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

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

Detailed Description
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This is an open-label Phase I/II, first-in-human, multi-center clinical study in sequential cohorts of patients with relapsed or refractory AML or CMML who have exhausted standard treatment options or for whom standard therapy is considered unsuitable. The study is designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and to explore anticancer activity of NMS-03592088, a FLT3 (Fms-like tyrosine kinase 3), KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog ) and CSF1R (Colony stimulating factor-1 receptor) inhibitor. The study drug will be administered orally once daily for 21 consecutive days followed by 7 days of rest (each cycle is 28 days, schedule A) or once daily for 28 consecutive days (each cycle is 28 days, schedule B). The study will be conducted in two parts: a Phase I dose escalation and dose expansion part including patients with AML and CMML and a single-stage Phase II exploratory study comprising two parallel cohorts of selected patients that are more likely to respond to the drug: a cohort of AML FLT3 mutated patients and a second one of patients with CMML. Patients previously treated with FLT3 inhibitors are allowed to participate.

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

Conditions
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Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML)

Intervention / Treatment
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* Drug: NMS-03592088


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I: 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 2017 European LeukemiaNet (ELN) recommendations CMML as defined by the World Health Organization (WHO) criteria. Phase II: Cohort 1 (FLT3 mut AML): Patients with confirmed diagnosis of AML as defined by the 2017 ELN recommendations positive for FLT3 internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD) point mutations in the bone marrow (BM) or peripheral blood (PB) as determined by the local standard test performed at study entry. Patients with an allelic frequency ≥10% will be considered to have FLT3-ITD-mutated disease. Patients must be refractory to at least 1 cycle of induction chemotherapy or relapsed after achieving remission with a prior therapy or unsuitable to receive standard therapy due to age, comorbidities or other factors. Prior treatment with a FLT3 inhibitor is allowed. Cohort 2 (CMML): • Patients with confirmed diagnosis of CMML, as defined by WHO criteria who have failed previous therapies or are unsuitable to receive standard therapy due to age, comorbidities or other factors. Applying to both Phase I and Phase II: Adult (age > or = 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 function. Adequate renal function. Patients must use effective contraception. Female patients must be surgically sterile or be postmenopausal, or must agree to the use of effective contraception during the period of therapy and in the following 90 days after discontinuation of study treatment. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy and in the following 90 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 Institutional Review Board/Ethic Committee (IRB/EC)-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. Exclusion Criteria: Current enrollment in another interventional clinical study Diagnosis of acute promyelocytic leukemia or breakpoint cluster region-Abelson (BCR-ABL)-positive leukemia 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 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 (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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is an open-label Phase I/II, first-in-human (FIH), non-randomized, multi-center study that will be conducted in two parts: a Phase I dose escalation including patients with AML and CMML and a single-stage Phase II exploratory study comprising two parallel cohorts of selected patients that are more likely to respond to the drug: a cohort of AML FLT3 mutated patients and a cohort of patients with CMML.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation and Expansion (Phase I)<br>Dose escalation will be applied until one patient experiences first cycle DLT (Dose Limiting Toxicity) or 2 patients at any dose level experience non-DLT NCI CTCAE Grade ≥2 drug-related toxicity during the first cycle. Once the Maximum Tolerated Dose (MTD) is identified, a maximum of 10 additional patients will be enrolled (dose expansion). | Drug: NMS-03592088<br>* NMS-03592088 will be administered orally once daily for 21 or 28 consecutive days of each treatment cycle. A treatment cycle will comprise 21 days of NMS-03592088 administration (Day 1 to 21) followed by 7 days of rest for a total of 28 days (4 weeks) period for Schedule A and 28 days of NMS-03592088 administration (Day 1 to 28) for a total of 28 days (4 weeks) period for Schedule B.<br>|
