luspatercept (drug to treat anemia) in patients to treat anemia associated with myelodysplastic syndromes (MDS-RS) and beta-thalassemia (Beta-Thal) in India

Phase 4

Recruiting

• Conditions: Other specified diseases of bloodand blood-forming organs,

• Registration Number: CTRI/2023/03/050272
• Lead Sponsor: BRISTOL MYERS SQUIBB INDIA PRIVATE LIMITED

Brief Summary

A PHASE 4 STUDY TO EVALUATE SAFETY AND EFFECTIVENESS OF LUSPATERCEPT (ACE-536) FOR THE TREATMENT OF ANEMIA DUE TO IPSS-R VERY LOW, LOW, OR INTERMEDIATE RISK MYELODYSPLASTIC SYNDROMES (MDS) WITH RING SIDEROBLASTS WHO REQUIRE RED BLOOD CELL TRANSFUSIONS IN SUBJECTS WHO HAVE HAD UNSATISFACTORY RESPONSE TO OR ARE INELIGIBLE TO ERYTHROPOIETIN BASED THERAPY AND IN SUBJECTS WITH TRANSFUSION DEPENDENT ANEMIA DUE TO BETA-THALASSEMIA

Detailed Description

Not available

Study Timeline

• Study Start: 2023-03-15
• Last Update Posted: 2024-02-08

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Beta-Thalassemia More than 18 years of age at the time of signing the informed consent form Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia Regularly transfused, defined as 6-20 Red Blood Cell (RBC) units in the 24 weeks prior to randomization and no transfusion-free period for more than 35 days during that period.
• Sites who prescribe transfusions and have the transfusion records only in volumes should use for conversion of volume to units the below criteria, in order to obtain number of units within the last 24 weeks to assess the eligibility: 1 unit in this protocol refers to a quantity of packed RBCs approximately 200-350 mL.
• sites who use transfusion bags within this range, or more than equal to 350 mL, the conversion in units should be done by dividing the volume transfused to the patient by 350 mL, 2.
• sites who use transfusion bags less than 200 mL, the conversion in units should be done by dividing the volume transfused to the patient by 200 mL.
• Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
• MDS More than 18 years of age at the time of signing the informed consent form Subject had documented diagnosis of MDS according to WHO/FAB (2016) classification that met IPSS-R classification of very low-, low-, or intermediate-risk disease, and the following: Ring sideroblasts (RS) more than equal to 15% of erythroid precursors in bone marrow.
• If the SF3B1 mutation is present, RS more than equal to 5% will be included.
• Less than 5% blasts in bone marrow and less than 1% peripheral blood blasts Peripheral blood white blood cell (WBC) count less than 13,000/μL Subject was refractory or intolerant to, or ineligible for, prior ESA treatment, as defined by any one of the following: Refractory to prior ESA treatment: Documentation of nonresponse or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g., with G-CSF).
• The ESA regimen must have been either: Recombinant human erythropoietin more than equal to 40,000 IU/week for at least 8 doses or equivalent; or 1050 mg/kg/week for at least 8 doses or equivalent Darbepoetin- darbepoetin alpha more than equal to 240 µg every week for at least 12 weeks or equivalent Intolerant to prior ESA treatment: Documentation of discontinuation of prior ESA-containing regimen, either as a single agent or in combination (e.g., with G-CSF), at any time after introduction due to intolerance or an AE ESA ineligible: Low chance of response to ESA based on endogenous serum EPO level more than 200 U/L for subjects not previously treated with ESAs If the patient was previously treated with ESAs or G-CSF/granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must have been discontinued more than equal to 4 weeks prior to the date of randomization Required RBC transfusions, as documented by the following criteria: Average transfusion requirement of more than equal to 2 units/8 weeks of packed RBCs (pRBCs) confirmed for a minimum of 16 weeks immediately preceding Luspatercept treatment Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been less than equal to 9.0 g/dL with symptoms of anemia or (less than equal to 7 g/dl in absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria.
• Red blood cell transfusions administered when Hgb levels were more than 9 g/dL and/or RBC transfusions administered for elective surgery ,infections or bleeding events will qualify as a required transfusion for the purpose of meeting eligibility criteria No consecutive 56-day period that was RBC transfusion free during the 16 weeks immediately preceding randomization Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.

Exclusion Criteria

• Beta-Thalassemia A diagnosis of Haemoglobin S/β-thalassemia or alpha (α)-thalassemia (e.g., Haemoglobin H).
• Deep Vein Thrombosis (DVT) or stroke requiring medical intervention more than equal to 24 weeks prior to randomization.
• Use of chronic anticoagulant therapy is excluded unless the treatment stopped at least 28 days prior to randomization.
• Anticoagulant therapies used for prophylaxis for surgery or high-risk procedures as well as low Molecular Weight (LMW) heparin for superficial venous thrombosis and chronic aspirin are allowed.
• Platelet count more than 1000 x 109/L Poorly controlled diabetes mellitus within 24 weeks prior to randomization as defined by short term (e.g., hyperosmolar or ketoacidotic crisis) and/or history of diabetic cardiovascular complications (e.g., stroke or myocardial infarction).
• Pregnant or lactating females.
• Uncontrolled hypertension.
• Controlled hypertension for this protocol is considered less than equal to Grade 1 according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (current active minor version).
• Major organ damage, including: Liver disease with alanine aminotransferase (ALT) more than 3 x the upper limit of normal (ULN) or history of evidence of cirrhosis.
• Heart disease, heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of randomization.
• Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant i.e., more than equal to Grade 3 NCI CTCAE version 4.0 (current active minor version).
• Creatinine clearance less than 60 mL/min (per Cockcroft-Gault formula).
• MDS MDS associated with del 5q cytogenetic abnormality Secondary MDS, i.e., MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
• Subject has known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding.
• Iron deficiency to be determined by serum ferritin ≤ 15 μg/L and additional testing if clinically indicated (e.g., calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron) Prior allogeneic or autologous stem cell transplant Known history of diagnosis of AML Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure Subject has uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment, or with a history of hypertensive crisis or hypertensive encephalopathy Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L) Platelet count < 50,000/μL (50 x 109/L) Estimated glomerular filtration rate (eGRF) or creatinine clearance < 40 mL/min/1.73 m2 or creatinine clearance < 40 mL/min.
• Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) Total bilirubin ≥ 2.0 x ULN.
• higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (i.e., ineffective erythropoiesis).

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Beta-Thalassemia	screening visit,every 3 weeks (up to 48 weeks) & 9-week follow-up period after the last cycle of study drug in B-Thalassemia. | MDS | Screening visit, every 3 week (up to 48 weeks) & 6-week follow-up period after the last cycle of study drug in MDS
Incidence of treatment related adverse events of grade 3 or higher adverse events: during the treatment period (up to 48 weeks) & during a 9-week follow-up period after the last cycle of study drug in B-Thalassemia.	screening visit,every 3 weeks (up to 48 weeks) & 9-week follow-up period after the last cycle of study drug in B-Thalassemia. | MDS | Screening visit, every 3 week (up to 48 weeks) & 6-week follow-up period after the last cycle of study drug in MDS
MDS	screening visit,every 3 weeks (up to 48 weeks) & 9-week follow-up period after the last cycle of study drug in B-Thalassemia. | MDS | Screening visit, every 3 week (up to 48 weeks) & 6-week follow-up period after the last cycle of study drug in MDS
Incidence of treatment related adverse events of grade 3 or higher adverse events: during the treatment period (up to 48 weeks) & during a 6-week follow-up period after the last cycle of study drug in MDS	screening visit,every 3 weeks (up to 48 weeks) & 9-week follow-up period after the last cycle of study drug in B-Thalassemia. | MDS | Screening visit, every 3 week (up to 48 weeks) & 6-week follow-up period after the last cycle of study drug in MDS

Secondary Outcome Measures

Name	Time	Method
Beta-Thalassemia	% of Participants Who Achieved RBC Transfusion Burden Reduction (≥33% Reduction from Baseline) from Week 13 to Week 24 with a reduction of at least 2 red-cell units over this 12-week interval.

Trial Locations

Locations (8)

All India Institute of Medical Sciences; 🇮🇳 Delhi, DELHI, India

Gauhati Medical college & Hospital; 🇮🇳 Kamrup, ASSAM, India

HCG - Bangalore institute of Oncology; 🇮🇳 Bangalore, KARNATAKA, India

KEM Hospital and Seth G S Medical College; 🇮🇳 Mumbai, MAHARASHTRA, India

Nilratan Sircar Medical College and Hospital; 🇮🇳 Kolkata, WEST BENGAL, India

Post Graduate Institute of Medical Education and Research; 🇮🇳 Chandigarh, CHANDIGARH, India

Rajiv Gandhi Cancer Institute and Research CentreÂ; 🇮🇳 Delhi, DELHI, India

Vedanta Institute of Medical Science; 🇮🇳 Ahmadabad, GUJARAT, India

All India Institute of Medical Sciences

🇮🇳Delhi, DELHI, India

Dr Tulika Seth

Principal investigator

011-26593363

drtulikaseth@gmail.com