A Dose Optimisation Study of ASLAN003 in Acute Myeloid Leukemia

ASLAN003-003 is a multi-center, Phase IIA study to evalute the efficacy of ASLAN003 in AML patients who are ineligible for standard treatment with an expansion cohort in relapsed/refractory patients, and to determine the appropriate dose of ASLAN003 in combination with azacitidine in older (more than or equal to 60 years) AML patients who have exhausted any approved and available treatment options.

ASLAN003-003 is a multi-center, Phase IIA study to determine the optimum dose of ASLAN003 based on the safety, efficacy, and tolerability of varying doses of ASLAN003 (100 mg QD, 200 mg QD, 100 mg BID, and possibly 200 mg BID) administered to AML subjects daily for a continuous 28-day treatment cycle until disease relapse, disease progression, unacceptable toxicity, or withdrawal of consent.

The study has 2 parts and plans to enroll a total of 44 to 56 patients with 18 to 24 patients in Part 1 and 26 to 32 patients in Part 2 (comprising Parts 2A and 2B). The Overall Complete Remission Rate will be evaluated in AML patients not eligible for standard treatment (Part 1) and in relapsed and refractory AML patients (Part 2A) using the optimum dose of ASLAN003 established in Part 1 of the study. In Part 2B of the study, the appropriate dose of ASLAN003 in combination with azacitidine in older (more than or equal to 60 years) AML patients who have exhausted any approved and available treatment options will be determined.

Eligibility Criteria:
Inclusion Criteria:

1. Patients who are of or older than 18 years old in the United States or are of or older than the legal age in the respective countries at the time when written informed consent is obtained
2. Patients who are able to understand and willing to sign the informed consent form (ICF)
3. Patients who are diagnosed with AML according to the 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia (refer to Appendix 1: WHO Classification of Acute Myeloid Leukemia)
4. Patients who have a sufficient archival or fresh BM aspiration sample for the evaluation of relevant exploratory endpoint.

Note: Patients who do not have sufficient archival BM aspiration sample and refuse to repeat the procedure may be enrolled in the trial only after written confirmation by ASLAN 5. Part 1: Patients who are ineligible for standard treatment of AML including to the following conditions:

* Patients who are ineligible for chemotherapy, and have exhausted any approved and available treatment options. More details on patients who are considered as ineligible or unfit for chemotherapy as per Ferrara et al, Leukemia, 2013 can be found in Appendix 4.
* Patients who have relapsed from prior remission;
* Patients who have failed to respond to prior therapy including chemotherapy, hypomethylating agents, and bone marrow transplantation.

  5. Part 2A: Patients who have relapsed or refractory AML to treatments including chemotherapy, hypomethylating agents, bone marrow transplantation, and other anti-leukemic agents
  * Relapsed patients who have bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development of extramedullary disease after prior CR or CRi
  * Refractory patients who have no CR or CRi after 2 courses of intensive induction treatment 5. Part 2B: Older patients (more than or equal to 60 years) AML patients who have exhausted any approved and available treatment options.

    6. Patients who have an ECOG performance status of ≤ 2 7. Patients with adequate renal and hepatic function, as defined below:
* Estimated Glomerular Filtration Rate (eGFR) or creatinine clearance (CrCl) (CrCl calculated by the Cockroft and Gault method) ≥ 40 ml/min/1.73 m2
* Total bilirubin, AST, and ALT ≤ 1.5 × ULN

Exclusion Criteria:

1. Patients who are diagnosed with de novo myeloid sarcoma without BM involvement
2. Patients who are diagnosed with acute promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA)
3. Patients who received any other standard or investigational treatment for their leukemia within the last 7 days before starting the first dose of study drug, with the exception of leukapheresis and hydroxyurea
4. Patients with unresolved serious toxicity (≥ CTCAE 4.03 Grade 2) from prior administration of standard or investigational treatment for their leukemia
5. Patients who have a positive test for human immunodeficiency virus (HIV), viral hepatitis C infection (patients with sustained viral response are not excluded), active viral hepatitis B infection (positive hepatitis B surface antigen \[HBsAg\]) with hepatitis B virus deoxyribonucleic acid (DNA) exceeding 2000 IU/ml
6. Patients who have a known history of liver cirrhosis Child-Pugh score B or C
7. Patients who have any history of other malignancy unless in remission for more than 1 year (skin carcinoma and carcinoma-in-situ of uterine cervix treated with curative intent is not exclusionary)
8. Female patients who are pregnant or breast-feeding
9. Patients with a known history of alcohol or drug addiction on the basis that there could be a higher risk of non-compliance to study treatment
10. Patients with a history or presence of a clinically significant condition which in the opinion of the Investigator could jeopardize the safety of the patient or the validity of the study results
11. Patients who have been previously treated with ASLAN003