| Experimental: AML FLT3 mutated (Phase II)<br>Cohort of AML FLT3 mutated patients. NMS-03592088 will be administered at the recommended Phase II dose (RP2D) defined in Phase I part. | Drug: NMS-03592088<br>* NMS-03592088 will be administered orally once daily for 21 or 28 consecutive days of each treatment cycle. A treatment cycle will comprise 21 days of NMS-03592088 administration (Day 1 to 21) followed by 7 days of rest for a total of 28 days (4 weeks) period for Schedule A and 28 days of NMS-03592088 administration (Day 1 to 28) for a total of 28 days (4 weeks) period for Schedule B.<br>|
| Experimental: CMML (Phase II)<br>Cohort of patients with CMML. NMS-03592088 will be administered at the recommended Phase II dose (RP2D) defined in Phase I part. | Drug: NMS-03592088<br>* NMS-03592088 will be administered orally once daily for 21 or 28 consecutive days of each treatment cycle. A treatment cycle will comprise 21 days of NMS-03592088 administration (Day 1 to 21) followed by 7 days of rest for a total of 28 days (4 weeks) period for Schedule A and 28 days of NMS-03592088 administration (Day 1 to 28) for a total of 28 days (4 weeks) period for Schedule B.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Number of Participants with drug related first-cycle dose limiting toxicities (DLTs) | DLT is defined as any grade ≥3 non-hematologic toxicity occurring in the first cycle of treatment for which the relationship to NMS-03592088 cannot be definitely excluded, with the exception of: alopecia, anorexia, fatigue; grade 3 infection and fever with neutropenia; grade 3 diarrhea or nausea that did not require tube-feeding or total parenteral nutrition, or diarrhea that could be managed to grade 2 or better with standard drugs. Hematological adverse events will not be considered as DLTs. However, prolonged myelosuppresion defined as Grade 4 neutropenia (ANC <500 mm3) after 2-week delay (i.e., 21 days off therapy) in the absence of evidence of active leukemia in the bone marrow or peripheral blood are considered as a DLT. DLTs are classified according to CTCAE version 5.0. | Between the date of the first dose administration in Cycle 1 and the date of the first dose administration in Cycle 2 which is expected to be 28 days or up to 42 days in case of dose delay. | 
| Phase II - FLT3 mutated AML - Overall Response Rate (ORR) | Percentage of Participants with Complete Remission (CR) + Incomplete Hematologic Recovery (CRi) + Morphologic Leukemia-free State (MLFS) + Partial Remission (PR). Responses will be assessed according to the ELN guidelines for Acute Myeloid Leukemia (AML). | From first dose of study drug to End of Treatment (up to 9 months of treatment) | 
| Phase II - CMML - Overall Response Rate (ORR) | Percentage of Participants with Complete Remission + Complete Cytogenetic Remission + Partial Remission + Marrow Response + Clinical benefit). Responses will be assessed according to the WHO Criteria for Chronic Myelomonocytic Leukemia (CMML). | From first dose of study drug to End of Treatment (up to 9 months of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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.) if the abnormality induces clinical signs or symptoms, needs active intervention, interruption or discontinuation of the study drug or is medically significant. A treatment-emergent AE is defined as abn AE observed after starting administration of the study drug up to 28 days after last dose of study medication intake. AEs will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 | Adverse Events: From the Informed Consent signature to 28 days after the last on-study treatment administration. | 
| Overall Survival (OS) | The time from the date of the first dose of study drug until the date of death for any cause. For a participant not known to have died by the end of study follow-up, OS will be censored at the date of the last contact OS will be calculated using Kaplan-Meier estimates. | From first dose of study drug up to data cut-off (approximately 18 months) | 
| Time to Response (TTR) | TTR is defined as the time from the first dose of study drug until the date of first response. TTR will be as evaluated for participants who achieved response during treatment, as defined for AML and CMML populations | From first dose of study drug up to data cut-off (approximately 18 months) | 
