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.

Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma.

Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation.Experimental Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1-5 and 8-12 of each 21-day cycle.Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes.Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307-15. ©2017 AACR.

Genome-wide transcriptional profiling in human squamous cell carcinoma of the skin identifies unique tumor-associated signatures.

The elucidation of specific genetic changes associated with human cancer pathogenesis has focused efforts to relate such changes to the neoplastic phenotype. To further our understanding of the genetic basis of human squamous cell carcinoma (SCC) of the skin, this study used a genome-wide (12 627 sequences) approach to determine transcriptional signatures in lesional and nonlesional sites from five SCC patients. Several novel genes involving the p53 pathway, anti-apoptotic pathways, signal transduction, structural loss and DNA replication, including BCL2A1, MUC4, PTPN11 (SHP2) and FGF9, are upregulated in SCC and could warrant further study regarding their role in disease pathogenesis. SCC pathology is likely combinatorial in nature involving the compounded changes from several cellular processes.

2,5-hexanedione and carbendazim coexposure synergistically disrupts rat spermatogenesis despite opposing molecular effects on microtubules.

2,5-Hexanedione (2,5-HD), a taxol-like promoter of microtubule assembly, and carbendazim (CBZ), a colchicine-like inhibitor of microtubule assembly, are two environmental testicular toxicants that target and disrupt microtubule function in Sertoli cells. At the molecular level, these two toxicants have opposite effects on microtubule assembly, yet they share the common physiologic effect of inhibiting microtubule-dependent functions of Sertoli cells. By studying a combined exposure to 2,5-HD and CBZ, we sought to determine whether CBZ would antagonize or exacerbate the effects of an initial 2,5-HD exposure. In vitro, 2,5-HD-treated tubulin had a decreased lag time and an increased maximal velocity of microtubule assembly. These 2,5-HD-induced in vitro alterations in microtubule assembly were normalized by CBZ exposure. In vivo, adult male rats were exposed to a 1% solution of 2,5-HD in the drinking water for 2.5 weeks. CBZ was administered by gavage (200 mg/kg body weight) at the same time as unilateral surgical ligation of the efferent ducts, 24 h before evaluation of the testis. Measures of testicular effect (testis weight, histopathologic changes [sloughing and vacuolization], and seminiferous tubule diameters) were all significantly altered with combined exposure. The testicular effects in the combined exposure group were either different (seminiferous tubule diameters), additive (% vacuolization), or greater than additive (% sloughing) compared to the effects of the individual toxicant exposure groups referenced to the controls. Therefore, CBZ coexposure does not antagonize the effects of an initial 2,5-HD exposure, as might be expected if their molecular effects on microtubule assembly were solely responsible for their combined toxicity; instead, 2,5-HD and CBZ act together to exacerbate the testicular injury.

Radiation exposure to family caregivers and nurses of pediatric neuroblastoma patients receiving 131I-metaiodobenzylguanidine (131I-MIBG) therapy.

PURPOSE: (131)I-MIBG provides molecularly targeted radiotherapy for pediatric neuroblastoma patients with relapsed or refractory disease. At our institution, designated family caregivers and nurses participate in the care of the child during hospital isolation for approximately 3-5 days post-administration. The purpose of this study was to measure radiation exposure to family caregivers and nurses caring for children with neuroblastoma during their stay in the hospital for (131)I-MIBG therapy. METHODS: Iodine-(131)I-MIBG therapy was administered to 14 children (mean age 6.7 ± 3.8 years, range 3-13 years) for relapsed or refractory neuroblastoma from 2009 to 2010. The administered activity ranged from 5.92 to 23.31 GBq (mean 13.65 ± 5.22 GBq). The mean administered activities were 8.77 ± 2.07 GBq (range 5.92-11.1 GBq) and 17.32 ± 3.4 GBq (range 11.84-23.31 GBq) for children less than 7 and 7 years or older, respectively. One or two designated caregivers received specific radiation safety training prior to treatment. One caregiver was allowed to stay in a room adjacent to the child to provide general patient care as instructed by nursing. Nurses assigned to the care of the patient also received specific radiation instructions. The total caregiver and nursing whole body radiation dose was determined using real-time personal dosimetry. RESULTS: There was no correlation between caregiver (r = -0.068, P = 0.817) or nursing (r = -0.031, P = 0.916) whole-body radiation dose and the patient-administered activity. The overall mean caregiver radiation dose was 1.79 ± 1.04 mSv, but the range of caregiver radiation doses varied by more than an order of magnitude (0.35-3.81 mSv), with no caregiver receiving more than 4.0 mSv. The overall mean nursing radiation dose was 0.44 ± 0.27 mSv per treatment, ranging from 0.15 to 1.08 mSv, with no nurse receiving more than 1.1 mSv. When grouped by patient age, there was no significant difference (P = 0.673) in the mean caregiver exposure for children less than 7 years, 1.94 ± 1.17 mSv (n = 6, range 0.7-3.81 mSv), compared to 1.69 ± 0.99 mSv (n = 8, range 0.35-3.37 mSv) for children 7 years or older. Similarly, there was no significant difference (P = 0.511) in mean nursing exposure for children less than 7 years, 0.5 ± 0.31 mSv (n = 6, range 0.18-1.08 mSv), compared to 0.4 ± 0.24 mSv (n = 8, range 0.15-0.94 mSv) for children 7 years or older. CONCLUSION: There was no significant correlation between caregiver or nursing radiation exposure and patient-administered activity or no significant difference between patient age. This may suggest that older children who tend to receive higher administered activities may require less direct caregiver support during their hospital stay. Most importantly, all caregivers and nurses received radiation doses allowed under current regulations for individuals exposed to therapy patients during hospital isolation (<5.0 mSv), although this does not include exposure the caregivers may receive once the patient leaves the hospital.

