Leukemia, Leukemia, Myeloid, Monocytic Leukemia
Conditions
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.
Interventions
DRUGEnasidenib mesylat dose escalation
Subjects will participate dose escalation with a starting dose of 100 mg. Enasidenib will be self administered orally and daily.
Sponsors
Tian Yi Zhang
Celgene Corporation
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response: Hematological Improvement - Erythroid (HI-E) | 16 weeks | Clinical response was assessed as the number of participants achieving a hematological improvement - erythroid (HI-E). Participants were 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Related Adverse Events | 12 months | Toxicity was assessed as the number of related non-serious adverse events and related serious adverse events (SAEs) reported by dose level (Cohort A or Cohort B) for the 12-cycle treatment period plus follow-up. |
| Time to Hematological Improvement - Erythroid (HI-E) | 16 weeks | Time to hematological improvement - erythroid (HI-E) was assessed as the time from first dose of enasidenib to the first observed hemoglobin response. Participants will be characterized and stratified as non-transfused (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 |
| Duration of Hematological Improvement - Erythroid (HI-E) | 16 weeks | 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) | 8 weeks | 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) | 8 weeks | Clinical response for neutrophils was assessed as the number of participants achieving a hematological improvement - neutrophils (HI-N). Response was defined as an absolute increase in neutrophils \> 0.5 × 10\^9/L that was also an increase of ≥ 100%. |
| Red Blood Cell (RBC) Transfusion Independence (RBC TI) | 12 months | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTian Yi Zhang, MD
Stanford University
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 18-29 years old | 0 Participants |
| Age, Customized 30-39 years old | 0 Participants |
| Age, Customized 40-49 years old | 1 Participants |
| Age, Customized 50-59 years old | 0 Participants |
| Age, Customized 60-69 years old | 1 Participants |
| Age, Customized 70-79 years old | 12 Participants |
| Age, Customized 80-89 years old | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 14 |
| other Total, other adverse events | 3 / 3 | 14 / 14 |
| serious Total, serious adverse events | 3 / 3 | 7 / 14 |
Outcome results
None listed