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 language | English |
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Pages (from-to) | 78-86 |
Number of pages | 9 |
Journal | Clin. Lymphoma Myeloma Leukemia |
Volume | 20 |
Issue number | 2 |
DOIs | |
Publication status | Published - 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