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

NCT05028751 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: KB-LANRA- 10012022-001279-15
• Study Type: interventional
• Target: 24
• Locations: 2 countries
• Sites: 17

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).

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

Outcome Measures

Primary Outcomes (3)

• Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

  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).

  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)

• Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA

  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.

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

• Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib

  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).

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

Secondary Outcomes (10)

• 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.

• Tmax of Gilteritinib

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

Study Arms (4)

LANRA 20 mg QD + Gilteritinib 120 mg QD

EXPERIMENTAL

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.

Drug: Lanraplenib; Drug: Gilteritinib

LANRA 40 mg QD + Gilteritinib 120 mg QD

EXPERIMENTAL

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.

Drug: Lanraplenib; Drug: Gilteritinib

LANRA 60 mg QD + Gilteritinib 120 mg QD

EXPERIMENTAL

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.

Drug: Lanraplenib; Drug: Gilteritinib

LANRA 90 mg QD + Gilteritinib 120 mg QD

EXPERIMENTAL

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.

Drug: Lanraplenib; Drug: Gilteritinib

Interventions

Lanraplenib DRUG

Orally via tablets

Also known as: LANRA

LANRA 20 mg QD + Gilteritinib 120 mg QD; LANRA 40 mg QD + Gilteritinib 120 mg QD; LANRA 60 mg QD + Gilteritinib 120 mg QD; LANRA 90 mg QD + Gilteritinib 120 mg QD

Gilteritinib DRUG

Orally via tablets

Also known as: XOSPATA®

LANRA 20 mg QD + Gilteritinib 120 mg QD; LANRA 40 mg QD + Gilteritinib 120 mg QD; LANRA 60 mg QD + Gilteritinib 120 mg QD; LANRA 90 mg QD + Gilteritinib 120 mg QD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kronos Bio: lead

Study Sites (17)

University of California Los Angeles (UCLA)

Los Angeles, California, 990095, United States

Location

The Blood and Marrow Transplant Group of Georgia

Atlanta, Georgia, 30342, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Froedtert Hospital

Milwaukee, Wisconsin, 53226, United States

Location

Hospital Universitario 12 de Octubre

Madrid, Avenida de Córdoba Sin Número, 28041, Spain

Location

Hospital Germans Trias i Pujol

Barcelona, Badalona, 08916, Spain

Location

MD Anderson Cancer Center Madrid

Madrid, Calle de Arturo Soria, 270, Spain

Location

Hospital Universitari Vall d'Hebrón

Barcelona, 08035, Spain

Location

Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)

Barcelona, 08908, Spain

Location

Hospital Clínic de Barcelona

Barcelona, 170, Spain

Location

Hospital San Pedro de Alcantara

Cáceres, 10001, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitari i Politècnic La Fe

Valencia, 46026, Spain

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

gilteritinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Limitations and Caveats

In light of the Sponsor's decision to terminate the trial at completion of Phase 1b, all analyses were restricted to results from Phase 1b participants only. Phase 2 was not enrolled.

Results Point of Contact

• Title: VP, Corporate Affairs
• Organization: Kronos Bio, Inc.

media@kronosbio.com

+16507815200

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2021
• First Posted: August 31, 2021
• Study Start: August 5, 2022
• Primary Completion: April 9, 2024
• Study Completion: April 9, 2024
• Last Updated: August 7, 2024
• Results First Posted: August 7, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (8); ES (9)