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: Clinical Lymphoma, Myeloma and Leukemia

C. Carlo-Stella, R. Delarue, L. Scarfo, P.J. Barde, A. Nair, S.L. Locatelli, L. Morello, M. Magagnoli, S. Vakkalanka, S. Viswanadha, A.J.M. Ferreri

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Tenalisib (RP6530) is a novel, highly specific, dual phosphoinositide-3 kinases (PI3K) δ/γ inhibitor with nano-molar potency. Material and Methods: 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. Results: 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. Conclusion: 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. © 2019 Elsevier Inc. 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. © 2019 Elsevier Inc.
Original languageEnglish
Pages (from-to)78-86
Number of pages9
JournalClin. Lymphoma Myeloma Leukemia
Volume20
Issue number2
DOIs
Publication statusPublished - 2020

Keywords

  • Dose escalation
  • Dose limiting toxicity
  • pAKT
  • Phase I
  • Tumor microenvironment
  • alanine aminotransferase
  • aspartate aminotransferase
  • bilirubin
  • hemoglobin
  • phospho protein kinase b
  • protein kinase B
  • tenalisib
  • unclassified drug
  • abdominal pain
  • adult
  • aged
  • anemia
  • Article
  • asthenia
  • atrial fibrillation
  • backache
  • body weight loss
  • cancer chemotherapy
  • cancer control
  • chronic lymphatic leukemia
  • classical Hodgkin lymphoma
  • clinical article
  • cohort analysis
  • constipation
  • coughing
  • decreased appetite
  • deep vein thrombosis
  • diarrhea
  • diffuse large B cell lymphoma
  • down regulation
  • drug absorption
  • drug capsule
  • drug dose escalation
  • drug efficacy
  • drug potency
  • drug safety
  • drug screening
  • dyspepsia
  • dyspnea
  • electrocorticography
  • elimination half-life
  • fatigue
  • febrile neutropenia
  • female
  • fever
  • flank pain
  • follicular lymphoma
  • France
  • good clinical practice
  • headache
  • hematologic malignancy
  • human
  • hypertension
  • hypertriglyceridemia
  • hyperuricemia
  • hypocalcemia
  • hypokalemia
  • hypoxia
  • IC50
  • Italy
  • life expectancy
  • lymphadenopathy
  • male
  • mantle cell lymphoma
  • marginal zone lymphoma
  • maximum plasma concentration
  • maximum tolerated dose
  • multicenter study
  • multiple cycle treatment
  • multiple myeloma
  • muscle spasm
  • nausea
  • nausea and vomiting
  • neutropenia
  • neutrophil count
  • nonhodgkin lymphoma
  • open study
  • perianal abscess
  • peripheral edema
  • peripheral T cell lymphoma
  • pharmacodynamic parameters
  • pharmacokinetic parameters
  • phase 1 clinical trial
  • plasma concentration-time curve
  • pneumonia
  • polydipsia
  • polyuria
  • rhinitis
  • risk assessment
  • septic shock
  • somnolence
  • steady state
  • tablet formulation
  • thrombocytopenia
  • time to maximum plasma concentration
  • treatment response
  • vomiting
  • Waldenstroem macroglobulinemia

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