Study of NMS-03592088 in Patients With Relapsed or Refractory AML or CMML

Acute Myeloid Leukemia (AML) Clinical Trial

Official title:

A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients With Relapsed or Refractory AML or CMML

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03922100
• Other study ID #: MKIA-088-001
• Secondary ID: 2018-002793-47
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 3, 2019
• Est. completion date: February 28, 2026

Study information

• Verified date: February 2024
• Source: Nerviano Medical Sciences
• Contact: Anders Elm Pedersen
• Phone: +39 0331-581111
• Email: clinicaltrials[@]nervianoms.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to explore safety, tolerability, including the maximum tolerated dose and the recommended Phase II dose (RP2D), and antitumor activity of NMS-03592088 in adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) or Chronic Myelomonocytic Leukemia (CMML).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: February 28, 2026
• Est. primary completion date: December 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with relapsed/refractory disease who have failed standard therapy or are unsuitable for standard treatment, with one the following confirmed diagnosis: AML as defined by the European LeukemiaNet (ELN)
• Patients with confirmed diagnosis of AML as defined by the 2022 ELN recommendations
• Patients must have failed standard of care.
• Adult (age = 18 years) patients
• Eastern Cooperative Oncology Group (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 and renal function
• Patients must use highly effective contraception.
• Signed and dated IEC or IRB-approved informed consent form.

Exclusion Criteria:

• Current enrollment in another interventional clinical study
• Diagnosis of acute promyelocytic leukemia or Breakpoint cluster region-Abelson (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 central nervous system (CNS)
• Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start and/or persistent non-hematologic 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
• Pregnancy.
• Breast-feeding or planning to breast feed during the study or within 3 months after study treatment.
• 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 active gastrointestinal disease
• Known active gastrointestinal ulcer
• Other severe or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation.
• Known diagnosis of myasthenia gravis

US only:

• Signs or symptoms of myasthenia gravis or stroke during screening
• Patients with myasthenia gravis specific autoantibodies or any known history of myasthenia gravis (MG) autoantibodies at screening window
• Concomitant medications with the potential to cause de novo myasthenia gravis, worsening of myasthenia gravis or cause myasthenia gravis-like symptoms
• Uncontrolled hypertension, atrial fibrillation or flutter, ventricular arrhythmia or receiving treatment for cardiac rhythm disorder or diabetes that is not adequately controlled Other protocol specific inclusion/exclusion criteria may apply

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Chronic Myelomonocytic Leukemia (CMML)
• Leukemia
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile

Intervention

Drug:
• NMS-03592088
Route of administration: Oral

Locations

Country	Name	City	State
France	Centre Hospitalier du Mans	Le Mans
France	Centre Hospitalier Universitaire de Nantes (CHU de Nantes) - Hotel-Dieu	Nantes
France	Hôpital Saint-Antoine	Paris
France	CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque	Pessac
France	Centre Hospitalier Lyon-Sud	Pierre-Bénite
Italy	ASST Papa Giovanni XXIII	Bergamo	BG
Italy	Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi	Bologna
Italy	ASST Spedali Civili di Brescia	Brescia
Italy	Azienda Ospedaliero-Universitaria Careggi	Firenze
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano	MI
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Fondazione Policlinico Universitario Agostino Gemelli	Roma
Italy	Istituto Clinico Humanitas	Rozzano	MI
Italy	Ospedale Le Molinette	Torino
Spain	Catalan Institute of Oncology (ICO)	Badalona
Spain	Hospital San Pedro de Alcántara	Cáceres
Spain	Hospital Universitari i Politècnic La Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Nerviano Medical Sciences

Countries where clinical trial is conducted

France,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase I - Number of Participants with drug related first-cycle dose limiting toxicities (DLTs)	DLTs will be classified according to NCI CTCAE version 5.0.	From the date of treatment initiation up to end of Cycle 1 (each Cycle is 28 days)
Primary	Phase II FLT3-ITD mut AML: Composite Complete Remission (CRc) Rate	Defined by the 2022 European LeukemiaNet (ELN) recommendations.	From the date of treatment initiation up to end of study (approximately 1.5 years)
Secondary	Number of participants with Adverse Events (AEs)	Safety will be assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.).	From the Informed Consent signature to 28 days after the last on-study treatment administration.
Secondary	Maximum plasma concentration (Cmax) of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422:	Plasma samples will be collected and used for pharmacokinetics assessments.	Phase 1 Dose Escalation and Dose Expansion Schedule A: Cycle 1 and Cycle 2 various timepoints; Phase 1 Dose Escalation Schedule B: Cycle 1, 2 and 3 various timepoints; Phase 1 Backfill Cycle 1 and Cycle 2 various timepoints (Each Cycle is 28 days)
Secondary	Time to maximum plasma concentration (Tmax) of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422:	Plasma samples will be collected and used for pharmacokinetics assessments.	Phase 1 Dose Escalation and Dose Expansion Schedule A: Cycle 1 and Cycle 2 various timepoints; Phase 1 Dose Escalation Schedule B: Cycle 1, 2 and 3 various timepoints; Phase 1 Backfill Cycle 1 and Cycle 2 various timepoints (Each Cycle is 28 days)
Secondary	Area under the plasma concentration versus time curve (AUC)] of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422: area under the plasma concentration versus time curve (AUC)]	Plasma samples will be collected and used for pharmacokinetics assessments.	Phase 1 Dose Escalation and Dose Expansion Schedule A: Cycle 1 and Cycle 2 various timepoints; Phase 1 Dose Escalation Schedule B: Cycle 1, 2 and 3 various timepoints; Phase 1 Backfill Cycle 1 and Cycle 2 various timepoints (Each Cycle is 28 days)
Secondary	Renal clearance of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422 excreted in urine (only Phase I)		Timepoints up to 24-hours post dose
Secondary	Fraction of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422 excreted in urine (only Phase I)		Timepoints up to 24-hours post dose
Secondary	Best response rate for participants with AML	Number and percentage of participants with CR, CRi, CRh, PR, MLFS, SD, No Response and Progressive Disease (PD).	From the date of treatment initiation up to end of study (approximately 1.5 years)
Secondary	Best response rate for participants with CMML	Number and percentage of participants with CR, CCR, PR, MR, CB and PD.	From the date of treatment initiation up to end of study (approximately 1.5 years)
Secondary	Overall Survival (OS)	OS is defined as the time from the date of the first dose of study drug until the date of death for any cause.	From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first
Secondary	Time to Response (TTR)	TTR is defined as the time from the first dose of study drug until the date of first response (CRc or PR).	From the date of treatment initiation up to end of study (approximately 1.5 years)
Secondary	Duration of Response (DoR)	Duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse of any type for participants who achieved CRc or PR.	From the date of first response up to end of study (approximately 1.5 years)
Secondary	Event-Free Survival (EFS)	For patients with diagnosis of AML the primary analysis measures the time from the date of treatment initiation to the date of first documentation of disease progression or hematologic relapse after CR/CRh/CRi, treatment failure or death from any cause, whichever comes first.; For patients with CMML, EFS will be defined as the time from treatment start until disease progression, relapse after CR, CCR, PR, MR or CB, treatment failure, or death from any cause, whichever comes first.	From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first
Secondary	Relapse-free Survival (RFS)	For patients with diagnosis of AML in the primary analysis it is measured only for patients achieving CR or CRi, and it is defined as the time from the date of first achievement of a CR/CRi until the date of relapse or death from any cause.; For patients with CMML diagnosis, RFS will be measured from the date of first achievement of CR, CCR, PR, MR or CB until the date of relapse or death from any cause.	From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first
Secondary	For AML and in Phase II only: Complete Remission (CR) Rate	Defined as the number of patients who achieve a CR as Best Response, divided by the number of participants in the analysis population.	From the date of first response up to end of study (approximately 1.5 years)
Secondary	For AML and in Phase II only: Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh) Rate	Defined as the number of patients who achieve a CR or CRh or CRi as best response, divided by the number of participants in the analysis population.	From the date of first response up to end of study (approximately 1.5 years)
Secondary	For AML and in Phase II only: Overall Response Rate (ORR: CRc + CRh + MLFS + PR)	Defined as the number of participants who achieve CR, CRi, CRh, MLFS or PR as best response, divided by the number of participants in the analysis population.	From the date of first response up to end of study (approximately 1.5 years)
Secondary	Rate of conversion from transfusion-dependence to transfusion-independence	Defined as the proportion of participants being post-baseline transfusion independent from baseline transfusion dependence.	From the date of first response up to end of study (approximately 1.5 years)