A Study of Gilteritinib (ASP2215) Combined With Chemotherapy in Children, Adolescents and Young Adults With FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)
1. Number of participants with dose limiting toxicity (DLT) (phase 1/dose escalation) (Time Frame - Up to 28 days): DLT is defined as any of the events meeting the DLT criteria that occur during DLT observation period & that is considered to be possibly or probably related to protocol therapy. Nonhematologic (NH) DLT will be defined as grade 3 NH toxicity at least possibly related to protocol therapy that persists for >48 hours without resolution to grade ≤ 2 or 4 NH toxicity, regardless of duration, at least possibly related to protocol therapy. Hy's law or treatment-related deaths will be considered as a DLT. Gilteritinib dosing will be interrupted if NH DLT occurs. Exceptions include toxicities commonly seen with intensive AML reinduction regimens. Hematologic DLT will be defined as failure to recover a peripheral absolute neutrophil count (ANC) >500/μL & non-transfusion dependent platelet count >20000/μL due to documented bone marrow aplasia/hypoplasia at day 42 from start of cycle 1 day 1. Failure to recover peripheral counts due to disease involvement of bone marrow will not be considered DLT
2. Complete Remission (CR) rate after 2 cycles of therapy (phase 2) (Time Frame - Up to 56 days): CR rate is defined as the number of participants who achieve the best response of CR divided by the number of participants in the analysis population. Complete remission is defined as having bone marrow regenerating normal hematopoietic cells and achieving a morphologic leukemia-free state and must have an absolute neutrophil count (ANC) ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they will be 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.
3. Composite complete remission (CRc) rate after 2 cycles of therapy (phase 2) (Time Frame - Up to 56 days): CRc rate is defined as the number of participants who achieve the best response of CRc (CR, CRp,or CRi) divided by the number of participants in the analysis population. Complete remission with incomplete platelet recovery (CRp) is defined as achieving CR except for incomplete platelet recovery (< 100 x 10^9/L) at a post baseline visit. Complete remission with incomplete hematologic recovery (CRi) is defined as achieving CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery at a post baseline visit. Red blood cell (RBC) and platelet transfusion independence is not required.
Secondary outcome:
1. Number of participants with Adverse Events (AEs) (Time Frame - Up to 2 years plus 28 day follow up): An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product whether or not considered related to the medicinal product.
2. Number of participants with vital sign abnormalities and /or adverse events (AEs) (Time Frame - Up to 2 years): Number of participants with potentially clinically significant vital sign values.
3. Number of participants with laboratory value abnormalities and/or adverse events (AEs) (Time Frame - Up to 2 years): Number of participants with potentially clinically significant laboratory values.
4. Number of participants with electrocardiogram (ECG) abnormalities and/or adverse events (AEs) (Time Frame - Up to 2 years): Number of participants with potentially clinically significant ECG values.
5. Percentage of inhibition of phosphorylated FLT3 in participants. (Time Frame - Up to 49 days): Inhibition of FLT3 phosphorylation after drug treatment will be determined relative to pre-treatment phosphorylated FLT3 levels in participants to assess the relationship with gilteritinib dose. Phosphorylated FLT3 will be measured by plasma inhibitory activity (PIA) assay.
6. Pharmacokinetics (PK) of gilteritinib: oral clearance (CL/F) (Time Frame - Up to 45 days): CL/F will be reported from the PK plasma samples collected.
7. PK of gilteritinib: apparent volume of distribution (Vd/F) (Time Frame - Up to 45 days): Vd/F will be reported from the PK plasma samples collected.
8. PK of gilteritinib: Maximum Concentration (Cmax) (Time Frame - Up to 45 days): Cmax will be reported from the PK plasma samples collected.
9. PK of gilteritinib: Time of Maximum Concentration (tmax) (Time Frame - Up to 45 days): tmax will be reported from the PK plasma samples collected.
10. PK of gilteritinib: Area Under the Concentration (AUC) (Time Frame - Up to 45 days): AUC will be reported from the PK plasma samples collected.
11. Duration of Event Free Survival (EFS) (Time Frame - Up to 2 years): EFS is defined as the time from the date of enrollment until the date of documented relapse (excluding relapse after PR), treatment failure or death, whichever occurs first. If a participant experiences relapse or death, the participant is defined as having EFS event related to either "relapse" or "death", and the event date is the date of relapse or death. If a participant fails to achieve any of the response of CR, CRp, CRi or PR during the treatment period, the participant is defined as having EFS event related to treatment failure, and the event date is the enrollment date. For a participant who is not known to have had a relapse or treatment failure or death event, EFS is censored at the date of last relapse-free disease assessment. Participant is not censored at hematopoietic stem cell transplant (HSCT).
12. Duration of Overall survival (OS) (Time Frame - Up to 4 years and 2 months): OS is defined as the time from the date of enrollment until the date of death from any cause. For a participant who is not known to have died by the end-of-study follow-up, OS is censored at the date of last contact.
13. The number of participants with negative minimal residual disease (MRD) status (Time Frame - Up to 2 years): MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
14. Number of participants with MRD negative status in relation to CR rate (Time Frame - Up to 2 years): MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
15. Number of participants with MRD negative status in relation to CRc rate (Time Frame - Up to 2 years): MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
16. Number of participants with MRD negative status in relation to Overall survival (OS) (Time Frame - Up to 2 years): MRD negative status will be defined as FLT3-internal tandem duplication (ITD) signal ratio ≤ 10^-4.
17. Clinical Outcome Assessment of Taste (Time Frame - Up to 57 days): The acceptability and palatability of gilteritinib oral formulation as assessed by the participant using a single scale. The 5 point facial hedonic scale has high to low as: Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much.
Experimental: Dose Escalation - 2 years to less than 21 years of age Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
Experimental: Dose Escalation - 1 year to less than 2 years of age Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
Experimental: Dose Escalation - 6 months to less than 1 year of age Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
Experimental: Dose Expansion Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the dose determined in dose escalation portion. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).
fludarabine: Administered by intravenous (IV) infusion
cytarabine: Administered by intravenous (IV) infusion
granulocyte colony-stimulating factor (G-CSF): Administered by subcutaneous injection
Quelle: ClinicalTrials.gov
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