التفاصيل البيبلوغرافية
| العنوان: |
Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. |
| المؤلفون: |
Yee, Andrew J1, Bensinger, William I2, Supko, Jeffrey G1, Voorhees, Peter M3, Berdeja, Jesus G4, Richardson, Paul G5, Libby, Edward N2, Wallace, Ellen E1, Birrer, Nicole E1, Burke, Jill N1, Tamang, David L6, Yang, Min6, Jones, Simon S6, Wheeler, Catherine A6, Markelewicz, Robert J6, Raje, Noopur S1 nraje@mgh.harvard.edu |
| المصدر: |
Lancet Oncology. Nov2016, Vol. 17 Issue 11, p1569-1578. 10p. |
| مصطلحات موضوعية: |
*MULTIPLE myeloma treatment, *CANCER relapse, *DEXAMETHASONE, *HISTONE deacetylase inhibitors, *DRUG dosage, *DRUG efficacy, *CANCER, *ANTINEOPLASTIC agents, *CLINICAL trials, *COMPARATIVE studies, *ENZYME inhibitors, *HETEROCYCLIC compounds, *RESEARCH methodology, *MEDICAL cooperation, *MULTIPLE myeloma, *RESEARCH, *THALIDOMIDE, *HYDROXY acids, *EVALUATION research |
| مصطلحات جغرافية: |
UNITED States |
| مستخلص: |
Background: Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma.Methods: In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40-240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three different regimens on days 1-21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, number NCT01583283.Findings: Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1-21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1-2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhoea (grade 1-2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% [95% CI 38-71]) of 38 patients had an overall response.Interpretation: The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma.Funding: Acetylon Pharmaceuticals. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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