The purpose of the phase 1 portion (dose escalation) of the study was to establish an optimally safe and biologically active recommended phase 2 dose (RP2D) and/or to determine maximum tolerated dose (MTD) for gilteritinib in sequential combination with fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG). The purpose of the phase 2 portion (dose expansion) was to determine complete remission (CR) rates and composite complete remission (CRc) rates after two cycles of therapy. The study also assessed safety, tolerability and toxicities of gilteritinib in combination with FLAG, evaluated FLT3 inhibition, assessed pharmacokinetics (PK), performed serial measurements of minimal residual disease, obtained preliminary estimates of 1-year event free survival (EFS) and overall survival (OS) rate and assessed the acceptability as well as palatability of the formulation. One cycle was defined as 28 days of treatment. A participant completing 1 or 2 treatment cycles in phase 1 or 2 had the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
9
Administered orally.
Administered by intravenous (IV) infusion
Administered by intravenous (IV) infusion
Administered by subcutaneous injection
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Site DE49004
Essen, North Rhine-Westphalia, Germany
SIte IT39001
Roma, Italy
Site ES34001
Barcelona, Spain
Site GB44001
Birmingham, United Kingdom
Site GB44005
Cardiff, United Kingdom
Site UK44007
Sutton, United Kingdom
Phase 1: Maximum Tolerated Dose (MTD) of Gilteritinib
MTD reflects the highest dose that did not cause a Dose Limiting Toxicity (DLT).DLT:any Grade ≥3 non-hematologic/extramedullary toxicity with the following exceptions that occurred during the DLT observations like alopecia, anorexia, or fatigue, grade 3 vomiting or diarrhea that resolved(with or without supportive care) to ≤ grade 2 within 48 hours, grade 3 nausea that resolved(with or without supportive care) to ≤ grade 2 within 7 days, grade 3 elevation in total bilirubin (TBL) that is asymptomatic and that returned to ≤ grade 2 elevation within 7 days, grade 3 elevation in hepatic transaminases\[alanine aminotransferase (ALT/SGPT) aspartate aminotransferase (AST/SGOT) and gammaglutamyl transferase (GGT)\] or Alkaline Phosphatase (ALP) level that returns to ≤ grade 2 elevation within 14 days, grade 3 fever with neutropenia, with/without infection, grade 3 infection/grade 4 infections expected as direct complication of cytopenia due to active underlying leukemia, grade 3 mucositis.
Time frame: C1D1 up to day 28
Phase 1: Recommended Phase 2 Dose (RP2D) of Gilteritinib
The RP2D was a safe dose of gilteritinib that demonstrated sufficient activity.
Time frame: C1D1 up to day 28
Phase 2: Complete Remission (CR) Rate
CR rate was defined as the number of participants with best response of CR divided by the number of participants in the analysis population. CR was defined as a morphologically leukemia-free state post-baseline and had absolute neutrophil count (ANC) \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. Derived and investigator-assessed responses are reported.
Time frame: From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days)
Phase 2: Composite CR (CRc) Rate
CRc was defined as participants who achieved either CR, complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi) at the visit. CR was defined as a morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. CRp was defined as met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi was defined as met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. Derived and investigator-assessed responses are reported.
Time frame: From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days)
Duration of CR
Duration of CR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. CR was defined as a morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts, and were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. Relapse was defined as a reappearance of leukemic blasts in the peripheral blood or \>= 5% blasts in the bone marrow aspirate (BMA) not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. Duration of CR was estimated using the Kaplan-Meier method.
Time frame: From the date of first CR until the date of documented relapse for participants who achieved CR (Maximum duration: 28 months)
Phase 1: Number of Participants With Dose Limiting Toxicity (DLT) of Gilteritinib
DLT: any Grade \>=3 non-hematologic/extramedullary toxicity with the following exceptions that occurred during the DLT observation: Alopecia, anorexia, or fatigue. Grade 3 vomiting or diarrhea that resolved(with or without supportive care) to \<= grade 2 within 48 hours. Grade 3 nausea that resolved(with or without supportive care) to \<= grade 2 within 7 days. Grade 3 elevation in TBL that was asymptomatic and that returned to \<= grade 2 elevation within 7 days. Grade 3 elevation in hepatic transaminases (ALT/SGPT, AST/SGOT) and GGT) or ALP level that returns to \<= grade 2 elevation within 14 days. Grade 3 fever with neutropenia, with or without infection. Grade 3 infection or grade 4 infections expected as direct complication of cytopenia due to active underlying leukemia. Grade 3 mucositis.
Time frame: C1D1 up to day 28
Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3)
Plasma inhibitory assay (PIA) of phosphorylated FLT3 was conducted by comparing baseline and post-treatment samples. Inhibition was summarized at each time point. PIA assay assesses the target inhibition in plasma. Plasma was incubated with a cell line expressing the drug target, and inhibition was reported as percent change from baseline (normalized to 100%).
Time frame: Baseline, predose on C1D15, C1D21, C2D8, C2D15, C2D21 and 4 to 6 hours post-dose on C1D21
Gilteritinib Plasma Concentration
Plasma samples were used for pharmacokinetic assessments.
Time frame: Predose on C1D8, C1D15, C1D21, C2D15, and 4 to 6 hours post-dose on C1D21
Pharmacokinetics (PK) of Gilteritinib: Oral Clearance (CL/F)
Time frame: Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21
PK of Gilteritinib: Apparent Volume of Distribution (Vd/F)
Time frame: Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21
PK of Gilteritinib: Maximum Plasma Concentration (Cmax)
Time frame: Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21
PK of Gilteritinib: Time to Observed Cmax (Tmax)
Time frame: Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21
PK of Gilteritinib: Area Under the Concentration (AUC)
Time frame: Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE was defined as an adverse event observed after starting administration of the study drug until 28 days from the last study treatment.
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Time frame: From first dose up to 28 days after last dose (maximum duration approximately 55 months)
Event Free Survival (EFS)
EFS was defined as the time from first study drug dose to documented relapse or death, whichever occurred first. If none of these events occurred, EFS was censored at the last relapse-free assessment. Relapse was defined as a reappearance of leukemic blasts in the peripheral blood or \>= 5% blasts in the BMA not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. EFS was estimated using the Kaplan-Meier method.
Time frame: From first dose to documented relapse or death, whichever occurred first (maximum duration: 55 month)
Overall Survival (OS)
OS was defined as the time from the date of enrollment until the date of death from any cause (death date - enrollment date + 1). For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact (date of last contact - enrollment date + 1). OS was estimated using the Kaplan-Meier method.
Time frame: From the date of enrollment until the date of death from any cause (maximum duration: 55 months)
Number of Participants With Negative Minimal Residual Disease (MRD) Status
MRD negative was defined as summed FLT3-ITD signal ratio of any post-baseline sample ≤10\^(-4).
Time frame: From baseline up to approximately 55 months
Percentage of Participants With MRD Negative Status in Relation to CR Rate
MRD negative was defined as summed FLT3-ITD signal ratio of any post-baseline sample \<=10\^(-4). CR rate was defined as the number of participants with best response of CR divided by the number of participants in the analysis population. CR was defined as a morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. Derived and investigator-assessed responses are reported.
Time frame: From baseline up to approximately 55 months
Percentage of Participants With MRD Negative Status in Relation to CRc Rate
MRD negative: summed FLT3-ITD signal ratio of any post-baseline sample \<=10\^(-4). CRc: participants who achieved either CR, complete remission with CRp or CRi at the visit. CR: morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were RBC and platelet transfusion independent. There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. CRp: all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. CRc rate: as number of participants with best response of CR divided by the number of participants in the analysis population. Derived and investigator-assessed responses are reported.
Time frame: From baseline up to approximately 55 months
Number of Participants With MRD Negative Status in Relation to OS
MRD negative: summed FLT3-ITD signal ratio of any post-baseline sample ≤10\^(-4). OS was defined as the time from the date of enrollment until the date of death from any cause (death date - enrollment date + 1). For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact (date of last contact - enrollment date + 1).
Time frame: From baseline up to approximately 55 months
Number of Participants With Gilteritinib Acceptability and Palatability for Tablet
Participants evaluated the taste of the study drug/tablets and indicated whether they would be willing (feeling) to take the study drug/tablets again by selecting one of the following categories: 'Like a lot,' 'Like a little,' 'Neither like nor dislike,' 'Dislike a little,' or 'Dislike a lot.'
Time frame: C1D1, C1D8