Clinical trial NCT05664737: A Study to Determine the Efficacy and Safety of Luspatercept in Adult Participants and to Evaluate the Safety and Pharmacokinetics in and Adolescent Participants With Alpha (α)-Thalassemia
Official title: A Phase 2, Study for the Treatment of Anemia With Alpha (α)-Thalassemia to Determine the Efficacy and Safety of Luspatercept (BMS-986346/ACE-536) in Adults and Evaluate the Safety and Pharmacokinetics in Adolescents
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Anemia
Keywords: Luspatercept
BMS-986346
ACE-536
α-thalassemia
Alpha Thalassemia
Reblozyl
Transfusions
Non-transfusion dependent
RBC transfusion dependent
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2022-12-27
Enrollment: 249
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to evaluate the efficacy and safety of luspatercept plus best supportive care (BSC) vs placebo plus BSC on anemia in adult participants with α-thalassemia hemoglobin H (HbH) disease and determine the safety and drug levels in adolescent participants.


Eligibility criteria: Key Inclusion Criteria:

* Adult participant≥ 18 years with documented diagnosis of A-Thal HbH disease with Transfusion dependence defined as:.

  1. TD participant: ≥ 6 RBC units during the 24 weeks prior to randomization.
  2. NTD participant:\< 6 RBC units during the 24 weeks prior to randomization(transfusion due to conditions other than A-Thal will not be considered)and, RBC transfusion-free during at least 8 weeks prior to randomization(unless transfusion was required to treat an acute medical condition other than A-Thal) and, mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded.
* Adult participant has Eastern Cooperative Oncology Group (ECOG) 34 score of 0 or 1.
* Adolescent participant 12 years to \< 18 years with documented diagnosis of A-Thal HbH disease with transfusion dependence defined as:.

  1. TD participant: ≥ 4 RBC events during the 24 weeks prior to enrollment and, no transfusion-free period for \> 56 days during the 24 weeks prior to enrollment. Participants must have a history of regular transfusions for at least 2 years.
  2. NTD participant:\< 4 RBC events during the 24 weeks prior to enrollment and RBC transfusion-free during at least 8 weeks prior to enrollment and, mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to enrollment, hemoglobin values within 21 days post-transfusion will be excluded.
  3. Participant has Karnofsky (age ≥16 years) or Lansky (age \< 16 years) performance status score ≥ 50 at screening.

Key Exclusion Criteria:

* Medical Conditions: Diagnosis of A-ThalTrait, Hb Bart hydrops, ATRx A-Thal, hemoglobin S/β-thalassemia, myelodysplasia subtype anemia, or with HbE homozygous beta gene mutation. Anemia related to nutritional deficiency, anemia of chronic disease, autoimmune hemolytic anemia, or any other hemolytic anemias. Undergone episodes of hemolysis not related to A-Thal within the 8 weeks prior to randomization.
* Participant has deep vein thrombosis (DVT), stroke or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24weeks prior to randomization.
* Participant has uncontrolled hypertension. Controlled hypertension for this protocol is considered: blood pressure value corresponding to ≤Grade 1 according to NCI CTCAE Version 5.0. with or without pharmacological treatment.
* Reproductive Status: Women who are pregnant, plan to get pregnant during the study, or who are breastfeeding.
* Prior/Concomitant: Undergone HSCTs or gene therapy (candidates for HSCT or gene therapy with waiting period of ≥ 12 months are eligible).
* Use of hydroxyurea treatment ≤ 12 weeks prior to enrollment for NTD participants and ≤ 24 weeks for TD participants.
* Participant who has extramedullary hematopoiesis (EMH) complications requiring treatment to control the growth of EMH mass(es) during the screening period.
* Any medical or psychiatric condition (including active infections, recent surgery, sequelae of diseases or interventions, clinically significant laboratory abnormalities or concurrent treatment) that in the opinion of the investigator would put the participant at unacceptable risk of participating in the study or that could affect interpretability of data.
* Other protocol-defined inclusion/exclusion criteria apply.

