events were fatigue, lymphocyte count decrease, neutrophil count decrease (each 1/7 pts, 14%) and tumor pain (2/7 pts, 29%). One Grade 4 lymphocyte count decrease was reported. Two patients had a serious adverse event (Grade 3 syncope and Grade 3 tumor pain). Two patients had dosing held for an adverse event; however, no patient withdrew from treatment due to any adverse events. One death occurred due to disease progression. Pharmacodynamic biomarker analysis showed significant reduction of MYC, PCNA, and MCL-1 mRNA in all patients across multiple timepoints. Antitumor activity consisted of 2 complete metabolic responses in 7 patients (29%) based on investigator-assessed FDG-PET scans. Due to the COVID pandemic, the patients withdrew consent after 3.7 and 2.3 years, respectively, of treatment. Both patients were in complete metabolic response. Conclusions: VIP152 had a manageable safety profile, on-target pharmacodynamic activity and signs of durable monotherapy antitumor activity in patients with DHL. These encouraging results warrant further evaluation of VIP152 in patients with MYC-driven lymphoma and solid tumors. Clinical trial information: NCT02635672.