| Duration of Response | 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. Participants who died without report of relapse will be considered non-events and censored at their last relapse-free disease assessment date. Other participants who will not relapse on study will be considered non-events and censored at the last relapse-free assessment date. Duration of response will be calculated using Kaplan-Meier method and therefore data will be estimated. | From date of first remission up to data cut-off (approximately 18 months) | 
| Relapse-Free Survival (RFS) | Duration of response is defined as the time from the date of first dose of study drug until the date of documented relapse/ Progression Disease of any type, as defined for AML and CMML populations. Participants who died without report of relapse will be considered non-events and censored at their last relapse-free disease assessment date. Other participants who will not relapse on study will be considered non-events and censored at the last relapse-free assessment date. Duration of response will be calculated using Kaplan-Meier method and therefore data will be estimated. | From first dose of study drug up to data cut-off (approximately 18 months) | 
| Composite Complete Remission Rate (CRc; CR+CRi+MLFS) [AML population only] |  | From first dose of study drug to End of Treatment (up to 9 months of treatment) | 
| Clinical Benefit rate (CBR; CRc + PR + Stable Disease) [AML population only] |  | From first dose of study drug to End of Treatment (up to 9 months of treatment) | 
| Maximum concentration (Cmax) of NMS-03592088, NMS-03593860 and NMS-03603422 after single and multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 (schedule A) and at Cycle 1, Cycle 2 and Cycle 3 (schedule B) at different timepoints. Phase II: between predose and 96 hours. | 
| Time to observed Cmax (Tmax) of NMS-03592088, NMS-03593860 and NMS-03603422 after single and multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 (schedule A) and at Cycle 1, Cycle 2 and Cycle 3 (schedule B) at different timepoints. Phase II: between predose and 96 hours. | 
| Area under the concentration-time curve to the last measurable concentration (AUClast) of NMS-03592088, NMS-03593860 and NMS-03603422 after single and multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 (schedule A) and at Cycle 1, Cycle 2 and Cycle 3 (schedule B) at different timepoints. Phase II: between predose and 96 hours. | 
| Terminal elimination half-life (t1/2) of NMS-03592088, NMS-03593860 and NMS-03603422 after multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 at different timepoints, only in schedule A. Phase II: between predose and 96 hours. | 
| Area under the plasma concentration vs. time curve to infinity (AUCinf) of NMS-03592088, NMS-03593860 and NMS-03603422 after multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 at different timepoints, only in schedule A. Phase II: between predose and 96 hours. | 
| Accumulation ratio (Rac) of NMS-03592088, NMS-03593860 and NMS-03603422 after multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 (schedule A) and at Cycle 1, Cycle 2 and Cycle 3 (schedule B) at different timepoints. Phase II: between predose and 96 hours. | 
| Oral plasma clearance (CL/F) of NMS-03592088 after multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 (schedule A) and at Cycle 1, Cycle 2 and Cycle 3 (schedule B) at different timepoints. Phase II: between predose and 96 hours. | 
| Apparent volume of distribution (Vd/F) of NMS-03592088 after multiple doses of NMS-03592088 | Plasma samples will be collected and used for pharmacokinetics assessments. | Phase I: at Cycle 1 (each cycle is 28 days) and Cycle 2 (schedule A) and at Cycle 1, Cycle 2 and Cycle 3 (schedule B) at different timepoints. Phase II: between predose and 96 hours. | 
| Renal clearance of NMS-03592088, NMS-03593860 and NMS-03603422 after multiple doses of NMS-03592088 | In patients enrolled starting from dose level 6 and treated following schedule A, urine will be collected at Day 1 Cycle 1 (predose) and during 24 hour-period after drug intake at Cycle 1, Day 21. In patients enrolled starting from the first dose level and treated following schedule B, urine will be collected at Day 1 Cycle 1 (predose) and during 24 hour-period after drug intake at Cycle 1, Day 28. Samples of urine will be used for pharmacokinetics assessments. | Phase I at Cycle 1 (each cycle is 28 days) (schedule A) and at Cycle 1 and Cycle 2 (schedule B) at different timepoints. |