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

• ClinicalTrials.gov Identifier: NCT05178342
• Recruitment Status: Terminated
• First Posted: January 5, 2022
• Last Update Posted: May 17, 2024
• Sponsor: University of Leipzig
• Collaborator: Curis, Inc.
• Information provided by (Responsible Party): Uwe Platzbecker, University of Leipzig

Tracking Information

• First Submitted Date: November 2, 2021
• First Posted Date: January 5, 2022
• Last Update Posted Date: May 17, 2024
• Actual Study Start Date: January 1, 2022
• Actual Primary Completion Date: March 6, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2021)

Erythroid response (HI-E) [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 21, 2022)

• HI-E response (erythroid response) duration [ Time Frame: 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.
• Time to HI-E (erythroid response) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: At the end of cycle 4 (each cycle is 28 days). ]
  Neutrophil (HI-N) responses according to IWG 2018 criteria
• Platelet (HI-P) responses [ Time Frame: At the end of cycle 4 (each cycle is 28 days). ]
  Platelet (HI-P) responses according to IWG 2018 criteria
• Safety of CA-4948 (toxicities and adverse events) [ Time Frame: 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
• Number of participants with clinically significant changes of selected laborotory parameters (parameters listed in detailed description) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: December 16, 2021)

• HI-E response (erythroid response) duration [ Time Frame: 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.
• Time to HI-E (erythroid response) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: At the end of cycle 4 (each cycle is 28 days). ]
  Neutrophil (HI-N) responses according to IWG 2018 criteria
• Platelet (HI-P) responses [ Time Frame: At the end of cycle 4 (each cycle is 28 days). ]
  Platelet (HI-P) responses according to IWG 2018 criteria
• Safety of CA-4948 (toxicities and adverse events) [ Time Frame: 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
• Safety of CA-4948 (laboratory parameters) [ Time Frame: 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 questionnaires EORTC QLQ-C30 [ Time Frame: 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.
• Impact of treatment assessed by using the validated questionnaires EORTC QLQ-FA12 [ Time Frame: 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Myelodysplastic Syndromes
• Anemia

Intervention

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 Name: Emavusertib

Study Arms

CA-4948 treatment

Single-arm design. all patients are treated with IMP

Intervention: Drug: CA-4948

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 3, 2024): 38
• Original Estimated Enrollment (submitted: December 16, 2021): 84
• Actual Study Completion Date: March 6, 2024
• Actual Primary Completion Date: March 6, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT05178342
• Other Study ID Numbers: LUCAS
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Uwe Platzbecker, University of Leipzig
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Leipzig
• Original Study Sponsor: Same as current
• Collaborators: Curis, Inc.

Investigators

• Principal Investigator: Uwe Platzbecker, Prof. Dr.; University Leipzig

• PRS Account: University of Leipzig
• Verification Date: May 2024