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

  • STATUS
    Recruiting
  • participants needed
    140
  • sponsor
    Nerviano Medical Sciences
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Updated on 3 February 2022
See if I qualify
remission
tyrosine
hydroxyurea
chronic myelomonocytic leukemia
induction chemotherapy
refractory acute myeloid leukemia (aml)
flt3 internal tandem duplication

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).

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.

Details
Condition Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML)
Treatment NMS-03592088
Clinical Study IdentifierNCT03922100
SponsorNerviano Medical Sciences
Last Modified on3 February 2022

Eligibility

 Yes No Not Sure

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. 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
\. Eastern Cooperative Oncology Group (ECOG) performance status 2
\. Adult (age > or = 18 years) patients
\. 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

Diagnosis of acute promyelocytic leukemia or breakpoint cluster region-Abelson (BCR-ABL)-positive leukemia
Current enrollment in another interventional clinical study
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
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remission
tyrosine
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induction chemotherapy
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flt3 internal tandem duplication

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