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Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study.
Lancet Oncol. 2018 04; 19(4):486-496.LO

Abstract

BACKGROUND

Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies.

METHODS

We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766.

FINDINGS

Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0-14·0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib.

INTERPRETATION

Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting.

FUNDING

TG Therapeutics.

Authors+Show Affiliations

Sarah Cannon Research Institute, Nashville, TN, USA; Tennessee Oncology, PLLC, Nashville, TN, USA.Sarah Cannon Research Institute, Nashville, TN, USA; Tennessee Oncology, PLLC, Nashville, TN, USA.Sarah Cannon Research Institute, Nashville, TN, USA; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA.Medical College of Wisconsin, Milwaukee, WI, USA.Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons/New York-Presbyterian Hospital, New York, NY, USA.Duke University Medical Center, Durham, NC, USA.John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA.Oncology Hematology Care, Cincinnati, OH, USA.The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.TG Therapeutics, New York, NY, USA.TG Therapeutics, New York, NY, USA.TG Therapeutics, New York, NY, USA.Rhizen Pharmaceuticals SA, La Chaux-de-Fonds, Switzerland.Vanderbilt University Medical Center, Nashville, TN, USA.Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons/New York-Presbyterian Hospital, New York, NY, USA. Electronic address: owenoconnor@columbia.edu.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29475723

Citation

Burris, Howard A., et al. "Umbralisib, a Novel PI3Kδ and Casein Kinase-1ε Inhibitor, in Relapsed or Refractory Chronic Lymphocytic Leukaemia and Lymphoma: an Open-label, Phase 1, Dose-escalation, First-in-human Study." The Lancet. Oncology, vol. 19, no. 4, 2018, pp. 486-496.
Burris HA, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486-496.
Burris, H. A., Flinn, I. W., Patel, M. R., Fenske, T. S., Deng, C., Brander, D. M., Gutierrez, M., Essell, J. H., Kuhn, J. G., Miskin, H. P., Sportelli, P., Weiss, M. S., Vakkalanka, S., Savona, M. R., & O'Connor, O. A. (2018). Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. The Lancet. Oncology, 19(4), 486-496. https://doi.org/10.1016/S1470-2045(18)30082-2
Burris HA, et al. Umbralisib, a Novel PI3Kδ and Casein Kinase-1ε Inhibitor, in Relapsed or Refractory Chronic Lymphocytic Leukaemia and Lymphoma: an Open-label, Phase 1, Dose-escalation, First-in-human Study. Lancet Oncol. 2018;19(4):486-496. PubMed PMID: 29475723.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. AU - Burris,Howard A,3rd AU - Flinn,Ian W, AU - Patel,Manish R, AU - Fenske,Timothy S, AU - Deng,Changchun, AU - Brander,Danielle M, AU - Gutierrez,Martin, AU - Essell,James H, AU - Kuhn,John G, AU - Miskin,Hari P, AU - Sportelli,Peter, AU - Weiss,Michael S, AU - Vakkalanka,Swaroop, AU - Savona,Michael R, AU - O'Connor,Owen A, Y1 - 2018/02/20/ PY - 2017/10/18/received PY - 2017/12/12/revised PY - 2017/12/14/accepted PY - 2018/2/25/pubmed PY - 2019/3/6/medline PY - 2018/2/25/entrez SP - 486 EP - 496 JF - The Lancet. Oncology JO - Lancet Oncol. VL - 19 IS - 4 N2 - BACKGROUND: Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies. METHODS: We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766. FINDINGS: Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0-14·0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib. INTERPRETATION: Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting. FUNDING: TG Therapeutics. SN - 1474-5488 UR - https://www.unboundmedicine.com/medline/citation/29475723/Umbralisib_a_novel_PI3Kδ_and_casein_kinase_1ε_inhibitor_in_relapsed_or_refractory_chronic_lymphocytic_leukaemia_and_lymphoma:_an_open_label_phase_1_dose_escalation_first_in_human_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(18)30082-2 DB - PRIME DP - Unbound Medicine ER -