Primary outcomes:
measure: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 12 weeks during Week 13-48 compared to 12-week interval immediately prior to date of first dose
timeFrame: Up to Week 48
measure: Number of participants with an increase from baseline of ≥ 1.0 grams (g)/decilitre (dL) in mean hemoglobin (Hb) values over the continuous 12-week interval from Week 13 to Week 24 in the absence of RBC transfusion
timeFrame: Up to Week 24
measure: Dose-limiting toxicities (DLTs) defined as observance of ≥ Grade 3-related hemolytic crises or ≥ Grade 3-related event outside of the known safety profile occurring within the 21 days from their first dose of study therapy
timeFrame: Up to Week 3
measure: Number of participants with adverse events (AEs)
timeFrame: Up to 8.5 years
measure: Pharmacokinetics (PK): Serum concentration of Luspatercept
timeFrame: Up to Week 102
Secondary outcomes:
measure: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 24-week interval on treatment compared to 24-week interval immediately prior to date of first dose
timeFrame: Up to Week 108
measure: The longest duration with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units
timeFrame: Up to Week 108
measure: Number of RBC transfusion units from week 1 to week 48
timeFrame: Up to Week 48
measure: Change from baseline in hemoglobin in the absence of transfusion at Week 24
timeFrame: Up to Week 24
measure: The longest duration of an increase from baseline of ≥ 1.0 g/dL in mean hemoglobin values starting from Week 13 in the absence of transfusion
timeFrame: Up to Week 108
measure: Time Duration with an increase from baseline of ≥ 1.0 g/dL in hemoglobin values in the absence of transfusion within 48 weeks
timeFrame: Up to Week 48
measure: Number of participants with an increase from baseline of ≥1.0 g/dL in mean Hb values over the continuous 12- week interval in the absence of transfusion
timeFrame: Up to Week 24
measure: ≥ 3 Increase from Baseline in Functional Assessment of Cancer Therapy Anemia Fatigue Subscale (FACT-An FS) Score from Baseline to the period from Week 13 to Week 24
timeFrame: Up to Week 24
measure: Number of participants with AEs
timeFrame: Up to 5 years
measure: Number of participants with laboratory abnormalities
timeFrame: Up to 5 Years
measure: Number of participants with immunogenicity
timeFrame: Up to 5 Years
measure: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during any continuous 24-week interval within 48 weeks compared to the 24-week interval immediately prior to the date of first dose
timeFrame: Up to Week 48
measure: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during any continuous 12-week interval compared to the 12-week interval immediately prior to the date of first dose
timeFrame: Up to Week 108
measure: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose
timeFrame: Up to Week 48
measure: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose
timeFrame: Up to Week 48
measure: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose
timeFrame: Up to Week 48
measure: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose
timeFrame: Up to Week 48
measure: Change from baseline in total RBC units transfused from Week 1 to Week 24, Week 25 to Week 48, and Week 1 to Week 48
timeFrame: Up to Week 48
measure: The longest duration of RBC transfusion-free period for participants who achieve transfusion-free period of ≥ 12 weeks
timeFrame: Up to Week 108
measure: The longest duration of reduction in transfusion burden for participants who achieve a response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction)
timeFrame: Up to Week 108
measure: Time from first dose to first day of response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction)
timeFrame: Up to Week 108
measure: Change from baseline in number of transfusion events at Week 48
timeFrame: Up to Week 48
measure: Number of participants who achieve RBC transfusion-free period of any continuous ≥ 12 weeks during treatment
timeFrame: Up to Week 108
measure: Number of participants who achieve RBC transfusion-free period of any continuous ≥ 24 weeks during treatment
timeFrame: Up to Week 108
measure: Time to first transfusion
timeFrame: Up to Week 108
measure: Number of transfusions
timeFrame: Within 48 Weeks
measure: Number of transfusion visits/units
timeFrame: Within 48 Weeks
measure: Change from baseline in mean hemoglobin values over the continuous 12-week interval from Week 13 to Week 24 and Week 37 to Week 48 in the absence of transfusions
timeFrame: Up to Week 48
measure: Number of participants achieving an increase from baseline of ≥1.0g/dL or ≥1.5g/dL in mean Hb values in absence of transfusions from Week 13 to Week 24, Week 37 to Week 48 and during any continuous 12-week window within 24 weeks and 48 weeks
timeFrame: Up to Week 48
measure: Time from first to last Hb measurement with increase from baseline by ≥ 1.0 g/dL
timeFrame: Up to Week 108
measure: Time to the first increase from baseline of ≥ 1.0 g/dL in mean Hb value
timeFrame: Up to Week 48
measure: Number of participants who achieve an increase in mean Hb of >10g/dL values during any continuous 12-week and 24-week interval within 48 weeks in the absence of transfusions
timeFrame: Up to Week 48
measure: Change from baseline in self-reported health-related quality of life (HRQoL) assessed by physical component summary (PCS) and mental component summary (MCS) of 36-item short-form health survey version2 (SF-36v2) at Week 24 and Week 48
timeFrame: Up to Week 48
measure: Change from baseline in non-transfusion dependent β-thalassemia patient-reported outcome (NTDT-PRO) Tiredness/weakness (T/W) and shortness of breath (SoB) domain scores from Week 13 to Week 24 and from Week 37 to Week 48
timeFrame: Up to Week 48
measure: Change from baseline in FACT-An FS Score at Week 24 and Week 48
timeFrame: Up to Week 48
measure: Change from baseline in Functional Assessment of Cancer Therapy Anemia Anemia Subscale (FACT-An AS) at Week 24 and Week 48
timeFrame: Up to Week 48
measure: Number of participants with at least one hemolytic crisis
timeFrame: Up to Week 108
measure: Rate of hemolytic crises
timeFrame: Up to Week 108
measure: Time to first hemolytic crisis
timeFrame: Up to Week 108
measure: Time to second hemolytic crisis
timeFrame: Up to Week 108
measure: Change from baseline in hemolysis markers at Week 24 and Week 48
timeFrame: Up to Week 48
measure: Change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48
timeFrame: Up to Week 48
measure: Pharmacokinetics (PK): Serum concentration of Luspatercept
timeFrame: Up to Week 108
measure: Percent Change from Baseline in Biomarkers for Erythropoiesis at Week 84
timeFrame: Baseline, Week 84
measure: Percent Change from Baseline in Biomarkers and Parameters for Iron Homeostasis at Week 84
timeFrame: Baseline, Week 84
measure: Change in mean corpuscular volume (MCV) at Week 48
timeFrame: Baseline, Week 48
measure: Change in mean corpuscular hemoglobin (MCH) at Week 48
timeFrame: Baseline, Week 48
measure: Change in nucleated red blood cells (nRBC) at Week 48
timeFrame: Baseline, Week 48
measure: Change in red blood cells (RBC) at Week 48
timeFrame: Baseline, Week 48
measure: The longest duration with reduction from baseline in the RBC transfusion burden
timeFrame: Up to Week 48
measure: The number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during an continuous 12 weeks during Weeks 13-48
timeFrame: Up to Week 48
measure: The number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during an continuous 24 weeks
timeFrame: Up to Week 48
measure: Number of participants achieving an increase from baseline of ≥1.0g/dL in mean Hb values in absence of transfusions from Week 13 to Week 24
timeFrame: Up to Week 24
measure: Cumulative time (in weeks) with an increase from baseline of ≥1.0g/dL in mean Hb values in absence of RBC transfusions within 48 weeks
timeFrame: Up to Week 48
measure: Number of participants who achieve an increase in mean Hb of >10g/dL values during any continuous 12-week interval during week 13 to week 48 in the absence of transfusions
timeFrame: Up to Week 48
measure: The longest duration with an increase from baseline of ≥1.0g/dL in mean Hb values in absence of transfusions
timeFrame: Up to Week 48
measure: Number of participants with antidrug antibody (ADA)
timeFrame: Up to Week 48
measure: Mean change in biomarkers for hemolysis
timeFrame: Up to Week 48
measure: Mean change in biomarkers and parameters for iron homeostasis
timeFrame: Up to 1 Year
measure: Hematologic assessments
timeFrame: Up to Week 48
measure: The change from baseline in the number of health care resource utilization (HCRU)
timeFrame: Up to Week 48
measure: Mean change from baseline in Pediatric Quality of Life Inventory (PedsQL) domain scores
timeFrame: Up to Week 48
measure: Mean change from baseline EQ-5D-5L utility index
timeFrame: Up to Week 48
measure: Mean change from baseline visual analogue scale (VAS) scores
timeFrame: Up to Week 48
Other outcomes:
Locations:
city: Halifax
country: Canada
facility: Local Institution - 0008
state: Nova Scotia
city: Foshan
country: China
facility: The First People's Hospital of Foshan
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-sen Memorial Hospital, Sun Yat-Sen University
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Maoming Shi
country: China
facility: Maoming People's Hospital
state: Guangdong
city: Shenzhen Shi
country: China
facility: Shenzhen Second People's Hospital
state: Guangdong
city: Liuzhou
country: China
facility: Liuzhou People's Hospital
state: Guangxi
city: Nanning Shi
country: China
facility: People's Liberation Army The 923rd Hospital
state: Guangxi
city: Haikou
country: China
facility: Local Institution - 0011
state: Hainan
city: Kunming
country: China
facility: Local Institution - 0012
state: Yunnan
city: Haikou
country: China
facility: Hainan General Hospital
city: Nanning
country: China
facility: The First Affiliated Hospital of Guangxi Medical University
city: Thessaloniki
country: Greece
facility: Local Institution - 0005
state: B
city: Larissa
country: Greece
facility: Local Institution - 0007
state: E
city: Rio
country: Greece
facility: Local Institution - 0018
state: G
city: Athens
country: Greece
facility: Local Institution - 0006
city: Goudi
country: Greece
facility: Local Institution - 0009
city: Hong Kong
country: Hong Kong
facility: Local Institution - 0025
state: HK
city: Hong Kong Island
country: Hong Kong
facility: Local Institution - 0024
city: Cagliari
country: Italy
facility: Local Institution - 0022
state: CA
city: Genova
country: Italy
facility: Local Institution - 0026
state: GE
city: Orbassano
country: Italy
facility: Local Institution - 0020
state: TO
city: Napoli
country: Italy
facility: Local Institution - 0028
city: Napoli
country: Italy
facility: Local Institution - 0019
city: Johor Bahru
country: Malaysia
facility: Local Institution - 0033
city: Kuala Lumpur
country: Malaysia
facility: Local Institution - 0032
city: Al-Ahsa
country: Saudi Arabia
facility: Local Institution - 0035
city: Riyadh
country: Saudi Arabia
facility: Local Institution - 0034
city: Singapore
country: Singapore
facility: Local Institution - 0036
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
state: KHH
city: Nan Gang Qu
country: Taiwan
facility: National Taiwan University Hospital
state: TPE
city: Taichung
country: Taiwan
facility: China Medical University Hospital
state: TXG
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Mueang Phitsanulok
country: Thailand
facility: Local Institution - 0031
city: Altındağ
country: Turkey
facility: Local Institution - 0027
city: Topkapı
country: Turkey
facility: Local Institution - 0021
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: