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Enasidenib in MDS &Non-proliferative Chronic Myelomonocytic Leukemia w/o IDH2 Mutation

Primary Purpose

Leukemia, Leukemia, Myeloid, Monocytic Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Enasidenib mesylat dose escalation
Sponsored by
Tian Yi Zhang
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Leukemia

Eligibility Criteria

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

Inclusion Criteria:

  1. Documented diagnosis of 1) MDS according to WHO/FAB classification that meets IRSS-R classification of very low or lower risk disease; and a diagnosed as de novo or secondary MDS (MDS RS eligible if refractory to or declined luspatercept therapy).

    OR 2) Dysplastic (nonproliferative) CMML with WBC <13.0/microL)

  2. No disease modifying therapy (HMA, hydrea) within 2 months of starting study
  3. Age ≥ 18 years of age
  4. ECOG ≤ 3
  5. Negative for IDH2 mutation by NGS or multiplex PCR (SNaPshot)
  6. Has symptomatic anemia defined as hemoglobin < 10.0 g/dL with any of the following.

    oTachypnea oShortness of breath oFatigue oMalaise oWorsening of cardiovascaular function oAsthenia oDyspnea on exertion oAngina oOther subject symptoms the subject reports as being associated with being anemic.

  7. Stated willingness to comply with all study procedures and availability for the duration of the study
  8. Ability to take oral medication and be willing to adhere to the medication regimen.
  9. Females of reproductive potential need to either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption, 28 days prior to starting enasidenib, during the study therapy, and for 30 days after last dose of enasidenib.
  10. For males of reproductive potential: agreement to use of condoms
  11. Adequate organ function defined as:

    • Hepatic function: total bilirubin <1.5 x ULN (unless attributable to Gilbert's disease), AST or ALT < 3x ULN
    • Renal function: creatinine clearance >30 mL/minute, calculated by Cockcroft-Gault formula
  12. Ability to understand and the willingness to sign the IRB approved informed consent document.
  13. Women of childbearing potential must have negative urine or serum pregnancy test

Exclusion Criteria:

  1. Use of concurrent other erythropoietic agents (including epoetin, darbepoetin), G-CSF within 30 days of study enrollment
  2. Less than 3 months of life expectancy
  3. Treatment with iron chelation therapy within 56 days of study start
  4. Significant cardiac disease (NYHA Class IV congestive heart failure, or unstable angina or myocardial infarction within the last 6 months
  5. Harbor IDH2 somatic mutations by NGS or PCR
  6. Pregnant or breast feeding
  7. Any uncontrolled bacterial, fungal, viral or other infection.
  8. No known HIV+ or active hepatitis B or C infection, defined as positive viral load for HBV or HCV or a positive surface antigen (HBsAg) test for hepatitis B.
  9. Have other causes of anemia: deficiencies in iron, B12, folate; nutritional deficiencies related to gastric surgery, anorexia nervosa, excessive zinc supplementation; gastrointestinal bleed. If nutritional deficiencies can be corrected, potential participant can be rescreened and enrolled if nutritionally replete and still meets eligibility criteria.
  10. Any other medical history, including laboratory results, deemed by the Principal Investigator likely to interfere with their participation in the study, or to interfere with the interpretation of the results

Sites / Locations

  • Stanford Cancer InstituteRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Enasidenib mesylat

Arm Description

Participants will self administer the enasidenib orally everyday.

