Acute Myeloid Leukemia (AML), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD)
Conditions
Keywords
ASP2215, Acute Myeloid Leukemia, FLT3, AML, gilteritinib
Brief summary
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).
Interventions
DRUGgilteritinib
Administered orally.
DRUGfludarabine
Administered by intravenous (IV) infusion
DRUGcytarabine
Administered by intravenous (IV) infusion
Administered by subcutaneous injection
Sponsors
Astellas Pharma Global Development, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 21 Years
Healthy volunteers
No
Inclusion criteria
* Subject is aged ≥ 6 months and \< 21 years of age\* at the time of signing informed consent and/or assent, as applicable. * \*For phase 2: Enrollment of subjects from 6 months to less than 1 year and 1 year to less than 2 years will be dependent on the establishment of recommended phase 2 dose (RP2D) in the respective age groups during phase 1. * Subject has a diagnosis of acute myeloid leukemia (AML) according to The French-American-British (FAB) classification with ≥ 5% blasts in the bone marrow, with or without extramedullary disease (except subjects with active central nervous system \[CNS\] leukemia). * In the phase 1 portion of the study, subject must be in first or greater relapse or refractory to induction therapy with no more than 1 attempt at remission induction (up to 2 induction cycles). * For the phase 2 portion of the study, subject must be in refractory to or at the first hematologic relapse after first-line remission induction AML therapy (up to 2 induction cycles). * Subject has fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. * Myelosuppressive chemotherapy: * For subject who relapses while receiving cytotoxic therapy, at least 21 days must have elapsed since the completion of cytotoxic therapy and prior to screening, unless the subject has recovered earlier than 21 days. * Cytoreduction with the following can be initiated and continued for up to 24 hours prior to the start of systemic protocol therapy (cycle 1 day -1). * hydroxyurea, * low dose cytarabine (100 mg/m\^2 per dose once daily for 5 days) or * other low dose/maintenance therapies as per local site practice. * Subject who has received other FLT3 inhibitors (e.g., lestaurtinib, sorafenib, etc) is eligible for this study. * Hematopoietic growth factors: at least 7 days must have elapsed since the completion of therapy with a growth factor and prior to screening. * Biologic (anti-neoplastic agent): at least 7 days must have elapsed since the completion of therapy with a biologic agent and prior to screening. For agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. * X-ray treatment (XRT): * 14 days must have elapsed for local palliative XRT for CNS chloromas and prior to screening; no washout period is necessary for other chloromas; * Prior to screening, 90 days must have elapsed if the subject had a prior traumatic brain injury or has received craniospinal XRT. * For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since HSCT and subject must not have active graft-versus-host disease (GVHD). * Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky score of ≥ 50 (if the subject is \< 16 years of age). A score \< 50 is acceptable if related to the subject's leukemia. * Subject must meet the following criteria as indicated on the clinical laboratory tests. * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit normal (ULN) for age * Total serum bilirubin ≤ 1.5 x ULN for age * Estimated glomerular filtration rate of \> 60 mL/min/1.73 m\^2. * A female subject is eligible to participate if she is not pregnant and at least 1 of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 180 days after the final study drug administration. * Female subject must agree not to breastfeed starting at Screening, and throughout the study period and for 60 days after the final study drug administration. * Female subject must not donate ova starting at Screening and throughout the study, and for 180 days after the final study drug administration. * A male subject with female partner(s) of childbearing potential must agree to use contraception during the treatment period and for at least 180 days after the final study drug administration. * A male subject must not donate sperm during the treatment period and for at least 120 days after the final study drug administration. * Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 180 days after the final study drug administration. * Subject and subject's parent(s) or legal guardian agrees not to participate in another interventional study while on treatment. * Live Vaccines - At least 6 weeks must have elapsed since the administration of the last dose of a live vaccine and prior to the initiation of study treatment (cycle 1, day -1) * Phase 1: Subject is positive for FLT3 (ITD and/or tyrosine kinase domain \[TKD\]) mutation in bone marrow or blood as determined by the local institution. * Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow or blood as determined by the local institution.
Exclusion criteria
* Subject has active CNS leukemia. * Subject has uncontrolled or significant cardiovascular disease, including: * Diagnosed or suspected congenital long QT syndrome or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes (TdP)); any history of arrhythmia will be discussed with the sponsor prior to subject's entry into the study * Prolonged Fridericia's Correction Formula (QTcF) interval on pre-entry electrocardiogram (ECG) (≥ 450 ms) * Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker) * Heart rate \< 50 beats/minute on pre-entry ECG * Uncontrolled hypertension * Complete left bundle branch block * Subject has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The subject needs to be off pressors and have negative blood cultures for 48 hours. * Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. * Subject has active clinically significant GVHD or is on treatment with immunosuppressive drugs for treatment of active GVHD, with the exception of subjects being weaned from systemic corticosteroids where the subject is receiving ≤ 0.5 mg/kg of prednisone (or equivalent) daily dose for prior GVHD. Subject has received calcineurin inhibitors within 4 weeks prior to screening, unless used as GVHD prophylaxis. * Subject has active malignant tumors other than AML. * Subject has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance; interfere with consent, study participation, follow-up or interpretation of study results. * Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below institutional lower limit of normal \[LLN\]). Repletion of potassium and magnesium levels during the screening period is allowed. * Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A/P-glycoprotein (P-gp). * Subject is known to have human immunodeficiency virus infection. * Subject has active hepatitis B or C, or other active hepatic disorder. * Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA are not eligible. * Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable. * Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is undetectable. * Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent and before starting gilteritinib. * Subject has a known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, granulocyte colony-stimulating factor (G-CSF) or any components of the formulation used.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum Tolerated Dose (MTD) of Gilteritinib | C1D1 up to day 28 | 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. |
| Phase 1: Recommended Phase 2 Dose (RP2D) of Gilteritinib | C1D1 up to day 28 | The RP2D was a safe dose of gilteritinib that demonstrated sufficient activity. |
| Phase 2: Complete Remission (CR) Rate | From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days) | 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. |
| Phase 2: Composite CR (CRc) Rate | From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days) | 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. |
| Duration of CR | From the date of first CR until the date of documented relapse for participants who achieved CR (Maximum duration: 28 months) | 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. |
| Phase 1: Number of Participants With Dose Limiting Toxicity (DLT) of Gilteritinib | C1D1 up to day 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK of Gilteritinib: Area Under the Concentration (AUC) | Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21 | — |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose up to 28 days after last dose (maximum duration approximately 55 months) | 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. |
| Event Free Survival (EFS) | From first dose to documented relapse or death, whichever occurred first (maximum duration: 55 month) | 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. |
| Overall Survival (OS) | From the date of enrollment until the date of death from any cause (maximum duration: 55 months) | 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. |
| Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | Baseline, predose on C1D15, C1D21, C2D8, C2D15, C2D21 and 4 to 6 hours post-dose on C1D21 | 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%). |
| Percentage of Participants With MRD Negative Status in Relation to CR Rate | From baseline up to approximately 55 months | 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. |
| Percentage of Participants With MRD Negative Status in Relation to CRc Rate | From baseline up to approximately 55 months | 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. |
| Number of Participants With MRD Negative Status in Relation to OS | From baseline up to approximately 55 months | 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). |
| Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D1, C1D8 | 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.' |
| Number of Participants With Negative Minimal Residual Disease (MRD) Status | From baseline up to approximately 55 months | MRD negative was defined as summed FLT3-ITD signal ratio of any post-baseline sample ≤10\^(-4). |
| Gilteritinib Plasma Concentration | Predose on C1D8, C1D15, C1D21, C2D15, and 4 to 6 hours post-dose on C1D21 | Plasma samples were used for pharmacokinetic assessments. |
| Pharmacokinetics (PK) of Gilteritinib: Oral Clearance (CL/F) | Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21 | — |
| PK of Gilteritinib: Apparent Volume of Distribution (Vd/F) | Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21 | — |
| PK of Gilteritinib: Maximum Plasma Concentration (Cmax) | Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21 | — |
| PK of Gilteritinib: Time to Observed Cmax (Tmax) | Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21 | — |
Countries
Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants positive for FMS-like tyrosine kinase 3 (FLT3) \[internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD)\] mutation in bone marrow or blood and positive for the FLT3 (ITD) mutation in bone marrow or blood were enrolled for phase 1 and phase 2 respectively.
Pre-assignment details
The sponsor decided not to open the phase 2 extension part of the study and terminated the study after completion of the phase 1 dose escalation part for Group 1, hence, no participants were enrolled for dose escalation groups 2 and 3. The decision to terminate the study was based upon enrollment challenges due to the rarity of Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) in children and not related to any safety or efficacy issues.
