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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Leukemia; Leukemia, Myeloid; Monocytic Leukemia
• Intervention / Treatment: Drug: Enasidenib mesylat dose escalation

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.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Veronica de Santiago; Phone Number: 650-725-4047; Email: desantv1@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Recruiting
      • Stanford Cancer Institute
      • Contact: Veronica de Santiago; Phone Number: 650-725-4047; Email: desantv1@stanford.edu
      • Principal Investigator: Tian Yi Zhang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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)
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 < 10.5 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.
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. Significant cardiac disease (NYHA Class IV congestive heart failure, or unstable angina or myocardial infarction within the last 6 months
4. Harbor IDH2 somatic mutations by NGS or PCR
5. Pregnant or breast feeding
6. Any uncontrolled bacterial, fungal, viral or other infection.
7. 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.
8. 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.
9. 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
10. Pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enasidenib mesylat; Participants will self administer the enasidenib orally everyday.	Drug: Enasidenib mesylat dose escalation; Subjects will participate dose escalation with a starting dose of 100 mg. Enasidenib will be self administered orally and daily.; Other Names: (Idhifa, AG 221)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	16 weeks
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.	12 months
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.	16 weeks.
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.	16 weeks.
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.	8 weeks
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.	8 weeks
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.	12 months

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: Tian Yi Zhang, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2022
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: March 7, 2022
• First Submitted That Met QC Criteria: March 7, 2022
• First Posted (Actual): March 16, 2022

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile
• Other Study ID Numbers: IRB- 62692; HEM0056 (Other Identifier: Stanford); NCI-2022-02837 (Other Identifier: Clinical Trial Reporting Program (CTRP))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No