Clinical Trials /

MAX-40279 in Subjects With Acute Myelogenous Leukemia (AML)

NCT03412292

Description:

This is a dose-escalation phase I trial to evaluate the safety and tolerability of MAX-40279 in subjects with acute myelogenous leukemia(AML).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MAX-40279 in Subjects With Acute Myelogenous Leukemia (AML)
  • Official Title: A Phase I Trial of MAX-40279 Given Orally to Subjects With Acute Myelogenous Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: Maxinovel
  • NCT ID: NCT03412292

Conditions

  • Acute Myelogenous Leukemia (AML)

Interventions

DrugSynonymsArms
MAX-40279MAX-40279-001MAX-40279

Purpose

This is a dose-escalation phase I trial to evaluate the safety and tolerability of MAX-40279 in subjects with acute myelogenous leukemia(AML).

Detailed Description

      The class III receptor tyrosine kinase FMS-related tyrosine kinase 3 (FLT3), is mutated and
      activated in about 30% of adult patients with AML. The mutations involve either an internal
      tandem duplication (ITD) (in about 25% of AML patients) or a point mutation in the tyrosine
      kinase domain (TKD) (in about 7% of patients). Patients with mutations in FLT3, particularly
      those with ITD mutations, have a worse prognosis, with lower rate of complete remission, and
      lower overall survival . Thus, inhibition of activated FLT3 kinase by a pharmacologic agent
      is an attractive therapeutic strategy in AML.

      The aberrant of fibroblast growth factor receptor (FGFR) might be a major reason fot
      resistance to targeted therapies, and FGFR inhibitors significantly suppress leukemia
      development in vivo.

      MAX-40279 is a dual inhibitor of FLT3 and FGFR. Our goal is to develpe this uqiue dual
      inhibitor to be a more effective and wider use for AML treatment than the current known FLT3
      inhibitors.
    

Trial Arms

NameTypeDescriptionInterventions
MAX-40279ExperimentalMAX-40279 is provided as a capsule for oral use at 5mg, 25mg. In the dose-escalation phase, patients will be enrolled sequentially into the 5 dose levels of MAX-40279 designated in this study: 20, 40, 70, 100 and 120 mg/day (3-6 patients per cohort),bid.For each dose level, a single dose of MAX-40279 will be first administered orally followed by 1 day observation, then continuous treatment will start 4 weeks treatment (per cycle). After completion of the dose escalation, additional patients will be enrolled into dose expansion at the Maximum tolerated dose(MTD), up to 12 patients will be enrolled into expansion cohorts.
  • MAX-40279

Eligibility Criteria

        Inclusion Criteria:

          1. Males and/or females over age 18

          2. Ability to understand the purposes and risks of the trial and signed informed consent
             forms approved by the investigator's Institutional Review Board (IRB)/Independent
             Ethics Committee (IEC) of the trial site was obtained before the entering the trial

          3. Subject has morphologically documented primary AML or AML secondary to myelodysplastic
             syndrome (MDS) as defined by the World Health Organization (WHO) criteria for which no
             established standard therapy is available

          4. ECOG performance status of 0 to 2

          5. Persistent chronic clinically significant nonhematological toxicities from prior
             treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental
             agents, radiation, HSCT, or surgery) must be Grade ≤ 1

          6. In the absence of rapidly progressing disease clearly documented by the investigator,
             the interval from prior treatment to time of MAX-40279 administration will be at least
             2 weeks (14 days) for prior cytotoxic agents or at least 5 half-lives for prior
             noncytotoxic agents, including immunosuppressive therapy post HSCT

          7. Acceptable liver function defined below:

               -  Total bilirubin ≤ 1.5 times upper limit of normal range (ULN)

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times
                  ULN;

          8. Acceptable renal function defined below:

             • Serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance (by the
             Cockcroft-Gault formula) ≥ 60 mL/min

          9. Acceptable coagulation status defined below:

               -  Prothrombin time < 1.3 times ULN

               -  Partial thrombin time < 1.3 times ULN

         10. No clinically significant abnormalities in urinalysis

         11. Female participants of child bearing potential agree not to be pregnant or lactating
             during the study and for three months following the last dose of study drug. Both men
             and women of reproductive potential must agree to use a highly effective method of
             birth control during the study and for three months following the last dose of study
             drug. A highly effective method of contraception is defined as one that results in a
             low failure rate, i.e., less than 1% per year, when used consistently and correctly

        Exclusion Criteria:

          1. Disease diagnosis of acute promyelocytic leukemia

          2. Previously treated malignancies other than the current disease, except for adequately
             treated non-melanoma skin cancer, in situ cancer, or other cancer from which the
             subject has been disease-free for at least 5 years at the trial entry

          3. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
             therapy

          4. Major surgery, other than diagnostic surgery, within 4 weeks prior to the trial entry,
             without complete recovery

          5. Percutaneous coronary intervention conducted within 6 months prior to the trial entry
             for cardiac infarction or angina pectoris

          6. Seizure disorders requiring anticonvulsant therapy

          7. Taking a medication that prolongs QT interval and has a risk of Torsades de Pointes,or
             a history of long QT syndrome

          8. Medical history of difficulty swallowing, malabsorption or other chronic
             gastrointestinal disease, or conditions that may hamper compliance and/or absorption
             of the tested product

          9. Participation in an investigational drug or device trial within 4 weeks prior to the
             trial entry

         10. Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C

         11. Recent venous thrombosis (including deep vein thrombosis or pulmonary embolism within
             1 year of study)

         12. History of upper gastrointestinal hemorrhage, peptic ulcer disease, or bleeding
             diathesis

         13. Subject is pregnant (positive serum beta human chorionic gonadotropin [β-HCG] test at
             screening) or is currently breast-feeding, their partner anticipates becoming
             pregnant/impregnating during the trial or within 6 months after receiving the last
             dose of trial treatment

         14. Concomitant disease or condition that could interfere with the conduct of the trial,
             or that would, in the opinion of the Investigator, pose an unacceptable risk to the
             subject in this trial

         15. Unwillingness or inability to comply with the trial protocol for any reason

         16. Legal incapacity or limited legal capacity

         17. Cardiac disease with New York Heart Association (NYHA) Class III or IV, including
             congestive heart failure, myocardial infarction within 6 months prior to the trial
             entry, unstable arrhythmia, or symptomatic peripheral arterial vascular
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse events (AEs)
Time Frame:8 weeks
Safety Issue:
Description:Incidence of treatment-related AEs

Secondary Outcome Measures

Measure:Tmax
Time Frame:First single dose(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 1 (the second dose)(pre-dose),Cycle 1 Day 15(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 28(pre-dose), Cycle 2 Day 28(pre-dose).
Safety Issue:
Description:Time to maximum plasma concentration
Measure:Cmax
Time Frame:First single dose(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 1 (the second dose)(pre-dose),Cycle 1 Day 15(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 28(pre-dose), Cycle 2 Day 28(pre-dose).
Safety Issue:
Description:Maximum plasma drug concentration
Measure:AUC
Time Frame:First single dose(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 1 (the second dose)(pre-dose),Cycle 1 Day 15(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 28(pre-dose), Cycle 2 Day 28(pre-dose).
Safety Issue:
Description:Area under the time-concentration curve
Measure:t1/2
Time Frame:First single dose(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 1 (the second dose)(pre-dose),Cycle 1 Day 15(pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24h post-dose), Cycle 1 Day 28(pre-dose), Cycle 2 Day 28(pre-dose).
Safety Issue:
Description:Observed terminal half-life
Measure:p-FLT3 Y591
Time Frame:First single dose(pre-dose), Cycle 1 Day 15(pre-dose), Cycle 1 Day 28(pre-dose), Cycle 2 Day 28(pre-dose).
Safety Issue:
Description:To examine the phosphorylation (activation) of either wild-type or mutated Fms-like Tyrosine Kinase-3(FLT3)
Measure:FGFR aberration
Time Frame:First single dose(pre-dose), Cycle 1 Day 15(pre-dose), Cycle 1 Day 28(pre-dose), Cycle 2 Day 28(pre-dose).
Safety Issue:
Description:To detect Fibroblast growth factor receptor(FGFR) mutation

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Maxinovel Pty., Ltd.

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