A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants With FLT3-mutated Relapsed or Refractory Acute Myeloid Leukemia (AML)

The MTD/RP2D was defined as the highest dose with either 0 of 3 or no more than 1 of 6 patients with LANRA-related DLTs. All decisions regarding dose escalation including declaration of the MTD/RP2D were made by the dose-escalation committee (DEC).

Time frame: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)

Population: The study was terminated before MTD/RP2D could be determined.

A DLT was defined as any of the following occurring within the DLT assessment period: * A nonhematologic toxicity of Grade ≥ 3 that was at least possibly related to LANRA (with noted exceptions). * Any toxicity that resulted in administration of \< 80% of the cumulative, Cycle 1 dose for either LANRA or gilteritinib. * Grade 4 neutropenia or thrombocytopenia lasting \> 28 days after treatment onset that was not attributed to active acute myeloid leukemia (AML) and was at least possibly related to LANRA. * Any toxicity that resulted in reduction in the dose of LANRA in Cycle 1. DLTs were graded for severity based on the NCI-CTCAE version 5.0 as follows: * Grade 3 - Severe. * Grade 4 - Life-threatening.

Time frame: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)

Population: Safety Population: Consisted of all participants who received ≥ 1 dose of either study drug and had at least 1 on-treatment safety-related observation.

A TEAE was any unfavorable or unintended sign, symptom, laboratory abnormality or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered causally related to the study drug or not that started after the first dose of the earliest study drug through the lesser of non-protocol anti-leukemic therapy initiation or end of treatment visit. A serious TEAE was defined as any TEAE that: * Resulted in death. * Was life-threatening. * Required or prolonged a pre-existing hospitalization. * Resulted in disability/incapacity. * Was a congenital anomaly/birth defect. * Was considered a significant medical event by the investigator. TEAEs were graded for severity based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 as follows: * Grade 1 - Mild. * Grade 2 - Moderate. * Grade 3 - Severe. * Grade 4 - Life-threatening. * Grade 5 - Death related to adverse event (AE).

Time frame: Cycle 1 Day 1 (each cycle was 28 days) to 30 days after last dose of either LANRA or gilteritinib or initiation of non-protocol antileukemic therapy, whichever was earlier (maximum duration of treatment was 183 days)

Population: Safety Population: Consisted of all participants who received ≥ 1 dose of either study drug and had at least 1 on-treatment safety-related observation.

AUC0-last was derived from plasma concentrations of LANRA using standard non-compartmental methods and actual sample times.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

Population: PK Population: Consisted of all participants with at least 1 post-dose LANRA plasma concentration with available data at each PK assessment time point.

AUC0-last was derived from plasma concentrations of gilteritinib using standard non-compartmental methods and actual sample times.

Time frame: Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

Population: PK Population: Consisted of all participants with at least 1 post-dose gilteritinib plasma concentration with available data at each PK assessment time point.

Cmax was derived from plasma concentrations of gilteritinib using standard non-compartmental methods and actual sample times.

Time frame: Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

Population: PK Population: Consisted of all participants with at least 1 post-dose gilteritinib plasma concentration with available data at each PK assessment time point.

Percentage of participants with cCR included CR and CR with partial hematologic recovery (CRh). CR required all of the following, per ELN 2017 criteria: * Bone marrow blasts \< 5 %. * Absence of circulating blasts and blasts with Auer rods. * Absence of extramedullary disease (ie, leukemia outside of bone marrow confirmed by biopsy). * Absolute neutrophil count \> 1.0 x 10\^9/L (1,000/μL). * Platelet count \>100 x 10\^9/L (100,000/μL). CRh required all aforementioned CR criteria except for the below: * Absolute neutrophil count \> 0.5 x 10\^9/L (500/μL) and/or; * Platelet count \> 50 x 10\^9/L (50,000/μL).

Time frame: Cycle 1 Day 1 until occurrence of documented CR or CRh (maximum duration of follow-up was 16.1 months).

Population: Efficacy Evaluable Population: Consisted of all participants who received ≥1 dose of either study drug and completed the first protocol-specified response assessment or discontinued study treatment for toxicity or died prior to the first response assessment. Participants with no post-baseline response assessments were considered non-responders.

DOR was defined as the time from first qualifying response (CR/CRh) until relapse or death from any cause, as assessed by study investigators. CR required all of the following: * Bone marrow blasts \< 5 %. * Absence of circulating blasts and blasts with Auer rods. * Absence of extramedullary disease (ie, leukemia outside of bone marrow confirmed by biopsy). * Absolute neutrophil count \> 1.0 x 10\^9/L (1,000/μL). * Platelet count \>100 x 10\^9/L (100,000/μL). CRh required all aforementioned CR criteria except for the below: * Absolute neutrophil count \> 0.5 x 10\^9/L (500/μL) and/or; * Platelet count \> 50 x 10\^9/L (50,000/μL). Relapse was defined as the reappearance of circulating blasts or ≥ 5% blasts in the bone marrow not attributable to any other cause or reappearance of cytologically or biopsy documented extramedullary disease.

Time frame: From first qualifying response (CR/CRh) until relapse or death from any cause (maximum duration of follow-up was 16.1 months).

Population: Efficacy Evaluable Population: Consisted of only participants who had a CR/CRh.

EFS was defined as the time from treatment onset until treatment failure (ie, failure to achieve CR/CRh, relapse from CR/CRh, or death from any cause). CR required all of the following: * Bone marrow blasts \< 5 %. * Absence of circulating blasts and blasts with Auer rods. * Absence of extramedullary disease (ie, leukemia outside of bone marrow confirmed by biopsy). * Absolute neutrophil count \> 1.0 x 10\^9/L (1,000/μL). * Platelet count \>100 x 10\^9/L (100,000/μL). CRh required all aforementioned CR criteria except for the below: * Absolute neutrophil count \> 0.5 x 10\^9/L (500/μL) and/or; * Platelet count \> 50 x 10\^9/L (50,000/μL). Relapse was defined as the reappearance of circulating blasts or ≥ 5% blasts in the bone marrow not attributable to any other cause or reappearance of cytologically or biopsy documented extramedullary disease.

Time frame: Cycle 1 Day 1 to treatment failure (ie, failure to achieve CR or CRh, relapse from CR/CRh or death from any cause) (maximum duration of follow-up was 16.1 months).

Population: Event free survival could not be estimated as no participants had a CR/CRh.

Cmax was derived from plasma concentrations of LANRA using standard non-compartmental methods and actual sample times.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

Population: Pharmacokinetic (PK) Population: Consisted of all participants with at least 1 post-dose LANRA plasma concentration with available data at each PK assessment time point.

Overall survival was defined as the time from enrollment until death from any cause. Overall survival was estimated using Kaplan-Meier methodology.

Time frame: Enrollment until death from any cause (maximum duration of follow-up was 16.1 months).

Population: Safety Population: Consisted of all participants who received ≥ 1 dose of either study drug and had at least 1 on-treatment safety-related observation. Participants alive at last follow-up were censored at the date of last contact.

Tmax was derived from plasma concentrations of LANRA using standard non-compartmental methods and actual sample times.

Time frame: Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

Population: PK Population: Consisted of all participants with at least 1 post-dose LANRA plasma concentration with available data at each PK assessment time point.

Tmax was derived from plasma concentrations of gilteritinib using standard non-compartmental methods and actual sample times.

Time frame: Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

Population: PK Population: Consisted of all participants with at least 1 post-dose gilteritinib plasma concentration with available data at each PK assessment time point.