Treatment of Anemia in Patients With Very Low, Low or Intermediate Risk Myelodysplastic Syndromes With CA-4948 (LUCAS)

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)

Anemia in LR-MDS patients

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Anemia
• Intervention / Treatment: Drug: CA-4948

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

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12200
    • Charité Berlin - Campus Benjamin Franklin, Med. Klinik m. S. Hämatologie, Onkologie, Tumorimmunologie
  • Cottbus, Germany, 03048
    • Carl-Thiem-Klinikum Cottbus gGmbH, 2. Med. Klinik
  • Dresden, Germany, 01307
    • Gemeinschaftspraxis Dr. Jacobasch Dresden, Hämatologie Onkologie
  • Düsseldorf, Germany, 40479
    • Marienhospital Düsseldorf, Klinik für Onkologie und Hämatologie, Palliativmedizin
  • Erlangen, Germany, 91052
    • ONCOSEARCH, Institut für Klinische Studien GbR
  • Koblenz, Germany, 56068
    • InVO-Institut für Versorgungsforschung in der Onkologie
  • Landshut, Germany, 84036
    • VK & K Studien GbR, Studienzentrum
  • Leipzig, Germany, 04103
    • University Leipzig, Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, Hämostaseologie
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein, Klinik für Hämatologie und Onkologie Campus Lübeck
  • Mainz, Germany, 55131
    • Universitätsklinikum Mainz, III. Medizinische Klinik und Poliklinik - Hämatologie, Internistische Onkologie und Pneumologie
  • Mannheim, Germany, 68167
    • Universitätsklinikum Mannheim, III. Medizinische Klinik - Hämatologie und Onkologie
  • Meschede, Germany, 59872
    • Klinikum Hochsauerland GmbH, Klinik f. Hämatologie, Onkologie, Palliativmedizin, Stammzelltransplantation
  • München, Germany, 81675
    • Klinikum rechts der Isar der TU München III. Medizinische Klinik - Hämatologie und Onkologie
  • Neumünster, Germany, 24534
    • Friedrich-Ebert-Krankenhaus GmbH, Klinik für Hämatologie, Onkologie und Nephrologie
  • Winnenden, Germany, 71364
    • Rems-Murr-Kliniken gGmbH, Hämatologie, Onkologie und Palliativmedizin

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: CA-4948 treatment; Single-arm design. all patients are treated with IMP	Drug: CA-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.; Other Names: Emavusertib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Erythroid response (HI-E)	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.	At the end of cycle 4 (each cycle is 28 days).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HI-E response (erythroid response) duration	To evaluate HI-E response from the first day of response until loss of response.	From the date of treatment start until date of documented loss of response, assessed up to 30 months.
Time to HI-E (erythroid response)	To evaluate the time between start of treatment and first day of response.	From the date of treatment start until first day of response, assessed up to end of cycle 4 (each cycle is 28 days).
Red blood cell (RBC) transfusions	To evaluate frequency of red blood cell transfusions in transfusion dependent patients	From the date of treatment start until the date of end of treatment, assessed up to 30 months.
Neutrophil (HI-N) responses	Neutrophil (HI-N) responses according to IWG 2018 criteria	At the end of cycle 4 (each cycle is 28 days).
Platelet (HI-P) responses	Platelet (HI-P) responses according to IWG 2018 criteria	At the end of cycle 4 (each cycle is 28 days).
Safety of CA-4948 (toxicities and adverse events)	Assessments will include characterization of toxicities; characterization of AEs including type, incidence, severity, seriousness, and relationship to treatment	From the date of treatment start until the end of study, assessed up to 30 months.
Number of participants with clinically significant changes of selected laborotory parameters (parameters listed in detailed description)	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.	From the date of treatment start until the end of study, assessed up to 30 months.
Impact of treatment assessed by using the validated European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30)	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.	From the date of treatment start until the end of study, assessed up to 30 months.
Impact of treatment assessed by using the validated European Organisation for Research and Treatment of Cancer cancer related fatigue questionnaire (EORTC QLQ- FA12)	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.	From the date of treatment start until the end of study, assessed up to 30 months.

Collaborators and Investigators

• Sponsor: University of Leipzig
• Collaborators: Curis, Inc.
• Investigators: Principal Investigator: Uwe Platzbecker, Prof. Dr., University Leipzig

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Actual): July 31, 2024
• Study Completion (Actual): July 31, 2024

Study Registration Dates

• First Submitted: November 2, 2021
• First Submitted That Met QC Criteria: December 16, 2021
• First Posted (Actual): January 5, 2022

Study Record Updates

• Last Update Posted (Actual): August 13, 2024
• Last Update Submitted That Met QC Criteria: August 12, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Anemia; MDS; Myelodysplastic Syndrome; IRAK4
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Anemia
• Other Study ID Numbers: LUCAS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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