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

2019-11-03 15:10:54 | BioPortfolio

Summary

This is a Phase 2a study to evaluate the safety and pharmacokinetics (PK) of luspatercept in pediatric subjects who require regular RBC transfusions due to β-thalassemia. At least 12 subjects are planned to be enrolled per each of the 4 age-group strata at 2 different dose levels. Any subject benefiting from the study treatment (at the Investigator's discretion), at the completion of the Treatment Period, will be offered the opportunity to continue luspatercept and long-term follow-up in the Long-term Treatment and Follow-up Period. Subjects entering the Long-term Treatment and Follow-up Period will continue to receive luspatercept at the same dose level as during the Treatment Period for up to 5 years from their first dose (Cycle 1 Day 1) or when the drug is approved for pediatric patients (whichever comes first). Subjects who receive treatment for the full 5 years will then have an End of Treatment visit and then a Post End of Treatment visit (12 weeks from last dose). Any subject that discontinues treatment prior to 5 years from Cycle 1 Day 1 will be have an End of Treatment visit, a Post End of Treatment visit (12 weeks from last dose), and then will continue in Long-Term Posttreatment Follow-up until 5 years from Cycle 1 Day 1 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 subjects who require regular red blood cell (RBC) transfusions due to β-thalassemia and to determine the recommended dose (RD) to be used in the planned confirmatory pediatric study.

The primary endpoints are the determination of the RD and the development of a PK model that describes the PK exposure data of luspatercept and associated variability.

The secondary endpoints include change in RBC transfusion burden, change in hemoglobin levels, safety, frequency of antidrug antibodies and its effect on safety and Exposure-response relationships for measures of activities and toxicity.

The study will consist of the following periods:

- Screening/Run-in Period

- Treatment Period

- Posttreatment Follow-up Period

- Long-term Treatment and Follow-up Period

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

Patients enrolled into the study should have β-thalassaemia (including Hemoglobin E/β-thalassaemia) with ≥ 4 RBC transfusions in the 24 weeks prior to enrollment with no transfusion-free period ≥ 42 days during that period.

Subjects in all planned dose escalation cohorts will receive luspatercept, administered as a subcutaneous (SC) injection, every 3 weeks (21 days) for up to 4 cycles (84 days) in the Treatment Period. Dose delay(s) and dose reduction(s) may be required for individual subjects.

Each dose escalation cohort will consist of up to 6 subjects. Subjects will be treated at one of 2 dose levels, 0.75 mg/kg or 1.0 mg/kg, and enrollment will be sequential in descending order of age:

- Cohort 1: 12 to < 18 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 2: 12 to < 18 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 3: 6 to < 12 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 4: 6 to < 12 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 5: 2 to < 6 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 6: 2 to < 6 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 7: 6 months to < 2 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 8: 6 months to < 2 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles).

The first dose of luspatercept should be administered at least 14 days after the last transfusion prior to enrollment. Subject enrollment via the Integrated Response Technology (IRT) system and study treatment administration should be on the same day (Cycle 1 Day 1), provided that the eligibility criteria are met. Otherwise, the subject will need to be rescreened.

Once all 6 subjects in a cohort have completed the first cycle (Study Day 22), a Dose Review Team (DRT), consisting of the Celgene Medical Monitor, Celgene lead safety physician, Celgene biostatistician, other Celgene functional area representatives or designees, as appropriate, and all active site Investigators and/or designees (at sites with a subject who has received study drug), will review all 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 Common Toxicity Criteria for Adverse Events, version 5.0 (NCI-CTCAE v.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 recommendations to enroll the next cohort at the next planned dose level and/or proceed to the next lower age group will be based in part upon the following criteria:

- If a DLT occurs in ≤ 1 subject (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level and/or next lower age group dose may proceed;

- If a DLT occurs in ≥ 2 subjects (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level and/or the next lower age group should not proceed;

- If a hemoglobin increase of ≥ 2.0 g/dL (confirmed within 14 days after initial study treatment administration and not attributable to RBC transfusion) occurs in ≥ 2 subjects (out of 6) in a cohort, the decision to proceed to the next planned dose level and/or the next lower age group will need to be evaluated by the DRT.

At least 12 subjects are planned to be enrolled with up to 12 subjects per age-group strata eligible for the Dose Determining Sets (DDS). With up to 4 age groups, a total of up to 48 subjects are to be included in the DDS.

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

The primary endpoints are the determination of the RD and the development of a pharmacokinetic (PK) model that describes the PK exposure data of luspatercept and associated variability.

The secondary endpoints include change in RBC transfusion burden, change in hemoglobin levels, safety, frequency of antidrug antibodies and its effect on safety and Exposure-response relationships for measures of activities and toxicity.

The study will consist of the following periods:

- Screening/Run-in Period

- Treatment Period

- Posttreatment Follow-up Period

- Long-term Treatment and Follow-up Period

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

Patients enrolled into the study should have β-thalassaemia (including Hemoglobin E/β-thalassaemia) with ≥ 4 RBC transfusions in the 24 weeks prior to enrollment with no transfusion-free period ≥ 42 days during that period.

Subjects in all planned dose escalation cohorts will receive luspatercept, administered as a subcutaneous (SC) injection, every 3 weeks (21 days) for up to 4 cycles (84 days) in the Treatment Period. Dose delay(s) and dose reduction(s) may be required for individual subjects.

Each dose escalation cohort will consist of up to 6 subjects. Subjects will be treated at one of 2 dose levels, 0.75 mg/kg or 1.0 mg/kg, and enrollment will be sequential in descending order of age:

- Cohort 1: 12 to < 18 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 2: 12 to < 18 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 3: 6 to < 12 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 4: 6 to < 12 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 5: 2 to < 6 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 6: 2 to < 6 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 7: 6 months to < 2 years: Luspatercept 0.75 mg/kg, administered SC once every 21 days (for up to 4 cycles)

- Cohort 8: 6 months to < 2 years: Luspatercept 1.0 mg/kg, administered SC once every 21 days (for up to 4 cycles)

The first dose of luspatercept should be administered at least 14 days after the last transfusion prior to enrollment. Subject enrollment via the Integrated Response Technology (IRT) system and study treatment administration should be on the same day (Cycle 1 Day 1), provided that the eligibility criteria are met. Otherwise, the subject will need to be rescreened.

Once all 6 subjects in a cohort have completed the first cycle (Study Day 22), a Dose Review Team (DRT), consisting of the Celgene Medical Monitor, Celgene lead safety physician, Celgene biostatistician, other Celgene functional area representatives or designees, as appropriate, and all active site Investigators and/or designees (at sites with a subject who has received study drug), will review all 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 Common Toxicity Criteria for Adverse Events, version 5.0 (NCI-CTCAE v.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 recommendations to enroll the next cohort at the next planned dose level and/or proceed to the next lower age group will be based in part upon the following criteria:

- If a DLT occurs in ≤ 1 subject (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level and/or next lower age group dose may proceed;

- If a DLT occurs in ≥ 2 subjects (out of 6) in a cohort within 21 days following the initial dose of luspatercept, the next planned dose level and/or the next lower age group should not proceed;

- If a hemoglobin increase of ≥ 2.0 g/dL (confirmed within 14 days after initial study treatment administration and not attributable to RBC transfusion) occurs in ≥ 2 subjects (out of 6) in a cohort, the decision to proceed to the next planned dose level and/or the next lower age group will need to be evaluated by the DRT.

At least 12 subjects are planned to be enrolled with up to 12 subjects per age-group strata eligible for the Dose Determining Sets (DDS). With up to 4 age groups, a total of up to 48 subjects are to be included in the DDS.

To minimize safety risk to subjects, 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.

Dose interruptions/delays and dose reductions may be used to manage toxicities. Subjects can receive study treatment for up to 4 cycles during the Treatment Period, until study treatment becomes intolerable, or the subject wishes to discontinue study treatment for any reason. The decision to discontinue a subject from study treatment, is the responsibility of the treating physician; however, prior to discontinuing a subject, it is recommended that the Investigator contact the Medical Monitor and forward appropriate supporting documents for review and discussion. Subjects are to undergo end-of-treatment evaluations when study treatment is discontinued. The reason for treatment discontinuation will be recorded in the electronic case report form (eCRF) pages and in the source document.

During the Treatment Period, any subjects discontinued from study treatment will continue to be assessed in the Posttreatment Follow-up Period for AEs, concomitant medications, concomitant procedures, transfusions, hematologic improvement, and subsequent therapies.

Any subject benefiting from the study treatment (at the Investigator's discretion), at the completion of the Treatment Period, will be offered the opportunity to continue luspatercept and long-term follow-up in the Long-term Treatment and Follow-up Period. Subjects entering the Long-term Treatment and Follow-up Period will continue to receive luspatercept at the same dose level as during the Treatment Period for up to 5 years from their first dose (Cycle 1 Day 1) or when the drug is approved for pediatric patients (whichever comes first). Subjects who receive treatment for the full 5 years will then have an End of Treatment (EOT) visit and then a Post End of Treatment visit (12 weeks from last dose). Any subject that discontinues treatment prior to 5 years from Cycle 1 Day 1 will be have an End of Treatment visit, a Post End of Treatment visit (12 weeks from last dose), and then will continue in Long-Term Posttreatment Follow-up until 5 years from Cycle 1 Day 1.

Study Design

Conditions

Beta-Thalassemia

Intervention

ACE-536, ACE-536

Location

Children's Hospital of Los Angeles
Los Angeles
California
United States
90027

Status

Not yet recruiting

Source

Celgene

Results (where available)

View Results

Links

Published on BioPortfolio: 2019-11-03T15:10:54-0500

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Medical and Biotech [MESH] Definitions

A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent.

A hereditary disorder characterized by reduced or absent DELTA-GLOBIN thus effecting the level of HEMOGLOBIN A2, a minor component of adult hemoglobin monitored in the diagnosis of BETA-THALASSEMIA.

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An adult hemoglobin component normally present in hemolysates from human erythrocytes in concentrations of about 3%. The hemoglobin is composed of two alpha chains and two delta chains. The percentage of HbA2 varies in some hematologic disorders, but is about double in beta-thalassemia.

A group of enzymes that catalyzes the hydrolysis of terminal, non-reducing beta-D-galactose residues in beta-galactosides. Deficiency of beta-Galactosidase A1 may cause GANGLIOSIDOSIS, GM1.

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