a phase i, two-part study to determine the recommended dose and evaluate the safety and tolerability of a novel oral arsenic trioxide formulation (orh-2014) in subjects with advanced hematological disorders

Conditions: Advanced Hematological Disorders

Summary: part 1 will be conducted as an open-label, non-randomized, non-placebo-controlled dose escalation study using pre-specified doses. subjects with the following advanced hematological disorders and no available therapies, and who satisfy all inclusion/exclusion criteria will be enrolled. the purpose is to identify the recommended dose of oral orh-2014 in subjects with advanced hematological disorders. part 2 will be an expansion phase conducted as a single-arm, open-label study to further evaluate the safety and tolerability of orh-2014 at the maximum tolerated dose (mtd) or recommended dose determined from part 1 in the fasted state. subjects with the same disease types as in part 1 will be enrolled. all subjects will receive oral orh-2014, in the fasted state, at the recommended dose for an initial period of up to 12 weeks. the purpose is to evaluate the safety and tolerability of oral orh-2014 in a population of subjects with advanced hematological disorders when administered at the recommended dose.


Eligibility criteria:
inclusion criteria: * female and male subjects ≥18 years of age with one of the following: * relapsed or refractory acute myelocytic leukemia (aml) with nucleophosmin-1 (npm1) mutations and no available therapies. * relapsed or refractory acute promyelocytic leukemia (apl), with no available therapies. note: prior exposure to arsenic trioxide is allowed; however, subjects who have failed arsenic trioxide within the last 12 months are not allowed. * relapsed or refractory myelodysplastic syndrome (mds), international prognostic scoring system intermediate or high-risk, with no available therapies * relapsed or refractory chronic myelomonocytic leukemia (cmml), and other mds/myeloproliferative neoplasm (mpn) overlap syndromes, with no available therapies * relapsed or refractory mantle cell lymphoma (mcl) with no adequate therapies. * negative pregnancy test at the screening visit for women of childbearing potential and willingness to use adequate birth control * not willing to undergo, not a candidate for, or not having a donor for immediate (within 3 months from the screening date) bone marrow transplantation. exclusion criteria: * eastern cooperative oncology group performance status of ≥3; * absolute myeloblast count ≥20,000/mm\^3; * administration of any antineoplastic therapy within 5 half-lives of the antineoplastic therapy before the first dose of orh-2014, with the exception of hydroxyurea that should be discontinued 1 day prior to the first dose of orh-2014 * presence of any remaining toxicities due to previous chemotherapy * participation in other clinical trials within at least 2 weeks of the first orh-2014 dose; * clinical evidence of active central nervous system leukemia; * active and uncontrolled infection * major surgery within 2 weeks prior to trial entry; * liver function tests above the following limits at screening: total bilirubin \>1.5 x upper limit of normal (uln) unless related to gilbert's syndrome or hemolysis; aspartate aminotransferase (ast) and/or alanine aminotransferase (alt) \>2.5 x uln; for subjects with liver involvement, ast and/or alt \>5 x uln; * serum creatinine \>1.5 x uln and/or creatinine clearance or estimated glomerular filtration rate \<30 ml/min * impaired cardiac function * myocardial infarction of unstable angina within 6 months prior to the planned start date of study drug.

Keywords: acute promyelocytic leukemia apl arsenic trioxide