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

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the safety of lanraplenib (LANRA) in combination with the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib, in participants with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML).

Official Title
-----------------
A Phase 1b/2 Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib (LANRA) in Combination With the FLT3 Inhibitor Gilteritinib, in Patients With FLT3-mutated Relapsed or Refractory AML

Conditions
-----------------
Acute Myeloid Leukemia, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Lanraplenib
* Drug: Gilteritinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults ≥18 years of age with acute myeloid leukemia (AML) and at least 1 prior line of therapy FMS-like tyrosine kinase 3 (FLT3)-mutated disease documented in a local reference laboratory at the time of consideration for enrollment in the study Have the ability to understand the requirements and procedures of the study and sign a written informed consent form Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 Adequate hepatic and renal function Prothrombin time (PT), activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation Negative serum ß-human chorionic gonadotropin (HCG) test in women of child-bearing potential (WOCBP) Left ventricular ejection fraction ≥50% confirmed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan Exclusion Criteria: Known central nervous system (CNS) involvement with leukemia Clinical signs/symptoms of leukostasis that have failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration Pregnant or breastfeeding women Active infection with hepatitis B, C or human immunodeficiency virus (HIV) infection Disseminated intravascular coagulation with active bleeding or signs of thrombosis Known active coronavirus disease 2019 (COVID-19) Administration of a live attenuated virus vaccine within 35 days before Cycle 1 Day 1 (C1D1) History of non-myeloid malignancy except for the following: adequately treated localized basal cell, or squamous cell carcinoma of the skin, or localized melanoma (with TNM stage either Tis [melanoma in-situ] or T1aN0M0) with complete resection; cervical carcinoma in situ; superficial bladder cancer; asymptomatic prostate cancer without known metastatic disease, with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for > 1 year prior to start of study therapy; or any other cancer that has been in complete remission without treatment for ≥3 years prior to enrollment Clinically significant heart disease Prolongation of the congenital long measure between Q wave and T wave in the electrocardiogram (QT) interval at baseline Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection at the time of study treatment initiation Current (within 30 days of study enrollment) drug-induced liver injury, chronic active hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis with inadequate response to ursodeoxycholic acid or other health authority approved therapy, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, orportal hypertension Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>Sequential cohorts of participants will receive escalating doses of lanraplenib (LANRA) once daily (QD) + gilteritinib QD in each 28 day cycle for determination of the maximally tolerated dose (MTD) / recommended Phase 2 dose (RP2D) of LANRA in combination with gilteritinib. | Drug: Lanraplenib<br>* Orally via tablets<br>* Other names: LANRA;Drug: Gilteritinib<br>* Orally via tablets<br>* Other names: XOSPATA®;|
| Experimental: Part 2: Expansion Cohort<br>Following identification of the maximally tolerated dose (MTD) / recommended Phase 2 dose (RP2D) of lanraplenib (LANRA) in combination with gilteritinib in Part 1, an expansion cohort will enroll. The expansion cohort will receive LANRA in combination with gilteritinib at the MTD / RP2D once daily (QD) in each 28 day cycle. | Drug: Lanraplenib<br>* Orally via tablets<br>* Other names: LANRA;Drug: Gilteritinib<br>* Orally via tablets<br>* Other names: XOSPATA®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Number of Participants who Experience a Treatment-Emergent Adverse Event (TEAE) |  | Cycle 1 Day 1 through 30 days after last dose (up to approximately 5 years; cycle is 28 days) | 
| Part 1 and Part 2: Number of Participants who Experience a Dose-Limiting Toxicity (DLT) for Lanraplenib (LANRA) |  | Cycle 1 Day 1 through pre-dose Cycle 2 Day 1 (cycle is 28 days) | 
| Part 1: Maximally Tolerated Dose (MTD) of Lanraplenib (LANRA) |  | Cycle 1 Day 1 through Cycle 2 Day 1 (cycle is 28 days) | 
| Part 1: Recommended Phase 2 Dose (RP2D) of Lanraplenib (LANRA) |  | Cycle 1 Day 1 through Cycle 2 Day 1 (cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximal Plasma Concentration (Cmax) of Lanraplenib (LANRA) |  | Cycle 1 Day 1 through Cycle 2 Day 1 (cycle is 28 days) | 
| Part 1: Time to Maximal Plasma Concentration (Tmax) of Lanraplenib (LANRA) |  | Cycle 1 Day 1 through Cycle 2 Day 1 (cycle is 28 days) | 
| Part 1: Area Under the Plasma Concentration x Time Curve from Hour 0 to the Last Measurable Time Point (AUC0-last) of Lanraplenib (LANRA) |  | Cycle 1 Day 1 through Cycle 2 Day 1 (cycle is 28 days) | 
| Part 1 and Part 2: Composite Complete Response (CR) Rate |  | Up to 5 years | 
| Part 1 and Part 2: Composite Complete Response (CR) with Partial Hematologic Recovery (CRh) |  | Up to 5 years | 
| Part 1 and Part 2: Duration of Response (DoR) |  | Up to 5 years | 
| Part 1 and Part 2: Event Free Survival (EFS) |  | Up to 5 years | 
| Part 1 and Part 2: Overall Survival (OS) |  | Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Myeloid Leukemia, Lanraplenib, LANRA, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia