A Study to Evaluate Long-term Safety in Participants Who Have Participated in Other Luspatercept (ACE-536) Clinical Trials

• ClinicalTrials.gov Identifier: NCT04064060
• Recruitment Status: Recruiting
• First Posted: August 21, 2019
• Last Update Posted: May 16, 2023
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: August 9, 2019
• First Posted Date: August 21, 2019
• Last Update Posted Date: May 16, 2023
• Actual Study Start Date: August 12, 2019
• Estimated Primary Completion Date: March 25, 2030 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 26, 2022)

• Adverse Events (AEs) [ Time Frame: From enrollment until at least 42 Day Safety Follow-up Phase or EOS (Approximately 5 years). ]
  Type, frequency, severity of AEs, relationship of treatment emergent adverse events to luspatercept
• Number of participants progressing to high/very high risk MDS or AML. [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Progression to high/very high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (MDS and myelofibrosis [MF] only).
• Percentage of participants progressing to high/very high risk MDS or AML [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Progression to high/very high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (MDS and myelofibrosis [MF] only)
• Number of participants developing other malignancies/pre-malignancies [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Development of other malignancies/pre-malignancies
• Percentage of participants developing other malignancies/pre-malignancies [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Development of other malignancies/pre-malignancies

Original Primary Outcome Measures (submitted: August 19, 2019)

• Adverse Events (AEs) [ Time Frame: From enrollment until at least 42 Day Safety Follow-up Phase or EOS (Approximately 5 years). ]
  Type, frequency, severity of AEs, relationship of treatment emergent adverse events to luspatercept
• Number of subjects progressing to high/very high risk MDS or AML. [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Progression to high/very high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (MDS and myelofibrosis [MF] only).
• Percentage of subjects progressing to high/very high risk MDS or AML [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Progression to high/very high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (MDS and myelofibrosis [MF] only)
• Number of subjects developing other malignancies/pre-malignancies [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Development of other malignancies/pre-malignancies
• Percentage of subjects developing other malignancies/pre-malignancies [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Development of other malignancies/pre-malignancies

Current Secondary Outcome Measures (submitted: July 26, 2022)

• Overall Survival [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
  Time from date of randomization until death from any cause
• Number of participants developing treatment emergent extramedullary hematopoiesis (EMH) masses [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]
• Percentage of participants developing treatment emergent EMH masses [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]

Original Secondary Outcome Measures (submitted: August 19, 2019)

Overall Survival [ Time Frame: Enrollment to Long-term post-treatment follow-up (Approximately, 5 years) ]

Time from date of randomization until death from any cause

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

Descriptive Information

• Brief Title: A Study to Evaluate Long-term Safety in Participants Who Have Participated in Other Luspatercept (ACE-536) Clinical Trials
• Official Title: A Phase 3b, Open-label, Single-arm, Rollover Study to Evaluate Long-term Safety in Subjects Who Have Participated in Other Luspatercept (ACE-536) Clinical Trials

Brief Summary

A Phase 3b, open-label, single-arm, rollover study to evaluate the long-term safety of luspatercept, to the following participants:

• Participants receiving luspatercept on a parent protocol at the time of their transition to the rollover study, who tolerate the protocol-prescribed regimen in the parent trial and, in the opinion of the investigator, may derive clinical benefit from continuing treatment with luspatercept
• Participants in the follow-up phase previously treated with luspatercept or placebo in the parent protocol will continue into long-term post-treatment follow-up in the rollover study until the follow-up commitments are met
• The study design is divided into the Transition Phase, Treatment Phase and Follow-up Phase. Participants will enter transition phase and depending on their background will enter either the treatment phase or the Long-term Post-treatment Follow-up (LTPTFU) phase
• Transition Phase is defined as one Enrollment visit
• Treatment Phase: For participants in luspatercept treatment the dose and schedule of luspatercept in this study will be the same as the last dose and schedule in the parent luspatercept study. This does not apply to participants that are in long-term follow-up from the parent protocol

• Follow-up Phase includes:

  - 42 Day Safety Follow-up Visit

• During the Safety Follow up, the participants will be followed for 42 days after the last dose of luspatercept, for the assessment of safety-related parameters and adverse event (AE) reporting

  - Long-term Post-treatment Follow-up (LTPTFU) Phase

• Participants will be followed for overall survival every 6 months for at least 5 years from first dose of luspatercept in the parent protocol, or 3 years of post-treatment from last dose, whichever occurs later, or until death, withdrawal of consent, study termination, or until a subject is lost to follow-up. Participants will also be monitored for progression to AML or any malignancies/pre-malignancies. New anticancer or disease related therapies should be collected at the same time schedule

Participants transitioning from a parent luspatercept study in post-treatment follow-up (safety or LTPTFU) will continue from the same equivalent point in this rollover study.

The rollover study will be terminated, and relevant participants will discontinue from the study when all participants fulfill at least 5 years from the first dose of luspatercept in the parent protocol, or 3 years of post-treatment from last dose, whichever occurs later.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Myelodysplastic Syndromes (MDS)
• Beta-thalassemia
• Myeloproliferative Neoplasm(MPN)-Associated Myelofibrosis

Intervention

Drug: Luspatercept

Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion protein consisting of a modified form of the extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the human immunoglobin G 1 (IgG1) Fc domain. ActRIIB receptor and its ligands are members of the transforming growth factor-β (TGF-β) superfamily. Members of the TGF-β superfamily ligands, through their binding to activin receptors, are involved in modulating the differentiation of late-stage erythrocyte precursors (normoblasts) in the bone marrow. Luspatercept for injection is formulated as a sterile, preservative-free, lyophilized cake/powder. Luspatercept for injection is available in 25 mg and 75 mg vials and when reconstituted with water for injection, each consists of 50 mg/mL luspatercept in a 10 mM citrate buffer-based solution

Other Name: ACE-536

Study Arms

Experimental: ACE-536

Luspatercept will be administered as a subcutaneous (SC) injection to participants by the study staff at the clinical site and administration will be documented in the subject's source record.

Intervention: Drug: Luspatercept

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 19, 2019): 665
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 25, 2030
• Estimated Primary Completion Date: March 25, 2030 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Participants must meet all the following criteria to be enrolled in this study:

1. Participant is ≥ 18 years at the time of signing the informed consent form (ICF).
2. Participant is willing and able to adhere to the study visit schedule and other protocol requirements.

3. Participant has been participating in a luspatercept trial and continues to fulfill all the requirements of the parent protocol and the participant has been either:

   1. Assigned to luspatercept treatment, continues to receive clinical benefit in the opinion of the investigator and should continue to receive luspatercept treatment, OR
   2. Assigned to placebo arm in the parent protocol (at the time of unblinding or in follow-up) and should cross over to luspatercept treatment, OR
   3. Assigned to the Follow-up Phase of the parent protocol, previously treated with luspatercept or placebo in the parent protocol who shall continue into Long-term Post-treatment Follow-up Phase in the rollover study until the follow-up commitments are met (unless requirements are met as per parent protocol to crossover to luspatercept treatment).
4. Participant understands and voluntarily signs an informed consent document prior to any study-related assessments or procedures being conducted.
5. Participant demonstrates compliance, as assessed by the investigator, with the parent study protocol requirements.
6. Applies to on treatment Participants only- females of childbearing potential (FCBP) defined as a sexually mature woman who:

1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reasons does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must:

1. Have two negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the participant practices true abstinence* from heterosexual contact.

2. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with highly effective, contraception without interruption, 35 days prior to starting investigational product (IP), during the study therapy (including dose interruptions), and for 84 days after discontinuation of study therapy.

   7. Applies to on treatment participants only- Male participants must:

a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 84 days following investigational product discontinuation even if he has undergone a successful vasectomy.

Exclusion Criteria:

The presence of any of the following will exclude a participant from enrollment:

1. Applies to on treatment participants only- Concomitant use of any medications/procedures that are prohibited in the parent luspatercept protocol.
2. Participant has met one or more criteria for study discontinuation as stipulated in the parent luspatercept protocol.
3. Applies to on treatment participants only- More than 26 days between last luspatercept dose in the parent protocol and first dose into ACE-536-LTFU-001 protocol unless dose delay or dose discontinuation criteria met.
4. Applies to on treatment participants only- Pregnant or breastfeeding females.
5. Participant has any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study.
6. Participant has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
7. Participant has any condition that confounds the ability to interpret data from the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: BMS Study Connect Contact Center www.BMSStudyConnect.com; 855-907-3286; Clinical.Trials@bms.com

• Listed Location Countries: Australia, Belgium, Bulgaria, Canada, France, Germany, Greece, Israel, Italy, Japan, Lebanon, Malaysia, Netherlands, Spain, Sweden, Taiwan, Thailand, Tunisia, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04064060
• Other Study ID Numbers: ACE-536-LTFU-001; U1111-1235-8123 ( Registry Identifier: WHO ); 2018-002915-93 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

BMS will provide access to individual anonymized participant data upon request from qualified researchers, and subject to certain criteria.

Additional information regarding Bristol Myer Squibb's data sharing policy and process can be found at: https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosurecommitment.html

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: See Plan Description
• Access Criteria: See Plan Description
• URL: https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html

• Current Responsible Party: Celgene
• Original Responsible Party: Same as current
• Current Study Sponsor: Celgene
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Celgene
• Verification Date: May 2023