To report on the first-in-human phase I study of VIP152 (NCT02635672), a highly selective and potent cyclin-dependent kinase 9 (CDK9) inhibitor, which was in progress. VIP152 was administered as a 30-minute intravenous, once-weekly infusion to adults with solid tumors or aggressive non–Hodgkin lymphoma that had not responded to or had been treated to the point of exhaustion and were refractory. The MTD was set at 30 mg after 37 patients received at least 1 VIP152 dose, with grade 3/4 neutropenia as the dose-limiting toxicity. Nausea and vomiting were the most prevalent adverse effects, both of grade 1/2 severity (75.7% and 56.8%, respectively). Grade 3/4 events occurred in at least one patient (22%), including neutropenia (11%), anemia (11%), abdominal discomfort (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). The MTD’s Day 1 exposure was greater than the predicted minimal therapeutic exposure and consistently resulted in maximum pathway modulation; accumulation did not ensue after repeated dosages. Stable disease was observed in seven of the 30 cancer patients (9.5 and 16.8 months for pancreatic and salivary gland cancers, respectively) T cells positive for MYC, BCL2/BCL6 translocations, and no T cell abnormalities were identified in 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) who achieved durable complete metabolic remission throughout the study. VIP152 monotherapy, given intravenously once a week, has shown promise in patients with advanced HGL and solid tumors in clinical trials.