Clinical trial NCT03922100: Study of NMS-03592088 in Patients With Relapsed or Refractory AML or CMML
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Chronic Myelomonocytic Leukemia (CMML)
Lead sponsor: Nerviano Medical Sciences
Sponsor class: INDUSTRY
First posted: 2019-04-19
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: This is an open-label Phase I/II, first-in-human (FIH), non-randomized, multi-center study conducted in two parts: a Phase I including patients with AML and CMML and a Phase II exploratory study comprising two parallel cohorts of AML FLT3 mutated patients.

The Phase II portion of the study is currently being conducted in EU only.
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Phase I - Number of Participants with drug related first-cycle dose limiting toxicities (DLTs)
timeFrame: From the date of treatment initiation up to end of Cycle 1 (each Cycle is 28 days)
measure: Phase II FLT3-ITD mut AML: Composite Complete Remission (CRc) Rate
timeFrame: From the date of treatment initiation up to end of study (approximately 1.5 years)
Secondary outcomes:
measure: Number of participants with Adverse Events (AEs)
timeFrame: From the Informed Consent signature to 28 days after the last on-study treatment administration.
measure: Maximum plasma concentration (Cmax) of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422:
timeFrame: 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)
measure: Time to maximum plasma concentration (Tmax) of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422:
timeFrame: 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)
measure: 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)]
timeFrame: 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)
measure: Renal clearance of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422 excreted in urine (only Phase I)
timeFrame: Timepoints up to 24-hours post dose
measure: Fraction of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422 excreted in urine (only Phase I)
timeFrame: Timepoints up to 24-hours post dose
measure: Best response rate for participants with AML
timeFrame: From the date of treatment initiation up to end of study (approximately 1.5 years)
measure: Best response rate for participants with CMML
timeFrame: From the date of treatment initiation up to end of study (approximately 1.5 years)
measure: Overall Survival (OS)
timeFrame: From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first
measure: Time to Response (TTR)
timeFrame: From the date of treatment initiation up to end of study (approximately 1.5 years)
measure: Duration of Response (DoR)
timeFrame: From the date of first response up to end of study (approximately 1.5 years)
measure: Event-Free Survival (EFS)
timeFrame: From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first
measure: Relapse-free Survival (RFS)
timeFrame: From the date of treatment initiation until death or up to 1.5 years from patient's first dose, whichever comes first
measure: For AML and in Phase II only: Complete Remission (CR) Rate
timeFrame: From the date of first response up to end of study (approximately 1.5 years)
measure: For AML and in Phase II only: Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh) Rate
timeFrame: From the date of first response up to end of study (approximately 1.5 years)
measure: For AML and in Phase II only: Overall Response Rate (ORR: CRc + CRh + MLFS + PR)
timeFrame: From the date of first response up to end of study (approximately 1.5 years)
measure: Rate of conversion from transfusion-dependence to transfusion-independence
timeFrame: From the date of first response up to end of study (approximately 1.5 years)
Other outcomes:
Locations:
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes (CHU de Nantes) - Hotel-Dieu
city: Pessac
country: France
facility: CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon-Sud
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
state: BG
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
state: MI
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
Study officials:
affiliation: ASST Papa Giovanni XXIII
name: Alessandro Rambaldi, MD
role: PRINCIPAL_INVESTIGATOR
References: