A Dose Optimisation Study of ASLAN003 in Acute Myeloid Leukemia

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.

• ASLAN003 (Drug): Patients will be administered with the study drug, ASLAN003. The study drug is to be administered orally, QD or BID. It is recommended to administer the study drug with food or within 30 minutes after food intake.

Primary outcomes

• Overall Complete Remission Rate [4 months after study treatment]: Defined as the proportion of patients with a best response of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), defined in accordance with the IWG Response Criteria in AML from day 29. Treatment failure is defined as not achieving any response 4 months after study treatment. IWG Response Criteria in AML defines CR or CRi as: 1. Complete remission (CR): Bone marrow blasts <5 percent; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); independence of red cell transfusions 2. CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (<1.0 x 109/L (1000/µL)) or thrombocytopenia (<100 x 109/L (100,000/µL))
• Number of Participants With Adverse Events [Through 28 days post last study medication administration]: Number of Participants with Adverse Events reported through 28 days post last study medication administration
• Safety Assessments [Through 28 days post last study medication administration]: Safety Assessments - Clinical laboratory test: Hematology and Chemistry

Secondary outcomes

• Relapse Free Survival [From 12 weeks post end of treatment (EOT) until the date of first documented relapse or date of death from any cause, whichever came first, assessed up to 24 months]: Defined as the time the criteria for remission (CR or CRi) are first met until there is evidence of patient relapse, regardless of whether the patient is still taking study drug. Relapse is defined as: * The reappearance of leukemic blasts in the peripheral blood or > 5% blasts in the bone marrow not attributable to any other cause; * The appearance of new dysplastic changes; * The reappearance of or development of cytologically proven extrameduallary disease; * The reappearance of a cytogenetic or molecular abnormality.
• Clinical Benefit Rate [4 months after study treatment]: Defined as the proportion of subjects with an AML IWG best response of CR, CRi or PR. IWG Response Criteria in AML defines CR, CRi or PR as: 1. Complete remission (CR): Bone marrow blasts <5 percent; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); independence of red cell transfusions 2. CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (<1.0 x 109/L (1000/µL)) or thrombocytopenia (<100 x 109/L (100,000/µL)) 3. Partial remission (PR): All hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25 percent; and decrease of pre-treatment bone marrow blast percentage by at least 50 percent
• % Change From Baseline in BM Blasts at Day 29 [Baseline and day 29]: Percent Change from Baseline in BM Blasts at Day 29

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Overall Complete Remission Rate (Primary), Count of participants, Participants: Part 1: ASLAN003 100mg QD 0; Part 1: ASLAN003 200mg QD 0; Part 1: ASLAN003 100mg BID 0; Part 1: ASLAN003 200mg BID 0
• Number of Participants With Adverse Events (Primary), Number, participants: Part 1: ASLAN003 100mg QD 5; Part 1: ASLAN003 200mg QD 6; Part 1: ASLAN003 100mg BID 6; Part 1: ASLAN003 200mg BID 6
• Safety Assessments (Primary), Number, participants: Part 1: ASLAN003 100mg QD 2; Part 1: ASLAN003 200mg QD 3; Part 1: ASLAN003 100mg BID 3; Part 1: ASLAN003 200mg BID 0
• Relapse Free Survival (Secondary)
• Clinical Benefit Rate (Secondary)
• % Change From Baseline in BM Blasts at Day 29 (Secondary), Number, Percentage change: Part 1: ASLAN003 100mg QD -34.43; Part 1: ASLAN003 200mg QD -8.33; Part 1: ASLAN003 100mg BID ; Part 1: ASLAN003 200mg BID

Adverse events

Time frame: From the time of informed consent and until 28 days after the last administration of study drug, up to 24 months.

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2018-05-31)
• Statistical Analysis Plan (PDF, 2019-10-18)