Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Participants Who Require Regular RBC Transfusions Due to Beta (β)-Thalassemia.

  • STATUS
    Recruiting
  • End date
    Sep 30, 2033
  • participants needed
    54
  • sponsor
    Celgene
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Updated on 4 June 2022
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hysterectomy
progesterone
blood transfusion
hemoglobin e
ace-536
luspatercept

Summary

This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in pediatric participants who require regular red blood cell transfusions due to β-thalassemia.

The study will be conducted in 2 parts: Part A will be in adolescent participants aged 12 to <18 years with two dose escalation cohorts of 6 participants each, followed by a dose expansion cohort of 30 participants. Part B will begin after a review of the safety in participants completing at least one year of treatment in Part A and will be in participants aged 6 to <12 with two dose escalation cohorts of 6 participants each.

Upon completion of the Treatment Period, participants of any cohort who are benefiting from the study treatment, will be offered the opportunity to continue luspatercept treatment in the Long-term Treatment Period for up to 5 years from their first dose (Cycle 1 Day 1).

Participants who discontinue study treatment any time will continue in the Posttreatment Follow-up Period for at least 5 years from their first dose of luspatercept (Cycle 1 Day 1), or 3 years from their last dose, whichever occurs later, or until they withdraw consent/assent, are lost to follow-up, or the End of Trial, whichever occurs first.

Description

This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in pediatric participants who require regular red blood cell (RBC) transfusions due to β-thalassemia and to determine the recommended dose (RD).

The primary endpoints are the determination of the RD and PK parameters (including Cmax, AUC, t1/2, CL/F and Vd/F).

The secondary endpoints include the safety of luspatercept in pediatric participants, the immunogenicity (frequency of antidrug antibodies) of luspatercept, mean change in RBC transfusion burden, mean change in hemoglobin levels, mean change from baseline in mean daily dose of iron chelation therapy (ICT), and mean change from baseline in serum ferritin.

The study will consist of the following periods:

  • Screening/Run-in Period
  • Treatment Period
  • Long-term Treatment Period
  • Posttreatment Follow-up Period

Participant screening procedures will occur during the Screening/Run-in Period, within 12 weeks prior to the start of study treatment. Participants who meet the study eligibility criteria will be enrolled into the Treatment Period.

The study will be conducted in a staggered manner, in descending order of age, with 2 parts as described below.

Part A

Adolescent participants aged 12 to < 18 years: Luspatercept 0.75 will be enrolled as outlined

below

Part A Dose Escalation Phase

Part A Dose Escalation Phase will explore up to 2 dose levels of luspatercept, 0.75 mg/kg and 1.0 mg/kg, to evaluate the safety and tolerability of luspatercept in this age group and determine the RD to be used for Part A Expansion Phase:

  • Cohort 1: 6 adolescent participants 12 to < 18 years of age receiving luspatercept 0.75 mg/kg, administered subcutaneously (SC) once every 21 days (for up to 4 cycles in the Treatment Period)
  • Cohort 2: 6 adolescent participants 12 to < 18 years of age receiving luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles in the Treatment Period)

Part A Expansion Phase

• Cohort 3 - The Expansion Cohort: 30 adolescent participants (12 to < 18 years of age) receiving luspatercept at the RD for up to 12 months in the Treatment Period.

Children from 6 years to < 12 years of age will be enrolled into Part B as outlined below:

Part B Dose Escalation Phase will explore 2 dose levels of luspatercept, 1.0 mg/kg and 1.25 mg/kg, to evaluate the safety and tolerability of luspatercept in this age group and determine the RD.

  • Cohort 4: 6 participants (6 to < 12 years of age) receiving luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles in the Treatment Period)
  • Cohort 5: 6 participants (6 to <12 years of age) receiving luspatercept 1.25 mg/kg, administered SC once every 21 days (for up to 4 cycles in the Treatment Period)

During the Treatment Period of both Part A Dose Escalation Phase and Part B Dose Escalation Phase, once all 6 participants in a dose escalation cohort have completed the first cycle (Study Day 22), the Dose Review Team (DRT), will review all available safety data, including dose-limiting toxicities (DLTs), adverse events (AEs), serious adverse events (SAEs), and laboratory results (including hematology and chemistry) reported during Cycle 1 of each dose level.

A DLT, using the current active version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, is defined as any of the following toxicities at any dose level occurring within 21 days of the first administered

dose
  • Treatment-related SAE of ≥ Grade 3
  • Treatment-related nonhematologic AE of ≥ Grade 3
  • Treatment-related hematologic AE of ≥ Grade 4

The DRT will make a recommendation as to whether or not to enroll the next cohort at the next planned dose level based in part upon the following criteria:

  • If a DLT occurs in ≤ 1 participant (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level may proceed;
  • If a DLT occurs in ≥ 2 participants (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level should not proceed;
  • If a hemoglobin increase of ≥ 2.0 g/dL (confirmed by central lab after initial study treatment administration and not attributable to RBC transfusion) occurs in ≥ 2 participants (out of 6) in a cohort, the decision to proceed to the next planned dose level will need to be evaluated by the DRT.

At least 6 participants eligible for the Dose Determining Set (DDS) are planned to be enrolled per dose escalation cohort with up to 2 cohorts per age group. With up to 4 2 age groups being considered, a total of up to 24 participants are to be included in the DDS.

To minimize safety risk to participants, best supportive care will be available, including RBC transfusions, iron-chelating agents, use of antibiotic therapy, antiviral and antifungal therapy, and/or nutritional support as needed.

Details
Condition Beta-Thalassemia
Treatment ACE-536
Clinical Study IdentifierNCT04143724
SponsorCelgene
Last Modified on4 June 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Participants must satisfy the following criteria to be enrolled into the
study
Participant must be 6 years to < 18 years of age at the time of signing the informed consent form (ICF)/informed assent form (IAF)
Participant (and when applicable, parent/legal representative) must understand and voluntarily sign an ICF/IAF prior to conducting any study-related assessments/procedures
Participant (and when applicable, parent/legal representative) is willing and able to adhere to the study visit schedule and other protocol requirements
Participant must have documented diagnosis of β-thalassemia or Hemoglobin/β-thalassemia
Participant is regularly transfused, defined as: ≥ 4 red blood cell transfusions in the 24 weeks prior to enrollment with no transfusion-free period ≥ 42 days during that period
Note: For the purpose of the study, transfusions administered over 2 or 3
consecutive days are considered as part of a single transfusion event
Participant must have a history of regular transfusions for at least 2 years
Participant has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 50 at screening
Female children of childbearing potential (FCCBP), females of childbearing potential (FCBP), and male participants that have reached puberty (and when applicable, parent/legal representative) must agree to undergo physician-approved reproductive education and discuss the side effects of the study therapy on reproduction
Female children of childbearing potential, defined as females who have achieved menarche and/or breast development in Tanner Stage 2 or greater and have not undergone a hysterectomy or bilateral oophorectomy and females of childbearing potential (FCBP)defined as a sexually mature woman who has achieved menarche at some point, has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) must meet the following conditions below (Note: Secondary amenorrhea from any cause does not rule out childbearing potential)
Female participants must, as appropriate to age and at the discretion of the site Investigator, either commit to true abstinence _from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective_ contraception without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based on multiple-dose PK data) after discontinuation of study therapy
Male participants, as appropriate to age and the discretion of the study physician
Medically supervised serum pregnancy tests with a sensitivity of at least 25 mIU/mL must be conducted in Female children of childbearing potential (FCCBP)/ females of childbearing potential (FCBP), including those who commit to complete abstinence. Female children of childbearing potential/ females of childbearing potential (FCBP)must have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. Female children of childbearing potential/ females of childbearing potential (FCBP)must agree to ongoing pregnancy testing during the course of the study, after the end of study treatment, and end of the study
Must practice true abstinence (which must be reviewed on a monthly basis) or agree to use a synthetic or latex condom during sexual contact with a pregnant female or a Female children of childbearing potential (FCCBP)/FCBP while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy
True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the participant. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.] Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progesterone/progestin containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen/progestin only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence

Exclusion Criteria

The presence of any of the following will exclude a participant from enrollment into the
Participant has any significant medical condition, laboratory abnormality, or
psychiatric illness that would prevent the participant from participating in the
study
Participant has any condition including the presence of laboratory abnormalities
which places the participant at unacceptable risk if he/she were to participate in the
study
Participant has any condition that confounds the ability to interpret data from the
study
Participant has a diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia
(eg, Hemoglobin H); β-thalassemia combined with α-thalassemia is allowed
Participant has of active hepatitis C (HCV) infection, as demonstrated by a positive
HCF-ribonucleic acid (RNS) test of sufficient sensitivity, or active infectious
study
hepatitis B (as demonstrated by the presence of hepatitis B surface antigen (HBsAG)
and/or hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) positive, or known positive
human immunodeficiency virus (HIV)
Note: Participants receiving antiviral therapies should have 2 negative HCV-RNA tests
months apart before ICF/IAF signature, ie, one test at the end of the antiviral
therapy and the second test 3 months following the first test
Participant has severe infection ≤ 28 days prior to enrollment. Additionally, in the
case of prior SARS-CoV-2 infection, symptoms must have completely resolved, and based
on Investigator assessment in consultation with the Clinical Trial Physician, there
are no sequelae that would place the participant at a higher risk of receiving
investigational treatment
Participant has received a live COVID-19 vaccine ≤ 28 days prior to screening
Participant has deep vein thrombosis (DVT), stroke, or other thromboembolic event(s)
(except clogged indwelling catheter) requiring medical intervention ≤ 24 weeks prior
to enrollment
Participant has chronic anticoagulant therapy ≤ 28 days prior to enrollment
(Anticoagulant therapies used for prophylaxis for surgery or high-risk procedures as
well as low molecular weight [LMW] heparin for superficial vein thrombosis [SVT] and
chronic aspirin are allowed)
Participant has platelet count > 1000 x 109/L
Participant has poorly controlled diabetes mellitus within 24 weeks prior to
enrollment as defined by short term (eg, hyperosmolar or ketoacidotic crisis) and/or
history of diabetic cardiovascular complications (eg, stroke or myocardial
infarction)
Participant has treatment with another investigational drug or device ≤ 28 days prior
to enrollment
Participant has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)
Participant underwent or is scheduled for HSCT or gene therapy
Participant has used an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to
enrollment
Participant use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior to
enrollment (allowed if initiated > 8 weeks before or during treatment)
Participant use of hydroxyurea treatment ≤ 24 weeks prior to enrollment
Participant is pregnant or breastfeeding female
Participant has uncontrolled hypertension. Controlled hypertension for this protocol
is considered ≤ Grade 1 according to NCI CTCAE version 5.0
Participant has major organ damage, including
Liver disease with alanine aminotransferase (ALT)/aspartate aminotransferase
(AST) > 3X the upper limit of normal (ULN) for age
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 years of enrollment
Symptomatic splenomegaly
Lung disease, including pulmonary fibrosis or pulmonary hypertension which are
clinically significant
A serum creatinine based on age/gender based on threshold derived from
Renal insufficiency defined as
Schwartz formula for estimating GFR utilizing child length and stature data
published by the Centers for Disease Control
Participant has proteinuria ≥ Grade 3 according to NCI CTCAE version 5.0
Participant use of chronic systemic glucocorticoids ≤ 12 weeks prior to enrollment
(physiologic replacement therapy for adrenal insufficiency is allowed). Single day
glucocorticoid treatment (eg, for prevention or treatment of transfusion reactions) is
allowed
Participant has history of malignancy with the exception of
Participant has major surgery ≤ 12 weeks prior to enrollment (participants must have
Curatively resected nonmelanoma skin cancer
completely recovered from any previous surgery prior to enrollment)
Curatively treated cervical carcinoma in situ
Participant has history of severe allergic or anaphylactic reactions or
hypersensitivity to recombinant proteins or excipients in the IP (see IB)
Participant use of cytotoxic agents, immunosuppressants ≤ 28 days prior to enrollment
(ie, antithymocite globulin (ATG) or cyclosporine)
Other solid tumor with no known active disease in the opinion of the
Investigator
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