A Phase 3 Open-label Randomized Study of Quizartinib (AC220) Monotherapy Versus Salvage Chemotherapy in Subjects With Feline McDonough Sarcoma (FMS)-Like Tyrosine Kinase 3 - Internal Tandem Duplication (FLT3-ITD) Positive Acute Myeloid Leukemia (AML) Refractory to or Relapsed After First-line Treatment With or Without Hematopoietic Stem Cell Transplantation (HSCT) Consolidation
Trial status: Open for Enrollment
Why is this study being done?
The primary objective of the study is to determine whether quizartinib monotherapy prolongs overall survival (OS) compared to salvage chemotherapy in subjects with FMS-like tyrosine kinase 3 - Internal Tandem Duplication (FLT3-ITD) positive AML who are refractory to or have relapsed within 6 months, after first-line AML therapy.
Who is eligible to participate?
1. Provision of written informed consent approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) with privacy language in accordance with national regulations (e.g., Health Insurance Portability and Accountability Act (HIPAA)) authorization for United States (US) sites prior to any study related procedures, including withdrawal of prohibited medications if applicable.
2. Age ≥18 years at the time of informed consent.
3. Morphologically documented primary Acute Myeloid Leukemia (AML) or AML secondary to Myelodysplastic Syndrome (MDS), as defined by World Health Organization (WHO) criteria, as determined by pathology review at the study site.
4. Refractory, or relapsed within six months AML after first-line therapy, with or without Haematopoietic Stem Cell Transplant (HSCT). First-line therapy can consist of 1 or 2 induction blocks with or without consolidation. Induction therapy must have included at least 1 cycle of an anthracycline/mitoxantrone containing induction block at a standard dose.
5. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as determined by a central laboratory with a cutoff of >3% FLT3 ITD/total FLT3).
6. Eligibility for pre-selected salvage chemotherapy, according to the Investigator's assessment.
7. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
8. Discontinuation of prior AML treatment before the start of study treatment (except hydroxyurea, which is permitted for blast control up to the day of starting study treatment) for at least 2 weeks for cytotoxic agents, or for at least 5 half-lives for non cytotoxic agents.
9. Serum creatinine ≤1.5×upper limit of normal (ULN), or glomerular filtration rate >25 mL/min/1.73m2, as calculated with the modified Cockcroft-Gault formula.
10. Serum potassium, magnesium, and calcium (serum calcium corrected for hypoalbuminemia) within institutional normal limits. Subjects with electrolytes outside the normal range will be eligible if these values are corrected upon retesting following any necessary supplementation.
11. Total serum bilirubin ≤1.5×ULN.
12. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5×ULN.
1. Acute Promyelocytic Leukemia (AML subtype M3).
2. AML secondary to prior chemotherapy for other neoplasms, except AML secondary to prior Myelodysplastic Syndrome (MDS).
3. History of another malignancy, unless the candidate has been disease-free for at least 5 years.
4. Persistent, clinically significant > Grade 1 non-hematologic toxicity from prior AML therapy.
5. Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation of treatment or treatment escalation within 21 days, and/or > Grade 1 persistent or clinically significant non hematologic toxicity related to HSCT.
6. History of or current, central nervous system involvement with AML.
7. Clinically significant coagulation abnormality, such as disseminated intravascular coagulation.
8. Prior treatment with quizartinib or participated in a prior quizartinib study.
9. Known presence of a FLT3-D835 mutation at study enrollment. For a candidate who has received prior FLT3-targeted therapy (with the exception of midostaurin), the absence of a baseline FLT3-D835 mutation at study enrollment must be documented.
10. Major surgery within 4 weeks prior to screening.
11. Radiation therapy within 4 weeks prior to screening.
12. Uncontrolled or significant cardiovascular disease
13. Active infection not well controlled by antibacterial or antiviral therapy.
14. Known infection with human immunodeficiency virus, or active hepatitis B or C, or other active clinically relevant liver disease.
15. Unwillingness to receive infusion of blood products according to the protocol.
16. In a man whose sexual partner is a woman of childbearing potential, unwillingness or inability to use an acceptable contraceptive method for the entire study period and for at least 3 months after study completion.
17. In a woman of childbearing potential, unwillingness or inability to use an acceptable contraceptive method for the entire study period and for at least 3 months after study completion.
18. Positive pregnancy test result.
20. Medical condition, serious intercurrent illness, or other circumstance that, in the Investigator's judgment, could jeopardize the candidate's safety as a study subject, or that could interfere with study objectives.