A Phase 2, Randomized, Open-Label Study of the Safety and Efficacy of Two Doses of Quizartinib (AC220; ASP2689) in Subjects with FLT3-ITD Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)
This is a randomized, open-label, Phase 2 study of AC220 monotherapy in FLT3-ITD positive AML subjects who are refractory to or have relapsed after second-line AML therapy with or without consolidating hematopoietic stem
cell therapy (HSCT).
Approximately 64 subjects will be randomized equally between two treatments arms of AC220, to receive a daily dose of 30 mg or 60 mg. About 4 people will take part in this study at UT Southwestern and Parkland Health and amp; Hospital System. AC220 will be taken as a once-daily oral solution for continuous 28-day cycles. AC220 will be self-administered at home when subjects are not scheduled for clinic visits. The subjects will be stratified according to sex, and no less than 12 subjects from either sex will be enrolled in each arm.
Subjects will be randomly assigned to 30 mg/day or 60 mg/day treatment arm.
AC220 treatment should continue until the subject is no longer clinically benefitting from the therapy in the opinion of the Investigator or until unacceptable toxicity occurs.
1. Subject has provided an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved signed Informed Consent and privacy disclosure as per national regulations (e.g., HIPAA Authorization for U.S. sites) prior to any study-related procedures (including withdrawal of
prohibited medication, if applicable).
2. Subject is male or female ≥ 18 years of age.
3. Subject has morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS) as defined by the World Health Organization (WHO) criteria, as determined by pathology review at the treating institution and has relapsed or is refractory after 1 second line
(salvage) regimen or after HSCT (Appendix 8).
4. Subject is positive for FLT3-ITD activating mutation in bone marrow or peripheral blood. The subject may be randomized based off local lab results. In addition, a sample will be sent to the central lab for confirmation (>10% allelic ratio). However, if the central lab result differs from local lab, the subject will be allowed to remain in the study.
5. ECOG performance status of 0 to 2 (Table 4).
6. In the absence of rapidly progressing disease clearly documented by the investigator, the interval from prior treatment to time of AC220 administration will be at least 2 weeks (14 days) for prior cytotoxic agents or at least 5 half-lives for prior noncytotoxic agents, including immunosuppressive therapy post HSCT.
7. Persistent chronic clinically significant nonhematological toxicities from prior treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, HSCT, or surgery) must be Grade ≤ 1.
8. Patients – both males and females – with reproductive potential are eligible if the following criteria is met:
• Female subject is:
o Post-menopausal (defined as at least 2 years without menses)
prior to Screening visit; or
o surgically sterile (at least 1 month prior to Screening visit; or
o of childbearing potential with contraception.
• Female subject of childbearing potential has a negative pregnancy test at the Screening visit and agrees to use contraception consisting of two forms of birth control (one of which must be a barrier method) throughout the study period.
• Male subject with partner(s) of childbearing potential must agree to use contraception consisting of two forms of birth control (one of which must be a barrier method) and agrees to no sperm donation throughout the study period.
9. Subject must have adequate renal, hepatic, and coagulation parameters as indicated by the following laboratory values:
• Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 2.5 x institutional upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 x institutional ULN
• Serum creatinine ≤ 1.5 x institutional ULN and glomerular filtration rate (GFR) > 30 mL/min (calculated by Cockcroft and Gault formula, Appendix 9).
10. Subject is able to comply with study procedures and follow-up examinations.