Clinical trial NCT05028751: A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants With FLT3-mutated Relapsed or Refractory 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Relapsed Acute Myeloid Leukemia
Refractory Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia
Lanraplenib
LANRA
Relapsed Acute Myeloid Leukemia
Refractory Acute Myeloid Leukemia
Lead sponsor: Kronos Bio
Sponsor class: INDUSTRY
First posted: 2021-08-31
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


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 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, or portal hypertension
* Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy
* Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia

Primary outcomes:
measure: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
timeFrame: 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)
measure: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA
timeFrame: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)
measure: Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib
timeFrame: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)
Secondary outcomes:
measure: Maximal Plasma Concentration (Cmax) of LANRA
timeFrame: 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.
measure: Time to Cmax (Tmax) of LANRA
timeFrame: 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.
measure: Area of the Plasma Concentration x Time Curve From Hour 0 to the Last Measurable Time Point (AUC0-last) of LANRA
timeFrame: 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.
measure: Cmax of Gilteritinib
timeFrame: Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.
measure: Tmax of Gilteritinib
timeFrame: Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.
measure: AUC0-last of Gilteritinib
timeFrame: Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.
measure: Composite Complete Remission (cCR) Rate Per European LeukemiaNet (ELN) 2017 Criteria
timeFrame: Cycle 1 Day 1 until occurrence of documented CR or CRh (maximum duration of follow-up was 16.1 months).
measure: Duration of Response (DOR)
timeFrame: From first qualifying response (CR/CRh) until relapse or death from any cause (maximum duration of follow-up was 16.1 months).
measure: Event-free Survival (EFS)
timeFrame: 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).
measure: Overall Survival
timeFrame: Enrollment until death from any cause (maximum duration of follow-up was 16.1 months).
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles (UCLA)
state: California
city: Atlanta
country: United States
facility: The Blood and Marrow Transplant Group of Georgia
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert Hospital
state: Wisconsin
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
state: Avenida De Córdoba Sin Número
city: Barcelona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Badalona
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
state: Calle De Arturo Soria
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
Study officials:
References: