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

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ClinicalTrials.gov Identifier: NCT03412292
Recruitment Status : Recruiting
First Posted : January 26, 2018
Last Update Posted : October 1, 2019
Sponsor:
Information provided by (Responsible Party):
Maxinovel Pty., Ltd.

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

Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia (AML) Drug: MAX-40279 Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of MAX-40279 Given Orally to Subjects With Acute Myelogenous Leukemia (AML)
Actual Study Start Date : August 1, 2018
Estimated Primary Completion Date : November 1, 2020
Estimated Study Completion Date : May 1, 2021


Arm Intervention/treatment
Experimental: MAX-40279

MAX-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.

Drug: MAX-40279

MAX-40279, is a multi-targeted kinase inhibitor inhibitor mainly target FLT3 and FGFR. It has a molecular weight of 496.56 Daltons, which has a formula of C24H25FN6O3S.

MAX-40279 is yellow powder. It is insoluble in water, methanol, ethanol, 0.1 mol/L hydrochloride solution or 0.1% saline; very slightly soluble in methylene dichloride and sparingly soluble in dimethylformamide. It is stable under strong acid, strong alkali, high temperatures and exposure to light.

MAX-40279 for clinical use is presented as a sterile yellow powder packaged in capsules at 5 mg, or 25 mg doses.

Other Name: MAX-40279-001




Primary Outcome Measures :
  1. Adverse events (AEs) [ Time Frame: 8 weeks ]
    Incidence of treatment-related AEs

  2. Maximum tolerated dose (MTD) [ Time Frame: 4 weeks ]
    MTD will be defined as the maximum dose level at which no more than 1 of 3 participants experience a dose-limiting toxicity (DLT) within the first 4 weeks of multiple dosing.


Secondary Outcome Measures :
  1. 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). ]
    Time to maximum plasma concentration

  2. 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). ]
    Maximum plasma drug concentration

  3. 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). ]
    Area under the time-concentration curve

  4. 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). ]
    Observed terminal half-life

  5. 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). ]
    To examine the phosphorylation (activation) of either wild-type or mutated Fms-like Tyrosine Kinase-3(FLT3)

  6. 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). ]
    To detect Fibroblast growth factor receptor(FGFR) mutation



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03412292


Contacts
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Contact: Chun Fong, MD +61394965000 chun.fong@austin.org.au
Contact: Hanying Bao, MD,Ph.D +86-021-51370693 hybao@maxinovel.com

Locations
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Australia, New South Wales
St Vincent's Hospital Sydney Limited Recruiting
Darlinghurst, New South Wales, Australia, 2010
Contact: Kent Robert         
Western NSW Local Health District Recruiting
Dubbo, New South Wales, Australia, 2830
Contact: Millard Stephen         
Principal Investigator: Douglas Lenton, DM         
Australia, Victoria
Monash Health Recruiting
Clayton, Victoria, Australia, 3168
Contact: Uhe Micheleine    +6139594 4044      
Principal Investigator: Jake Shortt         
Austin Health Recruiting
Heidelberg, Victoria, Australia, 3084
Contact: Chun Fong         
Sponsors and Collaborators
Maxinovel Pty., Ltd.

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Responsible Party: Maxinovel Pty., Ltd.
ClinicalTrials.gov Identifier: NCT03412292     History of Changes
Other Study ID Numbers: Maxinovel
First Posted: January 26, 2018    Key Record Dates
Last Update Posted: October 1, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms