Phase I/II Evaluation of NMS-03592088, a FLT3, KIT, and CSF1R Inhibitor, in Relapsed/Refractory Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia

Trial ID: 2023-508655-39-00
Protocol: MKIA-088-001
Sponsor: Nerviano Medical Sciences S.r.l.

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Diseases & Conditions

Acute myeloid leukaemia Chronic myelomonocytic leukaemia

Objectives

The primary objective of this Phase I/II study is to evaluate the **maximum tolerated dose (MTD)** or **maximum administered dose (MAD)** and the recommended Phase II dose (RP2D) of NMS-03592088, a **FLT3, KIT, and CSF1R inhibitor**, in adult patients with relapsed or refractory **Acute Myeloid Leukemia (AML)** or **Chronic Myelomonocytic Leukemia (CMML)**. This evaluation is crucial for determining the optimal dosing regimen for further clinical development, ensuring both efficacy and safety in patients who have exhausted standard treatment options or for whom standard therapy is unsuitable. The study involves two dosing schedules: Schedule A, where the drug is administered orally once daily for 21 consecutive days followed by 7 days of rest in a 28-day cycle, and Schedule B, where it is administered once daily for 28 consecutive days. In Phase II, the study aims to explore the antitumor activity of NMS-03592088 specifically in patients with **FLT3-ITD mutated AML**, which is significant for assessing the therapeutic potential of the drug in this genetically defined subset of AML patients.

Participants

The clinical trial involves a total of **25 participants** diagnosed with **Acute Myeloid Leukemia (AML)** or **Chronic Myelomonocytic Leukemia (CMML)** that is relapsed or refractory. The study population comprises adult patients aged 18 years and older, including both male and female subjects. Participants were selected based on their failure to respond to standard therapies or unsuitability for such treatments. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating a relatively stable general health status. Key lifestyle considerations include the requirement for participants to use highly effective contraception due to the potential induction of CYP3A4 by the investigational drug. The trial population is characterized by their ability to swallow capsules intact and their willingness to comply with the study's scheduled visits and procedures. The selection criteria ensure that participants have adequate hepatic and renal function, as defined by specific laboratory parameters. The trial does not exclude vulnerable populations, and the sponsor has not provided additional information regarding specific lifestyle habits such as diet or physical activity.

Plans and Procedures

The clinical trial is designed as a **Phase I/II** study to evaluate the investigational drug **NMS-03592088**, a **FLT3, KIT, and CSF1R inhibitor**, in patients with relapsed or refractory **Acute Myeloid Leukemia (AML)** or **Chronic Myelomonocytic Leukemia (CMML)**. The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The overall duration of the trial is estimated to extend until June 28, 2025, with recruitment having commenced on April 3, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a confirmed diagnosis of AML or CMML, age of 18 years or older, and an **ECOG performance status** of 2 or less. The trial consists of two phases: Phase I aims to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the recommended Phase II dose (RP2D) of NMS-03592088. This is achieved through oral administration once daily for 21 consecutive days followed by 7 days of rest in a 28-day cycle (Schedule A) or once daily for 28 consecutive days (Schedule B). Phase II focuses on exploring the antitumor activity of NMS-03592088 in patients with **FLT3-ITD** mutated AML.

Study visits will include regular follow-up assessments to monitor drug-related first-cycle dose-limiting toxicities (DLTs) in Phase I and to evaluate the composite complete remission (CRc) rate in Phase II. The end-of-study visit will conclude the participant's involvement, which is expected to last until the trial's completion or until early termination conditions are met. Early termination may occur if participants experience unacceptable toxicity, withdraw consent, or if the investigator deems it necessary for the participant's safety.

Participants are required to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. They must also adhere to strict contraceptive measures due to the potential induction of **CYP3A4** by NMS-03592088. The trial's primary endpoints include the assessment of DLTs in Phase I and the CRc rate in Phase II, with secondary endpoints focusing on additional efficacy and safety measures. The trial is not classified as low intervention, reflecting its comprehensive and rigorous approach to evaluating the investigational drug's potential benefits and risks.

Treatment

The clinical trial involves the administration of the experimental medication **NMS-03592088**, a chemical compound developed by Nerviano Medical Sciences. This investigational drug is formulated as a **hard capsule** and is intended for **oral use**. The study is designed to evaluate the safety and efficacy of NMS-03592088 in patients with relapsed or refractory acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML). The dosing regimen for NMS-03592088 includes two schedules: Schedule A involves administration once daily for 21 consecutive days followed by a 7-day rest period within a 28-day cycle, while Schedule B involves continuous daily administration for 28 consecutive days. The primary objective is to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the recommended Phase II dose (RP2D) of NMS-03592088.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the investigational drug NMS-03592088. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial aims to explore the antitumor activity of NMS-03592088, particularly in patients with FLT3-ITD mutated AML, who have exhausted standard treatment options or for whom standard therapy is deemed unsuitable.

Efficacy

Efficacy in this clinical trial will be assessed using specific primary endpoints tailored to each phase of the study. In Phase I, the primary endpoint is the evaluation of drug-related first-cycle dose limiting toxicities (DLTs). This will help determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the recommended Phase II dose (RP2D) of the investigational drug NMS-03592088. In Phase II, the primary endpoint is the **Composite Complete Remission (CRc) Rate** in patients with FLT3-ITD mutated acute myeloid leukemia (AML). This includes Complete Remission (CR) and Complete Remission with Incomplete Hematologic Recovery (CRi), as defined by the Investigators based on the 2022 European LeukemiaNet (ELN) recommendations.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients with relapsed/refractory disease who have failed standard therapy or are unsuitable for standard treatment, with the following confirmed diagnosis: • AML as defined by the ELN recommendations
Patients with confirmed diagnosis of AML as defined by the 2022 ELN recommendations positive for FLT3-ITD mutation in the BM or PB as determined by central laboratory test performed at study entry. Patients with very rapidly proliferative disease who, in the opinion of the Investigator, cannot wait for the central laboratory results can be enrolled based on a local test performed at study entry. Patients with an allelic ratio ≥ 0.05 will be considered to have FLT3ITD-mutated disease. Patients positive for FLT3- D835 or I836 mutations will not be eligible.
Patients must have failed standard of care including venetoclax and gilteritinib based therapies (cohort 1) or standard of care (cohort 2)
Adult (age >= 18 years) patients
ECOG performance status <= 2
The interval from prior antitumor treatment to time of NMS-03592088 administration should be at least 2 weeks for any agents other than hydroxyurea.
All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTCAE version 5.0 Grade ≤ 1
Adequate hepatic function, as defined by serum transaminases (i.e., AST/ALT) <= 2.5 x ULN, ALP <= 2.5 x ULN and total bilirubin <= 1.5 x ULN unless abnormality considered due to Gilbert’s syndrome (FR: in which case the limit is 2 mg/dL).
Adequate renal function, as defined by serum creatinine  1.5 x ULN and an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min as calculated by the BSA-unadjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, *  (eGFR (mL/min)= eGFR (mL/min/1.73 m2 ) x [BSA (m2)/1.73] where eGFR (mL/min/1.73 m2 ) = 141 x min(Scr/κ,1)α x max(Scr/κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if African American
Patients must use highly effective contraception. Female patients must be surgically sterile or be postmenopausal or must agree to the use of highly effective contraception during the period of therapy and in the following 90 (IT and ES) and 208 (FR) days after discontinuation of study treatment. Since NMS-03592088 has potential induction of CYP3A4, WOCBP must be advised that hormonal contraceptives might lose efficacy and must use alternate form of highly effective contraception. Male patients must be surgically sterile or must agree to use highly effective contraception during the period of therapy and in the following 90 (IT and ES) and 118 (FR) days after discontinuation of study treatment.
Capability to swallow capsules intact (without chewing, crushing, or opening)
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures
Signed and dated IEC or IRB-approved informed consent form indicating that the patient is aware of the neoplastic nature of his/her disease and has been informed of the procedures to be followed, the investigational nature of the therapy, potential benefits, side effects, discomforts, risks and alternative treatments.

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Exclusion Criteria

Current enrollment in another interventional clinical study
Diagnosis of acute promyelocytic leukemia or BCR-ABL-positive leukaemia
Currently active second malignancy, except for adequately treated basal or squamous cell skin cancer and/or cone biopsied in situ carcinoma of the cervix uteri and/or superficial bladder cancer.
Patients with known leukemia involvement of CNS.
Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start and/or persistent nonhematologic toxicities of Grade ≥2 related to the transplant
Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive treatment
Patients with QTcF interval ≥ 480 milliseconds or with risk factors for torsade de pointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history of prolonged QTc interval or family history of long QT syndrome). For patients receiving treatment with concomitant medications known to prolong the QTc interval, replacement with another treatment needs to be considered. If replacement or discontinuation is not clinically feasible, a careful risk/benefit evaluation should be performed prior to enrollment.
Pregnancy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within the screening period prior to start of study drug.
Breast-feeding or planning to breast feed during the study or within 3 months after study treatment.
Known hypersensitivity to any of the components of the NMS-03592088 drug product
Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis
Known active, life threatening or clinically significant uncontrolled systemic infection.
Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) C infection.
Known active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
Known active gastrointestinal ulcer
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
Known diagnosis of myasthenia gravis
France specific: Concomitant anticoagulant use that is not already stabilized therapeutically
France specific: Subjects under legal protection or unable to express their consent; subjects deprived of liberty; subjects who are not members or not beneficiaries of a social security scheme.