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NTX-301 in MDS/AML

Primary Purpose

Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
NTX-301
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

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

Inclusion Criteria:

  1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure.
  2. Men or women ≥18 years with one of the following conditions that is relapsed or refractory to at least one line of therapy:

    1. Acute myeloid leukemia as long as with myeloblast percentage in the marrow is ≤ 30% or the peripheral white blood cell count is less than 20,000 cells/μL in the absence of leukoreducing therapy (e.g., hydroxyurea, leukapheresis)
    2. MDS classified as intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria
    3. CMML classified as intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) criteria
  3. ECOG performance status of 0, 1, or 2
  4. Adequate organ function at screening defined as follows [reasonably minor changes pre-first dose are acceptable if deemed so by the investigator]:

    a) Hepatic:

    • Total bilirubin ≤2 × upper limit of normal (ULN); isolated bilirubin > 2 is acceptable if participant has a diagnosis of Gilbert's syndrome
    • Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤3 × ULN.

      b) Renal:

    • estimated glomerular filtration rate (by CKD-EPI method) ≥ 40 mL/min/1.73 m2 c) Cardiac:
    • Left ventricular ejection fraction greater than 45% or the institutional lower limit of normal by either ECHO or MUGA at entry.
  5. Patients must have recovered to grade 1 or less from prior toxicity or adverse events (exception of myelosuppression - neutropenia, anemia, thrombocytopenia - and alopecia). Note: Participants with treatment-related toxicities that are unlikely to resolve per the investigator may be enrolled on a case-by-case basis after discussion with the medical monitor
  6. Patients must have completed any chemotherapy, radiation therapy, or biologic therapy specific to their myeloid neoplasm ≥ 2 weeks or 5 half-lives (whichever is longer)
  7. Able to swallow, retain, and absorb orally administered medication
  8. Expected life ≥ 4 months
  9. Participants with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if all of the following are met:

    • 90 days or more have elapsed from the time of transplant
    • subject has been off systemic immunosuppressive medications (including but not limited to: cyclosporine, tacrolimus, mycophenolate mofetil, or corticosteroids) for at least 30 days prior to the first dose of NTX-301. Topical steroids are permitted
    • no signs or symptoms of acute graft versus host disease, other than Grade 1 skin involvement.
    • there are no signs or symptoms of chronic graft versus host disease requiring systemic therapy
  10. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG], CTFG 2014) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. A woman is considered of childbearing potential (ie, fertile) following menarche and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
  11. Subjects and their partners with reproductive potential must agree to use 2 highly effective contraceptive measures during the study and must agree not to become pregnant or father a child for 3 months after the last dose of study treatment. Contraceptive measures that may be considered highly effective comprise combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence, and surgically successful vasectomy. Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of birth control.

Exclusion Criteria:

  1. Diagnosis or presence of any of the following:

    • acute promyelocytic leukemia
    • core-binding factor AML in first relapse
    • extramedullary leukemia
    • symptomatic or untreated Central Nervous System (CNS) disease [note that lumbar puncture (LP) is not required for study enrollment unless there is clinical suspicion for CNS disease; patients with history of CNS disease are permitted to enroll if they have previously received appropriate therapy and CNS remission has been; participants on maintenance intrathecal chemotherapy may be enrolled and continue to receive therapy]
  2. Patients who are receiving any other investigational agents.
  3. Pregnant women and women who are breastfeeding are excluded from this study.
  4. Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to:

    • severe or uncontrolled infection
    • known HIV infection requiring protease inhibitor therapy
    • known Hepatitis B; defined as presence of hepatitis B surface antigen (HBsAg)
    • known Hepatitis C; if Hepatitis C antibody is positive, then this is defined as positive Hepatitis C RNA polymerase chain reaction (PCR) (or comparable test)
    • uncontrolled diabetes and/or hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements in the opinion of the investigator
    • Malabsorption syndrome or other conditions that would interfere with intestinal absorption.
  5. History of a second malignancy, excluding non-melanoma skin cell cancer, within the last three years. Participants with second malignancies that were indolent, in situ or definitively treated may be enrolled even if less than three years have elapsed since treatment. Consult the monitor if there are any queries.
  6. History of prior solid organ transplant
  7. History of prior sensitivity reaction to any cytidine derivates

Sites / Locations

  • University of Alabama at BirminghamRecruiting
  • Medical College of WisconsinRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

NTX-301

Arm Description

Outcomes

Primary Outcome Measures

Safety/tolerability: Incidence of treatment related adverse events (AEs) and dose-limiting toxicities (DLTs)

Secondary Outcome Measures

Efficacy: Clinical Benefit Rate (CBR)
Clinical Benefit Rate (CBR), as defined as the percentage of participants achieving a complete remission (CR), complete marrow remission (mCR), partial remission (PR), stable disease (SD) lasting at least 8 weeks, or hematologic improvement (HI), per International Working Group (IWG) criteria.
Efficacy: Overall response rate (ORR)
Overall response rate (ORR), defined as the percentage of participants achieving a CR, mCR, or PR, per IWG criteria.
Efficacy: Progression free survival (PFS)
Progression free survival (PFS), defined as time from first dose to disease progression, as defined by IWG criteria, or death due to any cause, whichever occurs earlier.
Efficacy: Overall survival (OS)
Overall survival (OS), defined as time from first dose to death due to any cause.
Pharmacodynamics (PD): Global methylation (assay) in blood and/or marrow leukemia samples
Pharmacokinetics (PK): Area under the curve (AUC)
Pharmacokinetics (PK): Maximum plasma concentration (Cmax)
Pharmacokinetics (PK): Time to reach maximum concentration (Tmax)
Pharmacokinetics (PK): Half life (t1/2)

Full Information

First Posted
November 12, 2019
Last Updated
August 7, 2023
Sponsor
University of Alabama at Birmingham
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1. Study Identification

Unique Protocol Identification Number
NCT04167917
Brief Title
NTX-301 in MDS/AML
Official Title
A Phase 1 Study of NTX-301, an Oral DNMT1 Inhibitor, in Patients With MDS and AML
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 6, 2021 (Actual)
Primary Completion Date
December 31, 2027 (Anticipated)
Study Completion Date
March 31, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham

4. Oversight

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

5. Study Description

Brief Summary
NTX-301 is a DNMT1 inhibitor. The drug is an oral drug with preclinical data that has shown preclinical anti-leukemic efficacy. This is the first clinical trial using NTX-301 in patients with myeloid malignancies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
NTX-301
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
NTX-301
Intervention Description
oral hypomethylating agent
Primary Outcome Measure Information:
Title
Safety/tolerability: Incidence of treatment related adverse events (AEs) and dose-limiting toxicities (DLTs)
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Efficacy: Clinical Benefit Rate (CBR)
Description
Clinical Benefit Rate (CBR), as defined as the percentage of participants achieving a complete remission (CR), complete marrow remission (mCR), partial remission (PR), stable disease (SD) lasting at least 8 weeks, or hematologic improvement (HI), per International Working Group (IWG) criteria.
Time Frame
3 years
Title
Efficacy: Overall response rate (ORR)
Description
Overall response rate (ORR), defined as the percentage of participants achieving a CR, mCR, or PR, per IWG criteria.
Time Frame
3 years
Title
Efficacy: Progression free survival (PFS)
Description
Progression free survival (PFS), defined as time from first dose to disease progression, as defined by IWG criteria, or death due to any cause, whichever occurs earlier.
Time Frame
3 years
Title
Efficacy: Overall survival (OS)
Description
Overall survival (OS), defined as time from first dose to death due to any cause.
Time Frame
3 years
Title
Pharmacodynamics (PD): Global methylation (assay) in blood and/or marrow leukemia samples
Time Frame
3 years
Title
Pharmacokinetics (PK): Area under the curve (AUC)
Time Frame
3 years
Title
Pharmacokinetics (PK): Maximum plasma concentration (Cmax)
Time Frame
3 years
Title
Pharmacokinetics (PK): Time to reach maximum concentration (Tmax)
Time Frame
3 years
Title
Pharmacokinetics (PK): Half life (t1/2)
Time Frame
3 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure. Men or women ≥18 years with one of the following conditions that is relapsed or refractory to at least one line of therapy: Acute myeloid leukemia as long as with myeloblast percentage in the marrow is ≤ 30% or the peripheral white blood cell count is less than 20,000 cells/μL in the absence of leukoreducing therapy (e.g., hydroxyurea, leukapheresis) MDS classified as intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria CMML classified as intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) criteria ECOG performance status of 0, 1, or 2 Adequate organ function at screening defined as follows [reasonably minor changes pre-first dose are acceptable if deemed so by the investigator]: a) Hepatic: Total bilirubin ≤2 × upper limit of normal (ULN); isolated bilirubin > 2 is acceptable if participant has a diagnosis of Gilbert's syndrome Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤3 × ULN. b) Renal: estimated glomerular filtration rate (by CKD-EPI method) ≥ 40 mL/min/1.73 m2 c) Cardiac: Left ventricular ejection fraction greater than 45% or the institutional lower limit of normal by either ECHO or MUGA at entry. Patients must have recovered to grade 1 or less from prior toxicity or adverse events (exception of myelosuppression - neutropenia, anemia, thrombocytopenia - and alopecia). Note: Participants with treatment-related toxicities that are unlikely to resolve per the investigator may be enrolled on a case-by-case basis after discussion with the medical monitor Patients must have completed any chemotherapy, radiation therapy, or biologic therapy specific to their myeloid neoplasm ≥ 2 weeks or 5 half-lives (whichever is longer) Able to swallow, retain, and absorb orally administered medication Expected life ≥ 4 months Participants with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if all of the following are met: 90 days or more have elapsed from the time of transplant subject has been off systemic immunosuppressive medications (including but not limited to: cyclosporine, tacrolimus, mycophenolate mofetil, or corticosteroids) for at least 30 days prior to the first dose of NTX-301. Topical steroids are permitted no signs or symptoms of acute graft versus host disease, other than Grade 1 skin involvement. there are no signs or symptoms of chronic graft versus host disease requiring systemic therapy Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG], CTFG 2014) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. A woman is considered of childbearing potential (ie, fertile) following menarche and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Subjects and their partners with reproductive potential must agree to use 2 highly effective contraceptive measures during the study and must agree not to become pregnant or father a child for 3 months after the last dose of study treatment. Contraceptive measures that may be considered highly effective comprise combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence, and surgically successful vasectomy. Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of birth control. Exclusion Criteria: Diagnosis or presence of any of the following: acute promyelocytic leukemia core-binding factor AML in first relapse extramedullary leukemia symptomatic or untreated Central Nervous System (CNS) disease [note that lumbar puncture (LP) is not required for study enrollment unless there is clinical suspicion for CNS disease; patients with history of CNS disease are permitted to enroll if they have previously received appropriate therapy and CNS remission has been; participants on maintenance intrathecal chemotherapy may be enrolled and continue to receive therapy] Patients who are receiving any other investigational agents. Pregnant women and women who are breastfeeding are excluded from this study. Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to: severe or uncontrolled infection known HIV infection requiring protease inhibitor therapy known Hepatitis B; defined as presence of hepatitis B surface antigen (HBsAg) known Hepatitis C; if Hepatitis C antibody is positive, then this is defined as positive Hepatitis C RNA polymerase chain reaction (PCR) (or comparable test) uncontrolled diabetes and/or hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements in the opinion of the investigator Malabsorption syndrome or other conditions that would interfere with intestinal absorption. History of a second malignancy, excluding non-melanoma skin cell cancer, within the last three years. Participants with second malignancies that were indolent, in situ or definitively treated may be enrolled even if less than three years have elapsed since treatment. Consult the monitor if there are any queries. History of prior solid organ transplant History of prior sensitivity reaction to any cytidine derivates
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Pankit Vachhani, MD
Phone
205-975-7850
Email
pvachhani@uabmc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Pam Hardwick, RN, OCN, CCRP
Phone
205-975-5387
Email
pamdixon@uab.edu
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pankit Vachhani, MD
Phone
205-975-7850
Email
pvachhani@uabmc.edu
First Name & Middle Initial & Last Name & Degree
Pam Hardwick, RN, OCN
Phone
205-975-5387
Email
pamdixon@uab.edu
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Guru Murthy, M.D.
Phone
414-805-2662
Email
gmurthy@mcw.edu
First Name & Middle Initial & Last Name & Degree
Hasan Abbas
Phone
414-805-2662
Email
habbas@mcw.edu

12. IPD Sharing Statement

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NTX-301 in MDS/AML

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