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
Overview
- Phase
- Phase 1
- Intervention
- Lanraplenib
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Kronos Bio
- Enrollment
- 24
- Locations
- 17
- Primary Endpoint
- Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib
- Status
- Terminated
- Last Updated
- last year
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).
Investigators
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
Arms & Interventions
LANRA 20 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 20 mg once daily (QD) as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a partial remission (PR) after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Lanraplenib
LANRA 20 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 20 mg once daily (QD) as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a partial remission (PR) after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Gilteritinib
LANRA 40 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 40 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Lanraplenib
LANRA 40 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 40 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Gilteritinib
LANRA 60 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 60 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Lanraplenib
LANRA 60 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 60 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Gilteritinib
LANRA 90 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 90 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Lanraplenib
LANRA 90 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 90 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
Intervention: Gilteritinib
Outcomes
Primary Outcomes
Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib
Time Frame: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)
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).
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
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)
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).
Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA
Time Frame: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)
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.
Secondary Outcomes
- Tmax of Gilteritinib(Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- Composite Complete Remission (cCR) Rate Per European LeukemiaNet (ELN) 2017 Criteria(Cycle 1 Day 1 until occurrence of documented CR or CRh (maximum duration of follow-up was 16.1 months).)
- Duration of Response (DOR)(From first qualifying response (CR/CRh) until relapse or death from any cause (maximum duration of follow-up was 16.1 months).)
- Maximal Plasma Concentration (Cmax) of LANRA(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.)
- Time to Cmax (Tmax) of LANRA(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.)
- Area of the Plasma Concentration x Time Curve From Hour 0 to the Last Measurable Time Point (AUC0-last) of LANRA(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.)
- Cmax of Gilteritinib(Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- AUC0-last of Gilteritinib(Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- Event-free Survival (EFS)(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).)
- Overall Survival(Enrollment until death from any cause (maximum duration of follow-up was 16.1 months).)