Myelodysplastic Syndromes, Anemia
Conditions
Keywords
MDS, Anemia, Myelodysplastic Syndrome, IRAK4
Brief summary
Anemia in LR-MDS patients
Detailed description
Anemia in non-transfusion dependent (NTD) or transfusion dependent (low or high transfusion burden, LTB/HTB) patients with very low, low or intermediate risk myelodysplastic syndromes
Interventions
DRUGCA-4948
Patients will be treated orally with CA-4948 at 300 mg BID (2x200mg) over 4 cycles. One cycle consists of 28 days, 21 of which are treatment days, followed by 7 days off. Patients with erythroid response (HI-E) after 4 cycles who tolerate CA-4948 may continue to receive CA-4948 until loss of HI-E response.
Sponsors
Curis, Inc.
University of Leipzig
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of de novo myelodysplastic syndrome (MDS) OR de novo myelodysplastic/myeloproliferative neoplasias (MDS/MPN) including MDS/MPN-RS-T, MDS/MPNu, aCML or CMML 2. Very low/low/intermediate risk disease: IPSS-R up to 3.5 for MDS; MDS/MPN \< 10% bone marrow blasts; for CMML low or intermediate risk according to CPSS-Score 3. Symptomatic anemia (based on valid and complete hemoglobin and transfusion history): * NTD (non transfusion dependent): \< 3 RBC transfusions and mean hemoglobin level \<10 g/dl within the last 16 weeks * LTB (low transfusion burden): 3-7 RBC transfusions within the last 16 weeks in at least two transfusion episodes, maximum 3 in 8 weeks * HTB (high transfusion burden): ≥ 8 RBC transfusions within the last 16 weeks, ≥ 4 in 8 weeks 4. Defined transfusion strategy 5. No available option of an approved MDS therapy and classification of prior erythropoiesis-stimulating agent (ESA) treatment as follows: * Cohort A: ESA exposed (and refractory or intolerant) * Cohort B: ESA naive AND serum erythropoietin level \>200 U/L
Exclusion criteria
Compliance with major study procedures * Inability to swallow and retain oral medications (\> 10 pills) * Patient does not accept bone marrow sampling during screening and after the treatment * Patient does not accept up to weekly peripheral blood sampling during screening and treatment Safety * ECOG performance status ≥ 3 * Inacceptable organ function 1. Serum creatinine \> 2 × ULN or calculated creatinine clearance \< 30 ml/min 2. AST \> 2 × ULN or ALT \> 2 × ULN 3. total bilirubin \> 2 × ULN (exception \>3 × ULN in patients with documented Gilbert's syndrome) Interfering treatments * Prior treatment with azacitidine or decitabine * Treatment with erythropoiesis stimulating agent (ESA), G-CSF, GM-CSF, lenalidomide, luspatercept and/or another investigational drug or device up to 14 days before registration * Treatment with iron chelation therapy 56 days before registration, except for subjects on a stable or decreasing dose for at least eight weeks prior to inclusion and during study treatment * Major surgery within 28 days prior to registration Concomitant diseases * Known human immunodeficiency virus infection (HIV) * Active infectious hepatitis (HBV or HCV) * Hepatitis virus detectable within 6 months before registration in patients with a history of hepatitis * History of other invasive malignancy, unless definitively treated with curative intent, provided it is deemed to be at low risk for recurrence by the treating physician * Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy that has not resolved to Grade ≤ 1 (except anemia and alopecia) * Known allergy or hypersensitivity to any component of the formulation of CA-494824 * Severe cardiovascular disease (e.g. myocardial infarction within 6 months registration, unstable angina within 6 months registration, NYHA Class III or greater congestive heart failure, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, known QTc abnormality \> 450 msec on ECG Formal requirements * Positive serum pregnancy test in women of childbearing potential * Women of childbearing potential and men who partner with a woman of childbearing potential unwilling to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of CA-4948 * Age under 18 years at registration * Inability to provide written informed consent * Simultaneous participation in another interventional clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 28 days prior registration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Erythroid response (HI-E) | At the end of cycle 4 (each cycle is 28 days). | To evaluate the proportion of patients who have an erythroid response (HI-E) according to the modified IWG 2018 criteria separately for both independent substudies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to HI-E (erythroid response) | From the date of treatment start until first day of response, assessed up to end of cycle 4 (each cycle is 28 days). | To evaluate the time between start of treatment and first day of response. |
| Red blood cell (RBC) transfusions | From the date of treatment start until the date of end of treatment, assessed up to 30 months. | To evaluate frequency of red blood cell transfusions in transfusion dependent patients |
| Neutrophil (HI-N) responses | At the end of cycle 4 (each cycle is 28 days). | Neutrophil (HI-N) responses according to IWG 2018 criteria |
| Platelet (HI-P) responses | At the end of cycle 4 (each cycle is 28 days). | Platelet (HI-P) responses according to IWG 2018 criteria |
| HI-E response (erythroid response) duration | From the date of treatment start until date of documented loss of response, assessed up to 30 months. | To evaluate HI-E response from the first day of response until loss of response. |
| Number of participants with clinically significant changes of selected laborotory parameters (parameters listed in detailed description) | From the date of treatment start until the end of study, assessed up to 30 months. | To ensure patient safety, close monitoring is carried and includes the analysis of: transaminases, bilirubin, amylase, lipase, troponin, lactate dehydrogenase, creatine kinase, uric acid, TSH, FT4, urine analysis. |
| Impact of treatment assessed by using the validated European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30) | From the date of treatment start until the end of study, assessed up to 30 months. | To assess patient-reported quality of life during CA-4948 treatment: 30 questions assessing the quality of life of oncology patients across 10 subscales will be analyzed. All subscales have a score range from 0 to 100 points. Function subscales: a higher score represents a higher quality of life. Symptoms subscales: higher score represents higher level of symptoms/problems, i.e., represents lower quality of life. |
| Impact of treatment assessed by using the validated European Organisation for Research and Treatment of Cancer cancer related fatigue questionnaire (EORTC QLQ- FA12) | From the date of treatment start until the end of study, assessed up to 30 months. | To assess patient-reported quality of life during CA-4948 treatment: 12 items, with four response categories for each item (coded with values from 1 to 4) will be analyzed. FA12 scores are transformed to the range 0-100: Higher levels indicate greater degrees of fatigue. |
| Safety of CA-4948 (toxicities and adverse events) | From the date of treatment start until the end of study, assessed up to 30 months. | Assessments will include characterization of toxicities; characterization of AEs including type, incidence, severity, seriousness, and relationship to treatment |
Countries
Germany
Outcome results
None listed