Denosumab for Prevention of Bone Complications After Bone Marrow Transplantation in Children

NCT ID: NCT02677246

Last Updated: 2018-09-06

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-31
• Study Completion Date: 2018-09-04

Brief Summary

Children treated by bone marrow transplantation (BMT) experience bone toxicity. Those bone damages are caused by both a decrease of bone formation and an increase of bone destruction after BMT.For long term survivors, bone complications are major determinants of impaired quality of life. No standard treatment currently exists to prevent those bone injuries. Denosumab is a treatment which specifically blocks bone destruction for 4 to 6 months in adults. This trial will study whether it is safe to prescribe Denosumab to children after BMT in the aim of preventing bone complications.

Detailed Description

Participant will receive one subcutaneous dose of Denosumab within 2 weeks after confirmation of bone marrow engraftment. The dose of treatment will be escalated between participants. Denosumab is supposed to be effective for several months (4 to 6 months). The biologic activity of Denosumab will be followed by the measure in the blood of a biomarker of bone destruction called CTX. This biomarker is supposed to decrease after Denosumab infusion, reflecting the blockade of bone destruction by the treatment. Bone density will be assessed by a radiologic test named DXA which a standard test. All blood and radiologic tests mandated by the study will be done at the same time as standard follow-up after bone marrow transplant. Thus, participants will not have extra visits at the outpatient clinic, or extra blood punctures, for the specific purpose of the study. Participants will be followed for 36 months after bone marrow transplantation.For experiencing graft versus host disease, a second dose of Denosumab will be allowed, followed by subsequent doses evry 4 to 6 months till a maximum of 4 doses within 24months after bone marrow transplantation.

Conditions

Disorder Related to Bone Marrow Transplantation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Denosumab

Phase 1, 3+3 design with inter-patient dose escalation from 1mg/kg/dose to 2mg/kg/dose, and possibility of a dose de-escalation of 0.5mg/kg/dose, A modification of 3+3 design is implemented to take into account the achievement of bone resorption blockade by Denosumab. CTX is a biologic marker of bone resorption. Provided a decrease of CTX blood level will be observed under the lower limit (2,5th percentile) for age and sex, or under 20% of the pre-treatment level, there will be no reason to continue escalating the dose. This modified 3+3 design prevents exposure of children to dose escalations that would not be needed regarding the medical and biological aims of this trial.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

Denosumab, one sub-cutaneous infusion, given within 2 weeks after engraftment defined as neutrophils > 0,5x10(9)/L and chimerism ≥ 10% of donor origin.

Before starting Denosumab several requirements have to be met: 1) Calcemia and Phosphatemia in the normal ranges, 2) adequate Calcium and Vitamin D intakes according to age.

Biological activity of Denosumab measured by CTX blood level, expected to last for 4 to 6 months after one infusion.

Possibility of subsequent infusions at the same dose level, every 5 to 6 months, for patient remaining on corticotherapy, provided no DLT occurred and provided CTX blood level decreased under the required threshold, after the previous infusions of Denosumab

Interventions

Denosumab

Denosumab, one sub-cutaneous infusion, given within 2 weeks after engraftment defined as neutrophils > 0,5x10(9)/L and chimerism ≥ 10% of donor origin.

Before starting Denosumab several requirements have to be met: 1) Calcemia and Phosphatemia in the normal ranges, 2) adequate Calcium and Vitamin D intakes according to age.

Biological activity of Denosumab measured by CTX blood level, expected to last for 4 to 6 months after one infusion.

Possibility of subsequent infusions at the same dose level, every 5 to 6 months, for patient remaining on corticotherapy, provided no DLT occurred and provided CTX blood level decreased under the required threshold, after the previous infusions of Denosumab

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age from 2 year to 21 years
• Allogenic hematopoietic stem cell transplantation (allo-HSCT) planned within 1 month.
• Informed consent signed by participant more than 18 year old, or parents or his/her legal guardian
• Teeth examination by a dentist in order to rule out or to treat latent teeth infections before allo-HSCT

Exclusion Criteria

• Refusal of signing informed consent
• Prior inclusion in another therapeutic trial with a time elapsed from the last research drug dose to Denosumab, shorter than 7 half-lifes of the research drug
• Osteopetrosis
• Bisphosphonates treatment within 12 months before entering the trial
• Tooth infection not treated before allo-HSCT
• Child-bearing and breastfeeding women

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St. Justine's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Pierre Teira, MD

MD, MSc

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Pierre Teira, MD

Role: PRINCIPAL_INVESTIGATOR

St. Justine's Hospital

Locations

St. Justine 's Hospital

Montreal, Quebec, Canada

Countries

Canada

Other Identifiers

HSJ001

Identifier Type: -

Identifier Source: org_study_id