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Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial.
Lancet Oncol. 2016 05; 17(5):622-31.LO

Abstract

BACKGROUND

Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma.

METHODS

This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988.

FINDINGS

Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine [20%] of 44 patients), neutropenia (three [7%]), and hyperglycaemia (three [7%]). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose.

INTERPRETATION

The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing.

FUNDING

Curis, Inc, and the Leukemia and Lymphoma Society.

Authors+Show Affiliations

Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: younesa@mskcc.org.Sarah Cannon Research Institute, Nashville, TN, USA.Sarah Cannon Research Institute, Nashville, TN, USA; Florida Cancer Specialists, Sarasota, FL, USA.Sarah Cannon Research Institute, Nashville, TN, USA.Memorial Sloan Kettering Cancer Center, New York, NY, USA.Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California, Los Angeles, CA, USA.Memorial Sloan Kettering Cancer Center, New York, NY, USA.Sarah Cannon Research Institute, Nashville, TN, USA.Curis, Inc, Lexington, MA, USA.Curis, Inc, Lexington, MA, USA.Curis, Inc, Lexington, MA, USA.Curis, Inc, Lexington, MA, USA.Curis, Inc, Lexington, MA, USA.Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Pub Type(s)

Clinical Trial, Phase I
Journal Article

Language

eng

PubMed ID

27049457

Citation

Younes, Anas, et al. "Safety, Tolerability, and Preliminary Activity of CUDC-907, a First-in-class, Oral, Dual Inhibitor of HDAC and PI3K, in Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma: an Open-label, Dose-escalation, Phase 1 Trial." The Lancet. Oncology, vol. 17, no. 5, 2016, pp. 622-31.
Younes A, Berdeja JG, Patel MR, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016;17(5):622-31.
Younes, A., Berdeja, J. G., Patel, M. R., Flinn, I., Gerecitano, J. F., Neelapu, S. S., Kelly, K. R., Copeland, A. R., Akins, A., Clancy, M. S., Gong, L., Wang, J., Ma, A., Viner, J. L., & Oki, Y. (2016). Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. The Lancet. Oncology, 17(5), 622-31. https://doi.org/10.1016/S1470-2045(15)00584-7
Younes A, et al. Safety, Tolerability, and Preliminary Activity of CUDC-907, a First-in-class, Oral, Dual Inhibitor of HDAC and PI3K, in Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma: an Open-label, Dose-escalation, Phase 1 Trial. Lancet Oncol. 2016;17(5):622-31. PubMed PMID: 27049457.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. AU - Younes,Anas, AU - Berdeja,Jesus G, AU - Patel,Manish R, AU - Flinn,Ian, AU - Gerecitano,John F, AU - Neelapu,Sattva S, AU - Kelly,Kevin R, AU - Copeland,Amanda R, AU - Akins,Amy, AU - Clancy,Myles S, AU - Gong,Lucy, AU - Wang,Jing, AU - Ma,Anna, AU - Viner,Jaye L, AU - Oki,Yasuhiro, Y1 - 2016/03/31/ PY - 2015/10/20/received PY - 2015/12/02/revised PY - 2015/12/03/accepted PY - 2016/4/7/entrez PY - 2016/4/7/pubmed PY - 2017/6/14/medline SP - 622 EP - 31 JF - The Lancet. Oncology JO - Lancet Oncol. VL - 17 IS - 5 N2 - BACKGROUND: Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma. METHODS: This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988. FINDINGS: Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine [20%] of 44 patients), neutropenia (three [7%]), and hyperglycaemia (three [7%]). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose. INTERPRETATION: The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing. FUNDING: Curis, Inc, and the Leukemia and Lymphoma Society. SN - 1474-5488 UR - https://www.unboundmedicine.com/medline/citation/27049457/Safety_tolerability_and_preliminary_activity_of_CUDC_907_a_first_in_class_oral_dual_inhibitor_of_HDAC_and_PI3K_in_patients_with_relapsed_or_refractory_lymphoma_or_multiple_myeloma:_an_open_label_dose_escalation_phase_1_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(15)00584-7 DB - PRIME DP - Unbound Medicine ER -