Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial.

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.

Financial Burden of Cancer Clinical Trial Participation and the Impact of a Cancer Care Equity Program.

INTRODUCTION: Cancer clinical trial (CT) participation rates are low and financial barriers likely play a role. We implemented a cancer care equity program (CCEP) to address financial burden associated with trial participation. We sought to examine the impact of the CCEP on CT enrollment and to assess barriers to participation. METHODS: We used an interrupted time series design to determine trends in CT enrollment before and after CCEP implementation. Linear regression models compared trial enrollment before and after the CCEP. We also compared patient characteristics before and after the CCEP and between CCEP and non-CCEP participants. We surveyed CCEP and non-CCEP participants to compare pre-enrollment financial barriers. RESULTS: After accounting for increased trial availability and the trends in accrual for prior years, we found that enrollment increased after CCEP implementation (18.97 participants per month greater than expected; p < .001). A greater proportion of CCEP participants were younger, female, in phase I trials, lived farther away, had lower incomes, and had metastatic disease. Of 87 participants who completed the financial barriers survey, 49 CCEP and 38 matched, non-CCEP participants responded (63% response rate). CCEP participants were more likely to report concerns regarding finances (56% vs. 11%), medical costs (47% vs. 14%), travel (69% vs. 11%), lodging (60% vs. 9%), and insurance coverage (43% vs. 14%) related to trial participation (all p < .01). CONCLUSION: CT participation increased following implementation of the CCEP and the program enrolled patients experiencing greater financial burden. These findings highlight the need to address the financial burden associated with CT participation. IMPLICATIONS FOR PRACTICE: Financial barriers likely discourage patients from participating in clinical trials. Implementation of a cancer care equity program (CCEP) seeking to reduce financial barriers by assisting with travel and lodging costs was associated with increased trial accrual. The CCEP provided assistance to patients particularly in need, including those living farther away, those with lower incomes, and those reporting financial barriers related to trial participation. These findings suggest that financial concerns represent a major barrier to patient participation in clinical trials and underscore the importance of efforts to address these concerns.