Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.Peer reviewe

Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia

Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25–90 mg for 14 or 21 consecutive days plus 14 or 7 days’ rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days’ rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30–50 mg twice-daily (BID) for 7 days plus 14 days’ rest in 21-day cycles. Results Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-013-0050-9) contains supplementary material, which is available to authorized users

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

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/1/bjh15394.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/2/bjh15394_am.pd

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial

BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development