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

Primary Purpose

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

Status
Unknown status
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
NMS-03592088
Sponsored by
Nerviano Medical Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia (AML)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Phase I:

  1. 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:

  2. 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.
  3. 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:

  4. Adult (age > or = 18 years) patients
  5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  6. The interval from prior antitumor treatment to time of NMS-03592088 administration should be at least 2 weeks for any agents other than hydroxyurea.
  7. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTCAE version 5.0 Grade ≤1
  8. Adequate hepatic function.
  9. Adequate renal function.
  10. 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.
  11. Capability to swallow capsules intact (without chewing, crushing, or opening)
  12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures
  13. 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:

  1. Current enrollment in another interventional clinical study
  2. Diagnosis of acute promyelocytic leukemia or breakpoint cluster region-Abelson (BCR-ABL)-positive leukemia
  3. 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.
  4. Patients with known leukemia involvement of CNS
  5. Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start and/or persistent non-hematologic toxicities of Grade ≥2 related to the transplant.
  6. Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive treatment
  7. 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.
  8. 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.
  9. Breast-feeding or planning to breast feed during the study or within 3 months after study treatment.
  10. Known hypersensitivity to any of the components of the NMS-03592088 drug product.
  11. 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
  12. Known active, life threatening or clinically significant uncontrolled systemic infection.
  13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
  14. Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) C infection.
  15. 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.
  16. Known active gastrointestinal ulcer
  17. 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.

Sites / Locations

  • ASST Papa Giovanni XXIIIRecruiting
  • ASST Grande Ospedale Metropolitano NiguardaRecruiting
  • Istituto Clinico HumanitasRecruiting
  • Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
  • ASST Spedali Civili di BresciaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Dose Escalation and Expansion (Phase I)

AML FLT3 mutated (Phase II)

CMML (Phase II)

Arm Description

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).

Cohort of AML FLT3 mutated patients. NMS-03592088 will be administered at the recommended Phase II dose (RP2D) defined in Phase I part.

Cohort of patients with CMML. NMS-03592088 will be administered at the recommended Phase II dose (RP2D) defined in Phase I part.

Outcomes

Primary Outcome Measures

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.
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).
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).

Secondary Outcome Measures

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
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.
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
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.
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.
Composite Complete Remission Rate (CRc; CR+CRi+MLFS) [AML population only]
Clinical Benefit rate (CBR; CRc + PR + Stable Disease) [AML population only]
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.
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.
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.
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.
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.
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.
Oral plasma clearance (CL/F) of NMS-03592088 after multiple doses of NMS-03592088
Plasma samples will be collected and used for pharmacokinetics assessments.
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.
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.

Full Information

First Posted
April 4, 2019
Last Updated
March 23, 2021
Sponsor
Nerviano Medical Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT03922100
Brief Title
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

