A First-in-human Study of Tenalisib (RP6530), a Dual PI3K δ/γ Inhibitor, in Patients With Relapsed/Refractory Hematologic Malignancies: Results From the European Study

• Published in: Clinical lymphoma, myeloma and leukemia Vol. 20; no. 2; pp. 78 - 86
• Main Authors: Carlo-Stella, Carmelo, Delarue, Richard, Scarfo, Lydia, Barde, Prajak J., Nair, Ajit, Locatelli, Silvia L., Morello, Lucia, Magagnoli, Massimo, Vakkalanka, Swaroop, Viswanadha, Srikant, Ferreri, Andrés J.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2020
• Subjects: Adult; Aged; Aged, 80 and over; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Dose escalation; Dose limiting toxicity; Europe; Female; Hematologic Neoplasms - drug therapy; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; pAKT; Phase I; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; Purines - pharmacology; Purines - therapeutic use; Tumor microenvironment; Young Adult; Europe; Dose limiting toxicity; pAKT; Phase I; Dose escalation; Tumor microenvironment
• ISSN: 2152-2650; 2152-2669
• DOI: 10.1016/j.clml.2019.10.013

Tenalisib (RP6530) is a novel, highly specific, dual phosphoinositide-3 kinases (PI3K) δ/γ inhibitor with nano-molar potency.
This was a phase I, open-label, 3 + 3 dose escalation, maximum tolerated dose determination study to evaluate the safety, pharmacokinetics, and efficacy of tenalisib in patients with relapsed/refractory hematologic malignancies. Tenalisib was administered orally twice/thrice daily in 28-day cycles with starting dose of 25 mg twice daily.
Thirty-five patients were enrolled across 11 dose levels. No dose limiting toxicity was reported at any of the dose levels. The most common treatment-emergent adverse events irrespective of causality were asthenia and cough in 15 (43%) patients and pyrexia in 13 (37%) patients. The most frequently reported related treatment-emergent adverse events were diarrhea, nausea, and vomiting. Related grade 3/4 adverse events were limited to events of hypertriglyceridemia, neutropenia, and diarrhea.
Pharmacokinetics showed rapid absorption. Based on maximum plasma concentration and area under the plasma-concentration time curve, dose proportionality was observed up to 400 mg dose. Of 31 patients included in the efficacy analysis, complete response was seen in 2 (7%) patients and partial response in 4 (13%) patients, with an overall response rate of 19% and a disease-control rate of 61%. The median duration of response was 5.7 months. Responders demonstrated a marked downregulation of phospho-AKT on C1D8.
Tenalisib demonstrated acceptable safety up to 1200 mg twice a day with no dose-limiting toxicities. Consistent clinical response was seen at doses 200 mg BID and above. Pharmacodynamics correlated well with clinical outcome. Further phase I/II studies are being undertaken to evaluate efficacy across different histologies.
Tenalisib (RP6530) is a novel, highly specific dual phosphoinositide-3 kinases (PI3K) δ/γ inhibitor with nano-molar potency. It demonstrated acceptable safety up to 1200 mg twice a day with no dose-limiting toxicities in patients with relapsed/refractory hematologic malignancies. Consistent clinical response was seen at doses 200 mg and above. Further phase I/II studies are being undertaken to evaluate efficacy across different histologies.