A Phase 3, Multicenter, Open-label, Randomized, Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes With Excess Blasts-2 (MDS-EB2) With FLT3 Mutations Eligible for Intensive Chemotherapy (HOVON 156 AML / AMLSG 28-18)
Overview
- Phase
- Phase 3
- Intervention
- Midostaurin
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Stichting Hemato-Oncologie voor Volwassenen Nederland
- Enrollment
- 777
- Locations
- 193
- Primary Endpoint
- Overal survival (OS)
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
Activating mutations in the fms like tyrosine kinase 3 (FLT3) gene are observed in approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML). Addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy prolongs event-free survival (EFS) and overall survival (OS) in patients with a FLT3 mutation. Gilteritinib is a more potent and more specific inhibitor of mutant FLT3 in comparison to midostaurin and has shown promising clinical activity in AML.
Detailed Description
AML and MDS-EB2 are malignant diseases of the bone marrow. The standard treatment for these diseases is chemotherapy. A subgroup of these diseases is characterized by a specific error in the DNA of the leukemic cells. This is the FLT3 mutation, which leads to a change of a certain protein (FLT3) on the blasts. This altered protein plays an important role in the development of leukemia and the survival of leukemic cells. FLT3 can be inhibited by the drug midostaurin. Adding midostaurin to chemotherapy leads to better treatment results in patients with AML. Therefore, the standard treatment for AML or MDS-EB2 with a FLT3 mutation (FLT3-AML) is a combination of chemotherapy and midostaurin. Gilteritinib is also a drug that inhibits FLT3. In laboratory studies, gilteritinib was found to be significantly more specific and potent than midostaurin in inhibiting FLT3. Gilteritinib has subsequently been studied in patients with AML, who relapsed after previous treatment with chemotherapy. This resulted in a much larger number of complete remissions than previously seen when comparable patients were treated with midostaurin.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥18 years
- •Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHO criteria (appendix A), with centrally documented FLT3 gene mutation (either TKD or ITD or both). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related. Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS. ESA and HMAs have to be stopped at least four weeks before registration.
- •FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of ≥ 0.05 (5%).
- •Considered to be eligible for intensive chemotherapy
- •Patient is suitable for oral administration of study drug
- •WHO/ECOG performance status ≤ 2
- •Adequate hepatic function as evidenced by
- •Serum total bilirubin ≤ 2.5 × upper limit of normal (ULN) unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
- •Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
- •Adequate renal function as defined by creatinine clearance \> 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
Exclusion Criteria
- •Prior chemotherapy for AML or MDS-EB2, including prior treatment with hypomethylating agents. Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell \[WBC\] counts \> 30 x 10\^9/L)
- •Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
- •Blast crisis after CML
- •Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any excipients
- •Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
- •Breast feeding at start of study treatment
- •Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
- •Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
- •Basal or squamous cell carcinoma of the skin;
- •Carcinoma in situ of the cervix;
Arms & Interventions
Arm A (Midostaurin)
Midostaurin (50 mg BID PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)
Intervention: Midostaurin
Arm B (Gilteritinib)
Gilteritinib (120 mg QD PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)
Intervention: Gilteritinib
Outcomes
Primary Outcomes
Overal survival (OS)
Time Frame: Approximately up to 70 months following first patient enrolment
Overall survival (OS), defined as the time from date of randomization to the date of death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive.
Secondary Outcomes
- Event-free survival (EFS)(Approximately up to 70 months following first patient enrolment)
- CR rate after remission induction(Approximately up to 70 months following first patient enrolment)
- EFS with modified CR (mEFS)(Approximately up to 70 months following first patient enrolment)
- CR and CRi rates after induction cycle 1 and after induction cycle 2(Approximately up to 70 months following first patient enrolment)
- Relapse-free survival (RFS) after CR(Approximately up to 70 months following first patient enrolment)
- Cumulative incidence of relapse (CIR) after CR(Approximately up to 70 months following first patient enrolment)
- Cumulative incidence of death (CID) after CR(Approximately up to 70 months following first patient enrolment)
- CR without minimal residual disease (CRMRD-) rate after induction cycle 2(Approximately up to 70 months following first patient enrolment)
- CR or CRi without minimal residual disease (CR/CRiMRD-) rate after induction cycle 2(Approximately up to 70 months following first patient enrolment)
- Frequency and severity of adverse events according to CTCAE v5.0(Continuously throughout the study, starting from informed consent until 30 days following the last administration of any study drug)
- Time to hematopoietic recovery after each chemotherapy treatment cycle(Approximately up to 70 months following first patient enrolment)
- Allogeneic stem cell transplantation (allo-SCT) rate(Approximately up to 70 months following first patient enrolment)
- Individual domain scores and visual analogue scale (VAS) score of the European Quality of Life 5 Dimensions (EQ-5D-5L) Questionnaire(At entry, 1st day of maintenance and every 3 months during maintenance until relapse or treatment discontinuation (approximately up to 70 months following first patient enrolment))
- Individual subdomain scores and the global health status/QoL scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)(At entry, 1st day of maintenance and every 3 months during maintenance until relapse or treatment discontinuation (approximately up to 70 months following first patient enrolment))