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Unknown status
Study Start Date
April 3, 2019 (Actual)
Primary Completion Date
September 30, 2023 (Anticipated)
Study Completion Date
September 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nerviano Medical Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
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)
Allocation
Non-Randomized
Enrollment
140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation and Expansion (Phase I)
Arm Type
Experimental
Arm Description
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).
Arm Title
AML FLT3 mutated (Phase II)
Arm Type
Experimental
Arm Description
Cohort of AML FLT3 mutated patients. NMS-03592088 will be administered at the recommended Phase II dose (RP2D) defined in Phase I part.
Arm Title
CMML (Phase II)
Arm Type
Experimental
Arm Description
Cohort of patients with CMML. NMS-03592088 will be administered at the recommended Phase II dose (RP2D) defined in Phase I part.
Intervention Type
Drug
Intervention Name(s)
NMS-03592088
Intervention Description
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.
Primary Outcome Measure Information:
Title
Phase I - Number of Participants with drug related first-cycle dose limiting toxicities (DLTs)
Description
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.
Time Frame
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.
Title
Phase II - FLT3 mutated AML - Overall Response Rate (ORR)
Description
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).
Time Frame
From first dose of study drug to End of Treatment (up to 9 months of treatment)
Title
Phase II - CMML - Overall Response Rate (ORR)
Description
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).
Time Frame
From first dose of study drug to End of Treatment (up to 9 months of treatment)
Secondary Outcome Measure Information:
Title
Number of participants with Adverse Events (AEs)
Description
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
Time Frame
Adverse Events: From the Informed Consent signature to 28 days after the last on-study treatment administration.
Title
Overall Survival (OS)
Description
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.
Time Frame
From first dose of study drug up to data cut-off (approximately 18 months)
Title
Time to Response (TTR)
Description
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
Time Frame
From first dose of study drug up to data cut-off (approximately 18 months)
Title
Duration of Response
Description
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.
Time Frame
From date of first remission up to data cut-off (approximately 18 months)
Title
Relapse-Free Survival (RFS)
Description
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.
Time Frame
From first dose of study drug up to data cut-off (approximately 18 months)
Title
Composite Complete Remission Rate (CRc; CR+CRi+MLFS) [AML population only]
Time Frame
From first dose of study drug to End of Treatment (up to 9 months of treatment)
Title
Clinical Benefit rate (CBR; CRc + PR + Stable Disease) [AML population only]
Time Frame
From first dose of study drug to End of Treatment (up to 9 months of treatment)
Title
Maximum concentration (Cmax) of NMS-03592088, NMS-03593860 and NMS-03603422 after single and multiple doses of NMS-03592088
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
Time to observed Cmax (Tmax) of NMS-03592088, NMS-03593860 and NMS-03603422 after single and multiple doses of NMS-03592088
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
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
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
Terminal elimination half-life (t1/2) of NMS-03592088, NMS-03593860 and NMS-03603422 after multiple doses of NMS-03592088
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
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
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
Accumulation ratio (Rac) of NMS-03592088, NMS-03593860 and NMS-03603422 after multiple doses of NMS-03592088
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
Oral plasma clearance (CL/F) of NMS-03592088 after multiple doses of NMS-03592088
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
Apparent volume of distribution (Vd/F) of NMS-03592088 after multiple doses of NMS-03592088
Description
Plasma samples will be collected and used for pharmacokinetics assessments.
Time Frame
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.
Title
Renal clearance of NMS-03592088, NMS-03593860 and NMS-03603422 after multiple doses of NMS-03592088
Description
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.
Time Frame
Phase I at Cycle 1 (each cycle is 28 days) (schedule A) and at Cycle 1 and Cycle 2 (schedule B) at different timepoints.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dejan Brkic
Phone
+39.3351351495
Email
dejan.brkic@nervianoms.com
First Name & Middle Initial & Last Name or Official Title & Degree
Lucia Zanetta
Phone
+39 3346014972
Email
lucia.zanetta@nervianoms.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alessandro Rambaldi, MD
Organizational Affiliation
ASST Papa Giovanni XXIII
Official's Role
Principal Investigator
Facility Information:
Facility Name
ASST Papa Giovanni XXIII
City
Bergamo
State/Province
BG
ZIP/Postal Code
24127
Country
Italy
Individual Site Status
Recruiting
Facility Name
ASST Grande Ospedale Metropolitano Niguarda
City
Milano
State/Province
MI
ZIP/Postal Code
20162
Country
Italy
Individual Site Status
Recruiting
Facility Name
Istituto Clinico Humanitas
City
Rozzano
State/Province
MI
ZIP/Postal Code
20089
Country
Italy
Individual Site Status
Recruiting
Facility Name
Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Individual Site Status
Not yet recruiting
Facility Name
ASST Spedali Civili di Brescia
City
Brescia
ZIP/Postal Code
25123
Country
Italy
Individual Site Status
Recruiting

12. IPD Sharing Statement

Learn more about this trial

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

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