Participants by arm
| Arm | Count |
|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) Participants aged 2 years to less than 21 years with R/R FLT3 ITD and/or TKD AML received 2 cycles (C1 and C2) induction therapy with gilteritinib in combination with FLAG (fludarabine, cytarabine and G-CSF) chemotherapy. Gilteritinib tablet was administered at a starting dose of 2 mg/kg/day (maximum 120 mg/day) orally QD from days 8 to 21. FLAG regimen consisted of fludarabine: 30 mg/m\^2 per day IV from day 1 to day 5; cytarabine: 2000 mg/m\^2 per day IV from day 1 to day 5; G-CSF (filgrastim): 5 μg/kg per day SC or IV from day -1 to day 5. Each cycle = 28 days. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Gilteritinib 2 mg/kg/Day (Escalation Phase) |
|---|---|
| Age, Continuous | 11.9 Years STANDARD_DEVIATION 2.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Percent Inhibition of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | 100.00 Percentage of pFLT3 STANDARD_DEVIATION 0 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 7 / 9 |
Outcome results
Primary
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)
Population: FAS population included participants who achieved CR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Duration of CR | NA days |
Primary
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
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Phase 1: Maximum Tolerated Dose (MTD) of Gilteritinib | 2 mg/kg/day |
Primary
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
Population: Safety Analysis Set (SAF) included all enrolled participants who took at least 1 dose of treatment regimen. Participants who were DLT evaluable were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Phase 1: Number of Participants With Dose Limiting Toxicity (DLT) of Gilteritinib | 0 Participants |
Primary
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
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Phase 1: Recommended Phase 2 Dose (RP2D) of Gilteritinib | 2 mg/kg/day |
Primary
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)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Phase 2: Complete Remission (CR) Rate | Derived | 33.3 Percentage of Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Phase 2: Complete Remission (CR) Rate | Investigator | 33.3 Percentage of Participants |
Primary
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)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Phase 2: Composite CR (CRc) Rate | Derived | 66.7 Percentage of Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Phase 2: Composite CR (CRc) Rate | Investigator | 55.6 Percentage of Participants |
Secondary
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)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Event Free Survival (EFS) | 123.00 days |
Secondary
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
Population: The pharmacokinetic analysis set (PKAS) included the administered population for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known. PKAS with available data was analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Gilteritinib Plasma Concentration | Cycle 1 Day 8 Pre-Dose | 0 nanogram (ng)/mL | Standard Deviation 0 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Gilteritinib Plasma Concentration | Cycle 1 Day 15 Pre-Dose | 251.93 nanogram (ng)/mL | Standard Deviation 202.55 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Gilteritinib Plasma Concentration | Cycle 1 Day 21 Pre-Dose | 225.25 nanogram (ng)/mL | Standard Deviation 135.18 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Gilteritinib Plasma Concentration | Cycle 1 Day 21 4-6 Hours Post-Dose | 439.00 nanogram (ng)/mL | Standard Deviation 209.62 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Gilteritinib Plasma Concentration | Cycle 2 Day 15 Pre-Dose | 145.07 nanogram (ng)/mL | Standard Deviation 67.09 |
Secondary
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
Population: FAS with available data was analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Tastes: Like a lot | 1 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Tastes: Like a little | 2 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Tastes: Neither like or dislike | 3 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Tastes: Dislike a little | 0 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Tastes: Dislike a lot | 0 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Feeling: Like a lot | 3 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Feeling: Like a little | 1 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Feeling: Neither like or dislike | 2 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Feeling: Dislike a little | 0 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D8 Feeling: Dislike a lot | 0 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Tastes: Like a lot | 1 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Tastes: Like a little | 1 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Tastes: Neither like or dislike | 5 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Tastes: Dislike a little | 0 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Tastes: Dislike a lot | 0 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Feeling: Like a lot | 3 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Feeling: Like a little | 1 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Feeling: Neither like or dislike | 3 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Feeling: Dislike a little | 0 Participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Gilteritinib Acceptability and Palatability for Tablet | C1D21 Feeling: Dislike a lot | 0 Participants |
Secondary
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
Population: MAS with available data was analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With MRD Negative Status in Relation to OS | 1 participants |
Secondary
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
Population: The MRD Analysis Set (MAS) included a subset of the FAS for which participants enrolled, received at least 1 dose of the treatment regimen, and had at least 1 post-baseline sample with MRD data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Negative Minimal Residual Disease (MRD) Status | 4 Participants |
Secondary
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.
Time frame: From first dose up to 28 days after last dose (maximum duration approximately 55 months)
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 9 Participants |
Secondary
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)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Overall Survival (OS) | NA months |
Secondary
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
Population: MAS with available data was analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percentage of Participants With MRD Negative Status in Relation to CRc Rate | Derived | 100.0 percentage of participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percentage of Participants With MRD Negative Status in Relation to CRc Rate | Investigator | 100.0 percentage of participants |
Secondary
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
Population: MAS with available data was analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percentage of Participants With MRD Negative Status in Relation to CR Rate | Derived | 75.0 percentage of participants |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percentage of Participants With MRD Negative Status in Relation to CR Rate | Investigator | 75.0 percentage of participants |
Secondary
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
Population: Pharmacodynamic Analysis Set (PDAS) included subset of the SAF for which sufficient pharmacodynamic measurements were collected. PDAS with available data was analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | Cycle 1 Day 15 Pre-Dose | 15.00 Percent Change of pFLT3 | Standard Deviation 14.41 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | Cycle 1 Day 21 Pre-Dose | 11.96 Percent Change of pFLT3 | Standard Deviation 11.85 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | Cycle 1 Day 21 4-6 Hours Post-Dose | 7.32 Percent Change of pFLT3 | Standard Deviation 9.14 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | Cycle 2 Day 8 Pre-Dose | 63.97 Percent Change of pFLT3 | Standard Deviation 25.4 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | Cycle 2 Day 15 Pre-Dose | 9.90 Percent Change of pFLT3 | Standard Deviation 2.95 |
| Gilteritinib 2 mg/kg/Day (Escalation Phase) | Percent Change of Phosphorylated FMS-like Tyrosine Kinase 3 (FLT3) | Cycle 2 Day 21 Pre-Dose | 6.03 Percent Change of pFLT3 | Standard Deviation 8.72 |
Secondary
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
Secondary
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
Secondary
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
Secondary
PK of Gilteritinib: Maximum Plasma Concentration (Cmax)
Time frame: Predose on C1D8, C1D15, C1D21, C2D15, and 4 and 6 hours post-dose on C1D21
Secondary
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