First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy

Abstract

Purpose: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. Patients and Methods: Adults with solid tumors or aggressive non–Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined. Results: Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in > 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). Conclusions: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.

Selective CDK9 Inhibition by Natural Compound Toyocamycin in Cancer Cells

“…Unfortunately, many of these inhibitors did not demonstrate significant anticancer effects in patients and were discontinued because of severe side effects. However, the 3rd generation of CDK9 inhibitors (BAY-1251152 and AT-7519) produced promising outcomes in patients with hematological malignancies and solid tumors, which will be evaluated further in future clinical trials [ 51 , 60 ].…”

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

“…Moreover, the high aqueous solubility of enitociclib (S w pH 4: 699 mg/L) enabled the formulation of the predicted human dose for iv administration [29] . Encouragingly, enitociclib monotherapy recently demonstrated an acceptable therapeutic window and a favorable safety profile along with evidence of clinical benefit in patients with advanced hematologic and solid tumors after once weekly iv administration [30] …”

“…[29] Encouragingly, enitociclib monotherapy recently demonstrated an acceptable therapeutic window and a favorable safety profile along with evidence of clinical benefit in patients with advanced hematologic and solid tumors after once weekly iv administration. [30] The idea to stabilize the bioactive conformation of enitociclib by macrocyclization led to an additional series of highly potent CDK9 inhibitors like macrocycle 23 (Figure 8) with significantly improved antiproliferative activities in various cell lines [IC 50 HeLa: 108 nM (enitociclib) vs. 11 nM (23)]. [31] Furthermore, macrocyclic inhibitors such as 23 revealed a significantly differentiated in vivo pharmacokinetic profile [t 1/2 (rat): 0.73 h (enitociclib) vs. 4.8 h ( 23)] and prolonged target residence time [TRT CDK9, 25 °C: 3 min (enitociclib) vs. > 333 min (23)].…”

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

“…[27] Encouragingly, enitociclib monotherapy recently demonstrated an acceptable therapeutic window and a favorable safety profile along with evidence of clinical benefit in patients with advanced hematologic and solid tumors after once weekly iv administration. [28] The idea to stabilize the bioactive conformation of enitociclib by macrocyclization led to an additional series of highly potent CDK9 inhibitors like macrocycle 23 (Figure 8) with significantly improved antiproliferative activities in various cell lines [IC50 HeLa: 108 nM (enitociclib) vs 11 nM (23)]. [29] Furthermore, macrocyclic inhibitors such as 23 revealed a significantly differentiated in vivo pharmacokinetic profile [t1/2 (rat): 0.73 h (enitociclib) vs 4.8 h ( 23…”