Glenn Michelson

A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18–90 mg/m2; MTD was 72 mg/m2. Twice-weekly schedule: 31 patients received 9–50 mg/m2; MTD was 40 mg/m2. DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to <5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 μmol/l plasma vosaroxin concentration (P<0.05). Vosaroxin exposure was dose proportional over 9–90 mg/m2. The average terminal half-life was ∼25 h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10–90 mg/m2; days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m2/day, days 1–5) or schedule B (2-hour intravenous infusion, 1 g/m2/day, days 1–5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m2 for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m2). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80–90 mg/m2; n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80–90 mg/m2. Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia.

REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia.

This phase 2 study (N = 116) evaluated single‐agent vosaroxin, a first‐in‐class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m2 d 1, 8, 15; B: 72 mg/m2 d 1, 8; C: 72 mg/m2 or 90 mg/m2 d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1‐year OS was 34%. Schedule C (72 mg/m2) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30‐d (7%) and 60‐d (17%) all‐cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1‐year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m2 d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997.

Phase II Multicenter Trial of Voreloxin as Second-Line Therapy in Chemotherapy-Sensitive or Refractory Small Cell Lung Cancer

Introduction: Voreloxin is an anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, causing double-strand breaks in DNA, irreversible G2 arrest, and rapid onset of apoptosis. Based on preclinical activity of voreloxin in chemoresistant tumors, early phase I clinical activity, and a mechanism of action similar to other topoisomerase II inhibitors such as the anthracyclines and etoposide, this phase II trial was undertaken as second-line treatment of small cell lung cancer (SCLC). Methods: Patients with extensive stage SCLC previously treated with one prior chemotherapy regimen were eligible. Patients with chemotherapy-sensitive or chemotherapy-refractory disease were considered as separate cohorts. Voreloxin (48 mg/m2) was administered on the first day of each 21-day cycle for up to six cycles. The primary end point was objective response rate. Results: Fifty-five patients were enrolled including 28 with refractory SCLC and 27 with sensitive SCLC; 47 were evaluable for response. Three patients with sensitive SCLC had an objective response, including one complete response and two partial responses (11% response rate based on intent to treat). No patients in the refractory cohort had a response. The primary grade 3 toxicity was neutropenia. Conclusion: Voreloxin has minimal activity in relapsed SCLC when administered at 48 mg/m2 in a 3-week schedule.

Abstract CT144: Preclinical and clinical studies and modeling and simulation to identify phase II dose for cerdulatinib: a dual SYK/JAK inhibitor for the treatment of B-cell malignancies

Background. Subsets of B cell lymphomas appear to rely on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, and thus a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways. Cerdulatinib is a dual SYK/JAK inhibitor being evaluated in patients with relapsed/refractory B cell malignancies in a dose escalation study. Patient PK and PD parameters indicated nonlinearity at doses above 30 mg QD. Exposure at the 45 mg dose was 3-fold higher than at 30 mg QD. As the dose was further increased up to 100 mg QD, the Cssmax and AUC values plateaued. PD results also appeared to plateau achieving approximately 50-90% target inhibition in peripheral blood assays at steady-state Cmin to Cmax, respectively. The target therapeutic exposure for oncology, based on pre-clinical models, is a Cssmin >1.5uM which would lead to >90% SYK/JAK inhibition at the trough concentration Objective. Pre-clinical and clinical PK/PD relationships and correlations between SYK/JAK inhibition and tumor response will be presented. A physiological-based PK (PBPK) model was developed to elucidate the relationship between dose, dosing schedule, and exposure. The goal of developing a PBPK model was to provide a strategy to increase exposure in patients to therapeutic target levels. Methods. This is a 3+3 dose escalation study with 28-day cycles and doses studied from 15 mg to 100 mg QD, and up to 45 mg BID. PK, PD, and safety were monitored. SYK and JAK inhibition was determined by multiple whole blood assays measuring signaling via the B cell antigen receptor, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured. Physiochemical parameters and in vitro ADME parameters were used to construct a PBPK model. Results. Exposure correlated well with PD and tumor responses in the dose escalation study. Low pH dependent solubility was identified as the rate-limiting factor in increasing plasma concentrations. The PBPK model predicted BID dosing would result in significantly higher plasma levels. The Cssmin concentration of QD doses from 40 to 100 mg QD was ∼0.70 uM while for the 45 mg BID dose for the first 3 patients the Cssmin was ∼1.5 uM. Complete target inhibition at this Cssmin was achieved with good tolerability. Conclusions. The preliminary PBPK model identified the pH dependent low solubility of cerdulabinib as the rate-limiting factor of absorption with increasing doses. Subsequent evaluation of 45 mg BID doses in patients provided higher Cmin, Cmax, and AUC values for all patients treated at this dose level and PD markers indicated complete inhibition of both pathways. We are now enrolling additional patients at this dose, in preparation for selecting our final phase II dose. Citation Format: Janet M. Leeds, Greg Coffey, Anjali Pandey, Pam B. Conley, Karen Rowland Yeo, Alice B. Ke, John T. Curnutte, Glenn Michelson. Preclinical and clinical studies and modeling and simulation to identify phase II dose for cerdulatinib: a dual SYK/JAK inhibitor for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT144.