Outcomes

Primary Outcome Measures

Clinical Response: Hematological Improvement - Erythroid (HI-E)
Clinical response was assessed as the number of participants achieving a hematological improvement - erythroid (HI-E). Participants will be characterized and stratified as nontransfused (NTD), low-transfusion burden (LTB) and high-transfusion burden (HTB), with response defined as follows. NTD = greater than or equal to 2 consecutive Hb measurements, greater than or equal to 1.5 g/dL for a period of minimum 8 week in an observation period of 16 to 24 week compared to the lowest mean of 2 Hb measurements LTB = 0 units of RBC transfusions HTB = greater than or equal to 4 unit or greater than or equal to 50% reduction in RBC transfusions The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Related Adverse Events
Toxicity will be assessed as the number of related non serious adverse events and related serious adverse events (SAEs) reported for the 12 cycle treatment period plus follow up. The outcome will be reported as numbers without dispersion.
Time to Hematological Improvement - Erythroid (HI-E)
Time to hematological improvement - erythroid (HI-E) will be assessed as the time from first dose of enasidenib to the first observed hemoglobin response. Participants will be characterized and stratified as nontransfused (NTD), low-transfusion burden (LTB) and high-transfusion burden (HTB), with response defined as follows. NTD = greater than or equal to 2 consecutive Hb measurements, greater than or equal to 1.5 g/dL for a period of minimum 8 week in an observation period of 16 to 24 week compared to the lowest mean of 2 Hb measurements LTB = 0 units of RBC transfusions HTB = greater than or equal to 4 unit or greater than or equal to 50% reduction in RBC transfusions The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Duration of Hematological Improvement - Erythroid (HI-E)
Duration of Hematological Improvement - Erythroid (HI-E) will be assessed as the time from recorded response to loss of response. Participants will be characterized and stratified as nontransfused (NTD), low-transfusion burden (LTB) and high-transfusion burden (HTB), with response defined as follows. NTD = greater than or equal to 2 consecutive Hb measurements, greater than or equal to 1.5 g/dL for a period of minimum 8 week in an observation period of 16 to 24 week compared to the lowest mean of 2 Hb measurements LTB = 0 units of RBC transfusions HTB = greater than or equal to 4 unit or greater than or equal to 50% reduction in RBC transfusions The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Clinical Response: Hematological Improvement - Platelets (HI-P)
Clinical response for platelets was assessed as the number of participants achieving a hematological improvement - platelets (HI-P). Participants will be characterized and stratified as platelets < or ≥ 20 x 10^9/L, with response defined as follows. < 20 x 10^9/L = increase in platelets from < 20 x 10^9/L to > 20 x 10^9/L AND by ≥ 100% ≥ 20 x 10^9/L = absolute increase in platelets of 30 x 10^9/L The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Clinical Response: Hematological Improvement - Neutrophils (HI-N)
Clinical response for neutrophils was assessed as the number of participants achieving a hematological improvement - neutrophils (HI-N). Response defined as an absolute increase in neutrophils > 0.5 x 10^9/L that is also an increase of ≥ 100%. The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Red Blood Cell (RBC) transfusion independence (RBC TI)
Clinical response for red blood cells was assessed as the number of participants who were transfusion dependent that achieve red blood cell (RBC) transfusion independence (RBC TI) for for 8 weeks or longer. The outcome will be reported as the number of participants that achieve the response, a number without dispersion.

Secondary Outcome Measures

Full Information

First Posted
March 7, 2022
Last Updated
April 10, 2023
Sponsor
Tian Yi Zhang
Collaborators
Celgene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT05282459
Brief Title
Enasidenib in MDS &Non-proliferative Chronic Myelomonocytic Leukemia w/o IDH2 Mutation
Official Title
A Phase Ib/II, Single Center, Open-Label, Safety and Efficacy Study to Improve Anemia in Subjects on Enasidenib With Lower Risk Myelodysplastic Syndrome and Non-proliferative Chronic Myelomonocytic Leukemia Without an IDH2 Mutation
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 12, 2022 (Actual)
Primary Completion Date
January 2024 (Anticipated)
Study Completion Date
January 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Tian Yi Zhang
Collaborators
Celgene Corporation

4. Oversight

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

5. Study Description

Brief Summary
This is a phase 1b/2, open-label, single arm study to evaluate if enasidenib is safe and effective in improving anemia and decreasing transfusion needs in subjects diagnosed with lower risk myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML) without a mutation in isocitrate dehydrogenase type 2 (IDH2 wildtype). Other objectives include assessment of improvements in platelet production and characterization of the mechanism of action of enasidenib in enhancing endogenous erythropoiesis.
Detailed Description
Primary Objective(s)- To determine the efficacy (response rate) of enasidenib in improving anemia and decreasing RBC transfusion dependence. Secondary Objective(s)- To determine the tolerability, safety and durability of the erythroid response and identify laboratory parameters as clinical markers of response.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Leukemia, Myeloid, Monocytic Leukemia

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Enasidenib mesylat
Arm Type
Experimental
Arm Description
Participants will self administer the enasidenib orally everyday.
Intervention Type
Drug
Intervention Name(s)
Enasidenib mesylat dose escalation
Other Intervention Name(s)
(Idhifa, AG 221)
Intervention Description
Subjects will participate dose escalation with a starting dose of 100 mg. Enasidenib will be self administered orally and daily.
Primary Outcome Measure Information:
Title
Clinical Response: Hematological Improvement - Erythroid (HI-E)
Description
Clinical response was assessed as the number of participants achieving a hematological improvement - erythroid (HI-E). Participants will be characterized and stratified as nontransfused (NTD), low-transfusion burden (LTB) and high-transfusion burden (HTB), with response defined as follows. NTD = greater than or equal to 2 consecutive Hb measurements, greater than or equal to 1.5 g/dL for a period of minimum 8 week in an observation period of 16 to 24 week compared to the lowest mean of 2 Hb measurements LTB = 0 units of RBC transfusions HTB = greater than or equal to 4 unit or greater than or equal to 50% reduction in RBC transfusions The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Time Frame
16 weeks
Title
Related Adverse Events
Description
Toxicity will be assessed as the number of related non serious adverse events and related serious adverse events (SAEs) reported for the 12 cycle treatment period plus follow up. The outcome will be reported as numbers without dispersion.
Time Frame
12 months
Title
Time to Hematological Improvement - Erythroid (HI-E)
Description
Time to hematological improvement - erythroid (HI-E) will be assessed as the time from first dose of enasidenib to the first observed hemoglobin response. Participants will be characterized and stratified as nontransfused (NTD), low-transfusion burden (LTB) and high-transfusion burden (HTB), with response defined as follows. NTD = greater than or equal to 2 consecutive Hb measurements, greater than or equal to 1.5 g/dL for a period of minimum 8 week in an observation period of 16 to 24 week compared to the lowest mean of 2 Hb measurements LTB = 0 units of RBC transfusions HTB = greater than or equal to 4 unit or greater than or equal to 50% reduction in RBC transfusions The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Time Frame
16 weeks.
Title
Duration of Hematological Improvement - Erythroid (HI-E)
Description
Duration of Hematological Improvement - Erythroid (HI-E) will be assessed as the time from recorded response to loss of response. Participants will be characterized and stratified as nontransfused (NTD), low-transfusion burden (LTB) and high-transfusion burden (HTB), with response defined as follows. NTD = greater than or equal to 2 consecutive Hb measurements, greater than or equal to 1.5 g/dL for a period of minimum 8 week in an observation period of 16 to 24 week compared to the lowest mean of 2 Hb measurements LTB = 0 units of RBC transfusions HTB = greater than or equal to 4 unit or greater than or equal to 50% reduction in RBC transfusions The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Time Frame
16 weeks.
Title
Clinical Response: Hematological Improvement - Platelets (HI-P)
Description
Clinical response for platelets was assessed as the number of participants achieving a hematological improvement - platelets (HI-P). Participants will be characterized and stratified as platelets < or ≥ 20 x 10^9/L, with response defined as follows. < 20 x 10^9/L = increase in platelets from < 20 x 10^9/L to > 20 x 10^9/L AND by ≥ 100% ≥ 20 x 10^9/L = absolute increase in platelets of 30 x 10^9/L The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Time Frame
8 weeks
Title
Clinical Response: Hematological Improvement - Neutrophils (HI-N)
Description
Clinical response for neutrophils was assessed as the number of participants achieving a hematological improvement - neutrophils (HI-N). Response defined as an absolute increase in neutrophils > 0.5 x 10^9/L that is also an increase of ≥ 100%. The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Time Frame
8 weeks
Title
Red Blood Cell (RBC) transfusion independence (RBC TI)
Description
Clinical response for red blood cells was assessed as the number of participants who were transfusion dependent that achieve red blood cell (RBC) transfusion independence (RBC TI) for for 8 weeks or longer. The outcome will be reported as the number of participants that achieve the response, a number without dispersion.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Documented diagnosis of MDS according to WHO/FAB classification that meets IRSS-R classification of low or intermediate risk disease; and a diagnosed as denovo or secondary MDS (MDS-RS eligible if refractory to or declined luspatercept therapy) OR Dysplastic (nonproliferative) CMML with WBC < 13.0/microL) No disease-modifying therapy (HMA, hydrea) within 2 months of starting study Age ≥ 18 years of age ECOG ≤ 3 Negative for IDH2 mutation by NGS or multiplex PCR (SNaPshot) Has symptomatic anemia defined as hemoglobin < 10.5 g/dL with any of the following. Tachypnea Shortness of breath Fatigue Malaise Worsening of cardiovascular function Asthenia Dyspnea on exertion Angina Other subject symptoms the subject reports as being associated with being anemic. Stated willingness to comply with all study procedures and availability for the duration of the study Ability to take oral medication and be willing to adhere to the medication regimen. Females of reproductive potential need to either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption, 28 days prior to starting enasidenib, during the study therapy, and for 30 days after last dose of enasidenib For males of reproductive potential: agreement to use of condoms Adequate organ function defined as: Hepatic function: total bilirubin <1.5 x ULN (unless attributable to Gilbert's disease), AST or ALT < 3x ULN Renal function: creatinine clearance > 30 mL/minute, calculated by Cockcroft-Gault formula Ability to understand and the willingness to sign the IRB approved informed consent document. Women of childbearing potential must have negative urine or serum pregnancy test Exclusion Criteria: Use of concurrent other erythropoietic agents (including epoetin, darbepoetin), G-CSF within 30 days of study enrollment Less than 3 months of life expectancy Significant cardiac disease (NYHA Class IV congestive heart failure, or unstable angina or myocardial infarction within the last 6 months Harbor IDH2 somatic mutations by NGS or PCR Pregnant or breast feeding Any uncontrolled bacterial, fungal, viral or other infection. No known HIV+ or active hepatitis B or C infection, defined as positive viral load for HBV or HCV or a positive surface antigen (HBsAg) test for hepatitis B. Have other causes of anemia: deficiencies in iron, B12, folate; nutritional deficiencies related to gastric surgery, anorexia nervosa, excessive zinc supplementation; gastrointestinal bleed. If nutritional deficiencies can be corrected, potential subject can be rescreened and enrolled if nutritionally replete and still meets eligibility criteria. Any other medical history, including laboratory results, deemed by the Principal Investigator likely to interfere with their participation in the study, or to interfere with the interpretation of the results Pregnant or breast feeding
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Veronica de Santiago
Phone
650-725-4047
Email
desantv1@stanford.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tian Yi Zhang, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford Cancer Institute
City
Palo Alto
State/Province
California
ZIP/Postal Code
94305
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Veronica de Santiago
Phone
650-725-4047
Email
desantv1@stanford.edu
First Name & Middle Initial & Last Name & Degree
Tian Yi Zhang, MD

12. IPD Sharing Statement

Learn more about this trial

Enasidenib in MDS &Non-proliferative Chronic Myelomonocytic Leukemia w/o IDH2 Mutation

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