Study of NMS-03592088 in Patients With Relapsed or Refractory AML or CMML
- Conditions
- Chronic Myelomonocytic Leukemia (CMML)Acute Myeloid Leukemia (AML)
- Interventions
- Registration Number
- NCT03922100
- Lead Sponsor
- Nerviano Medical Sciences
- Brief 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 200
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description NMS-03592088 NMS-03592088 Phase I Dose Escalation * Schedule A - Starting dose of 20 mg/day * Schedule B - Starting dose of 120 mg/day Only one dose level open for enrollment except EU backfill cohorts. Phase II Dose Expansion (Exploratory) - (EU) Recommended Phase II Dose (RP2D) of NMS-03592088 in Phase 1 * Cohort 1: Patients who have failed standard of care including venetoclax and gilteritinib based therapies * Cohort 2: Patients who have failed standard of care
- Primary Outcome Measures
Name Time Method Phase I - Number of Participants with drug related first-cycle dose limiting toxicities (DLTs) From the date of treatment initiation up to end of Cycle 1 (each Cycle is 28 days) DLTs will be classified according to NCI CTCAE version 5.0.
Phase II FLT3-ITD mut AML: Composite Complete Remission (CRc) Rate From the date of treatment initiation up to end of study (approximately 1.5 years) Defined by the 2022 European LeukemiaNet (ELN) recommendations.
- Secondary Outcome Measures
Name Time Method Maximum plasma concentration (Cmax) of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422: 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) Plasma samples will be collected and used for pharmacokinetics assessments.
Time to maximum plasma concentration (Tmax) of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422: 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) Plasma samples will be collected and used for pharmacokinetics assessments.
Best response rate for participants with AML From the date of treatment initiation up to end of study (approximately 1.5 years) Number and percentage of participants with CR, CRi, CRh, PR, MLFS, SD, No Response and Progressive Disease (PD).
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 Overall Survival (OS) From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first OS is defined as the time from the date of the first dose of study drug until the date of death for any cause.
For AML and in Phase II only: Overall Response Rate (ORR: CRc + CRh + MLFS + PR) From the date of first response up to end of study (approximately 1.5 years) 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.
Best response rate for participants with CMML From the date of treatment initiation up to end of study (approximately 1.5 years) Number and percentage of participants with CR, CCR, PR, MR, CB and PD.
For AML and in Phase II only: Complete Remission (CR) Rate From the date of first response up to end of study (approximately 1.5 years) Defined as the number of patients who achieve a CR as Best Response, divided by the number of participants in the analysis population.
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 Number of participants with Adverse Events (AEs) From the Informed Consent signature to 28 days after the last on-study treatment administration. Safety will be assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.).
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)] 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) Plasma samples will be collected and used for pharmacokinetics assessments.
Time to Response (TTR) From the date of treatment initiation up to end of study (approximately 1.5 years) TTR is defined as the time from the first dose of study drug until the date of first response (CRc or PR).
Duration of Response (DoR) From the date of first response up to end of study (approximately 1.5 years) 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.
Event-Free Survival (EFS) From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first 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.Relapse-free Survival (RFS) From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first 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.Rate of conversion from transfusion-dependence to transfusion-independence From the date of first response up to end of study (approximately 1.5 years) Defined as the proportion of participants being post-baseline transfusion independent from baseline transfusion dependence.
For AML and in Phase II only: Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh) Rate From the date of first response up to end of study (approximately 1.5 years) 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.
Trial Locations
- Locations (11)
Fondazione Policlinico Universitario Agostino Gemelli
🇮🇹Roma, Italy
Hospital Universitari i Politècnic La Fe
🇪🇸Valencia, Spain
Centre Hospitalier du Mans
🇫🇷Le Mans, France
Centre Hospitalier Universitaire de Nantes (CHU de Nantes) - Hotel-Dieu
🇫🇷Nantes, France
CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
🇫🇷Pessac, France
Centre Hospitalier Lyon-Sud
🇫🇷Pierre-Bénite, France
ASST Papa Giovanni XXIII
🇮🇹Bergamo, BG, Italy
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, MI, Italy
Istituto Clinico Humanitas
🇮🇹Rozzano, MI, Italy
Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
🇮🇹Bologna, Italy
ASST Spedali Civili di Brescia
🇮🇹Brescia, Italy