A comparison of the biological effective dose of 50-kV electronic brachytherapy with (192)Ir high-dose-rate brachytherapy for vaginal cuff irradiation.

PURPOSE: Advantages for electronic brachytherapy (EBT) of the vaginal cuff include decreased physical dose to the bladder and rectum. Here we compare (192)Ir with EBT using biological effective dose (BED) to account for the different radiobiological effectiveness (RBE) predicted for low-energy x-rays. METHODS AND MATERIALS: Fifteen data sets from five consecutive postoperative endometrial cancer patients treated with EBT were analyzed. Treatment planning was performed using PLATO software. The dose was prescribed as 21Gy in three fractions to a depth of 0.5cm. Physical dose, BED(3), and BED(10) were evaluated for the mucosa, bladder, and rectum. An RBE value of 1.5 was used for BED calculations. RESULTS: Mucosal physical dose is 28.4% greater with EBT (36.6 vs. 28.5Gy, p<0.05). However, the BED(10) is increased by 79.1% (55.6 vs. 99.6Gy, p<0.05) and the BED(3) by 71.5% (118.8 vs. 203.7Gy, p<0.05). The physical dose (dose to 50% volume of the organ) to the bladder (9.3 vs. 6.6Gy, p<0.05) and rectum (7.2 vs. 4.2Gy, p<0.05) are reduced with EBT. BED(3) to the rectum and bladder are also reduced but to a lesser extent (13 vs. 8.3Gy, p<0.05; 18.9 vs. 14.7Gy, p=0.06, respectively). CONCLUSIONS: BED takes into account the higher RBE of low-energy photons generated with EBT and provides a more accurate estimate of the biological effect. When using EBT, physical dose may underestimate the biological effect on the vaginal mucosa and overestimate the benefit for the bladder and rectum. Dose adjustment for EBT based on BED should be considered.

Xenobiotic and endobiotic transporter mRNA expression in the blood-testis barrier.

A major function of xenobiotic and endobiotic transporters is to move a wide range of organic substances across cell membranes. Sertoli cells play an important role in protecting developing germ cells by forming a physiological barrier, limiting exposure to potentially toxic substrates, or conversely, facilitating uptake of xenobiotics within the testis. The aim of this study was to quantitatively determine the constitutive expression of various transporters in isolated Sertoli cells from adult Sprague-Dawley rats. The following mRNA levels were measured in isolated Sertoli cells by the branched DNA signal amplification method, multidrug resistance (Mdr) protein 1a, 1b, and 2; multiple drug resistance protein (Mrp) 1, 2, 3, 4, 5, 6, 7, and 8; sodium taurocholate cotransporting polypeptide; bile salt excretory protein; ileal bile acid transporter; AbcG5 and AbcG8; organic anion transporting polypeptide (Oatp) 1, 2, 3, 4, 5, 9, and 12; prostaglandin transporter (Pgt); testis-specific transporter (Tst) 1 and Tst2; organic anion transporter (Oat) 1, 2, 3, and K; organic cation transporter (Oct) 1, 2, 3, N1, and N2; divalent metal transporter (Dmt) 1, Menke's, and Wilson's; zinc transporter (Znt) 1; equilibrative nucleoside transporter (Ent) 1 and 2; concentrative nucleoside transporter (Cnt) 1 and 2; and peptide transporter (Pept) 1 and 2. Levels were also determined in whole testis, liver, kidney, and ileum to provide a reference for determining relative expression levels. Mrp8, Tst1 and 2, and Ent1 and 2 were expressed in Sertoli cells at higher levels than in liver, kidney, or ileum, whereas Mrp1, 5, and 7, Mdr2, Oatp3, Oat2, OctN2, Dmt1, Menke's, Wilson's, and Znt1 were all significantly expressed in Sertoli cells, but Sertoli cell expression was not the tissue of highest expression. The remaining transporters were expressed at low levels in isolated Sertoli cells. Additionally, expression levels of Mrp1, Mrp7, Mrp8, Tst1, Tst2, OctN2, Wilson's, Znt1, Ent1, and Ent2 were greater in isolated Sertoli cells than in whole testis. Constitutive expression of transporters in Sertoli cells may provide an insight into the range of xenobiotics that can potentially be transported by Sertoli cells and thereby provide a mechanistic under standing of blood-testis barrier function.