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.

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.