Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML)
Conditions
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).
Interventions
DRUGNMS-03592088
Route of administration: Oral
Sponsors
Nerviano Medical Sciences
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I - Number of Participants With Drug Related First-cycle Dose Limiting Toxicities (DLTs) | From screening to end of first 28-days cycle (47 months) | DLTs were classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. |
| Phase II - Number of Participants Who Achieved Composite Complete Remission (CRc) Rate i.e. Complete Remission (CR) + Complete Remission With Incomplete Hematologic Recovery (CRi). | At Screening; Day 1 of Cycle 2 and Cycle 3; and Day 1 at subsequent even cycle; up to End of Treatment visit (within 7 days of the final dose of study drug), up to 17 months | CR = complete remission; CRc = composite complete remission rate; CRh = complete remission with partial hematologic recovery, CRi = complete remission with incomplete hematologic recovery; MLFS = morphologic leukemia free state; ORR = overall response rate; SD = stable disease Categories defined by the 2022 European LeukemiaNet (ELN) recommendations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events (TEAEs) Graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0 Criteria | Adverse events were collected from screening visit and assessed up to 18 months | TEAE with maximum Common Terminology Criteria (CTC) grade (graded by NCI CTCAE Version 5.0) experienced by each participant is presented. If an AE was reported for a participant more than once during treatment, the worst CTC Grade is presented here. Phase 2 started before Phase 1 completed. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. |
| Pharmacokinetic Parameters: Maximum Plasma Concentration (Cmax), Last Measurable Concentration (Clast), and Average Concentration (Cavg) of NMS-03592088 | Schedule A: Day 1 and Day 21 Schedule B: Day 1 and Day 28 | Plasma samples were collected and used for pharmacokinetics assessments. Mean values of PK parameters are presented with the coefficient of variation (CV%) |
| Pharmacokinetic Parameters: Time to Maximum Plasma Concentration (Tmax), Time to Last Measurable Concentration (Tlast), and Terminal Elimination Half-life (t½,z) of NMS-03592088 | Schedule A: Day 1 and 21 Schedule B: Day 1 and 28 | Plasma samples were collected and used for pharmacokinetics (PK) assessments. Mean values of PK parameters are presented with the coefficient of variation (CV%) |
| Pharmacokinetic Parameter: Area Under the Concentration-time Curve to the Last Measurable Concentration (AUClast) and Area Under the Concentration-time Curve From Time Zero to 24 Hour (AUC0-24) of NMS-03592088 | Schedule A: Day 1 and Day 21 Schedule B: Day 1 and Day 28 | Plasma samples were collected and used for pharmacokinetics (PK) assessments. Mean values of PK parameters are presented with the coefficient of variation (CV%) |
| Pharmacokinetic Parameters: Apparent Volume of Distribution (V/F) and Apparent Volume of Distribution at Steady State (Vss/F) | Schedule A: Day 21 | Plasma samples were collected and used for pharmacokinetics (PK) assessments. Mean values of PK parameters are presented with the coefficient of variation (CV%) |
| Pharmacokinetic Parameters: Apparent Plasma Clearance (CL/F) and Apparent Plasma Clearance at Steady State (CLss/F) | Schedule A: Day 1 and Day 21 Schedule B: Day 1 and Day 28 CL/F: Evaluation of CL/F for Day 1 of all arms in Schedule A and Schedule B and Day 28 of Schedule B has not been performed | Plasma samples were collected and used for pharmacokinetics (PK) assessments. Mean values of PK parameters are presented with the coefficient of variation (CV%) |
| Pharmacokinetic Parameters: Accumulation Ratios (RA) for AUC0-24 and Cmax | Schedule A: Day 21 Schedule B: Day 28 Evaluation of Accumulation ratios (RA) for AUC0-24 and Cmax on Day 1 of all arms in Schedule A and Schedule B has not been performed. | Plasma samples were collected and used for pharmacokinetics assessments. Mean values of PK parameters are presented with the coefficient of variation (CV%). |
| Pharmacokinetic Parameters: Fraction Excreted Unchanged (FE) of NMS-03592088 | Schedule A: Day 21 Schedule B: Day 28 Evaluation of Fraction excreted unchanged (FE) for Arms 20, 40, 80, 120 and 180 mg of Schedule A and Arm 360+150 mg of Schedule B has not been performed. | Urine samples were collected and used for pharmacokinetics (PK) assessments. Only cohorts with available data are presented. The assessment was performed only during the Phase I of the study. Mean values of PK parameters are presented with the coefficient of variation (CV%) |
| Best Response Rate for Participants With Acute Myeloblastic Leukemia (AML). | From the date of treatment initiation up to end of study (approximately 1.5 years) | For participants with AML diagnosis the number and percentage of participants with best response achieved on treatment in the following categories: CR, CRi, CRh, PR, MLFS, SD, No Response and Progressive Disease (PD). CR= complete response; CRh= Complete Remission with Partial Hematologic Recovery, CRi= Complete Remission with Incomplete Hematologic Recovery; CRc= Complete Remission Rate; MLFS= Morphologic leukemia free state; ORR= Overall Response Rate; PR= Partial Remission; SD= Stable Disease |
| For AML and in Phase II Only: Number of Participants Who Achieved Complete Remission (CR) | From the date of first response up to end of study (approximately 1.5 years) | Number of participants who achieved a CR as Best Response. |
| 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 participants who achieved a CR or CRh or CRi as best response, divided by the number of participants in the analysis population. |
| 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 achieved CRi or MLFS as best response, divided by the number of participants in the analysis population. |
| Rate of Participants Bridged To Hemopoietic Stem Cell Transplantation | From the date of first response up to end of study (approximately 1.5 years) | Defined as proportion of participants bridged to hemopoietic stem cell transplantation |
Countries
France, Italy, Spain
Contacts
PRINCIPAL_INVESTIGATORAlessandro Rambaldi, MD
ASST Papa Giovanni XXIII
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants |
| (Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS = 0 | 0 participants |
| (Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS = 1 | 3 participants |
| (Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS = 2 | 1 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 9 / 10 | 3 / 3 | 4 / 4 | 6 / 6 | 4 / 4 | 9 / 15 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 10 / 10 | 3 / 3 | 4 / 4 | 6 / 6 | 3 / 4 | 14 / 15 |
| serious Total, serious adverse events | 0 / 3 | 2 / 3 | 2 / 3 | 0 / 3 | 2 / 3 | 3 / 4 | 8 / 10 | 3 / 3 | 4 / 4 | 6 / 6 | 4 / 4 | 14 / 15 |
Outcome results
None listed