Clinical trial NCT05178342: Treatment of Anemia in Patients With Very Low, Low or Intermediate Risk Myelodysplastic Syndromes With CA-4948
Official title: A Phase II, Open-Label, Multicenter Study of Orally Administered CA-4948 for the Treatment of Anemia in Patients With Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Anemia
Keywords: MDS
Anemia
Myelodysplastic Syndrome
IRAK4
Lead sponsor: University of Leipzig
Sponsor class: OTHER
Collaborators: name: Curis, Inc.
First posted: 2022-01-05
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Erythroid response (HI-E)
timeFrame: At the end of cycle 4 (each cycle is 28 days).
Secondary outcomes:
measure: HI-E response (erythroid response) duration
timeFrame: From the date of treatment start until date of documented loss of response, assessed up to 30 months.
measure: Time to HI-E (erythroid response)
timeFrame: From the date of treatment start until first day of response, assessed up to end of cycle 4 (each cycle is 28 days).
measure: Red blood cell (RBC) transfusions
timeFrame: From the date of treatment start until the date of end of treatment, assessed up to 30 months.
measure: Neutrophil (HI-N) responses
timeFrame: At the end of cycle 4 (each cycle is 28 days).
measure: Platelet (HI-P) responses
timeFrame: At the end of cycle 4 (each cycle is 28 days).
measure: Safety of CA-4948 (toxicities and adverse events)
timeFrame: From the date of treatment start until the end of study, assessed up to 30 months.
measure: Number of participants with clinically significant changes of selected laborotory parameters (parameters listed in detailed description)
timeFrame: From the date of treatment start until the end of study, assessed up to 30 months.
measure: Impact of treatment assessed by using the validated European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30)
timeFrame: From the date of treatment start until the end of study, assessed up to 30 months.
measure: Impact of treatment assessed by using the validated European Organisation for Research and Treatment of Cancer cancer related fatigue questionnaire (EORTC QLQ- FA12)
timeFrame: From the date of treatment start until the end of study, assessed up to 30 months.
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité Berlin - Campus Benjamin Franklin, Med. Klinik m. S. Hämatologie, Onkologie, Tumorimmunologie
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum Cottbus gGmbH, 2. Med. Klinik
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Dr. Jacobasch Dresden, Hämatologie Onkologie
city: Düsseldorf
country: Germany
facility: Marienhospital Düsseldorf, Klinik für Onkologie und Hämatologie, Palliativmedizin
city: Erlangen
country: Germany
facility: ONCOSEARCH, Institut für Klinische Studien GbR
city: Koblenz
country: Germany
facility: InVO-Institut für Versorgungsforschung in der Onkologie
city: Landshut
country: Germany
facility: VK & K Studien GbR, Studienzentrum
city: Leipzig
country: Germany
facility: University Leipzig, Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, Hämostaseologie
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Klinik für Hämatologie und Onkologie Campus Lübeck
city: Mainz
country: Germany
facility: Universitätsklinikum Mainz, III. Medizinische Klinik und Poliklinik - Hämatologie, Internistische Onkologie und Pneumologie
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim, III. Medizinische Klinik - Hämatologie und Onkologie
city: Meschede
country: Germany
facility: Klinikum Hochsauerland GmbH, Klinik f. Hämatologie, Onkologie, Palliativmedizin, Stammzelltransplantation
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München III. Medizinische Klinik - Hämatologie und Onkologie
city: Neumünster
country: Germany
facility: Friedrich-Ebert-Krankenhaus GmbH, Klinik für Hämatologie, Onkologie und Nephrologie
city: Winnenden
country: Germany
facility: Rems-Murr-Kliniken gGmbH, Hämatologie, Onkologie und Palliativmedizin
Study officials:
affiliation: University Leipzig
name: Uwe Platzbecker, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: