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

NCT02677246 | Withdrawn Phase 1 DMC

• 1 other identifier: HSJ001
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Disorder Related to Bone Marrow Transplantation

Keywords

Bone marrow transplantation; Children; Bone complications; Denosumab.

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerable Dose (MTD)

  The MTD is defined as: * the maximum dose level at which 0 to 1 out of 6 patients experience dose-limiting toxicity (DLT) and above which 2 or more patients encounter DLT. * or the dose of Denosumab necessary for blocking bone resorption for at least 4 months in 6 consecutive patients, if dose limiting toxicities are not observed

  MTD will be definitively established at 6 months after the last patient has been entered into the study. Given the anticipated rate of accrual, the primary outcome measure should be determined within 2 years after opening the study.

Secondary Outcomes (7)

• Evolution of CTX (a biological marker of bone resorption) level in blood

  Dosage before transplantation, before beginning Denosumab, then monthly till 6 months, then at 12 months, 18 months, 24 and 36 months after starting Denosumab

• Evolution of P1NP (a biological marker of bone synthesis) level in blood

  Dosage before transplantation and before beginning Denosumab, then monthly till 6 months, then at 9 months, 12 months, 18 months, 24 months and 36 months after starting Denosumab

• Osteonecrosis (apart from jaw osteonecrosis)

  At 1 year, 2 years and 3 years after bone marrow transplantation

• Fracture

  At 1 year, 2 years and 3 years after bone marrow transplantation

• Bone Mineral Density (BMD)

  Before bone marrow transplantation, then 6 months, 12 months, 24 months and 36 months after starting Denosumab

Study Arms (1)

Denosumab

EXPERIMENTAL

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.

Drug: Denosumab

Interventions

Denosumab 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

Denosumab

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• Refusal of signing informed consent
• Osteopetrosis
• Bisphosphonates treatment within 12 months before entering the trial
• Tooth infection not treated before allo-HSCT
• Child-bearing and breastfeeding women

Sponsors & Collaborators

• St. Justine's Hospital: lead

Study Sites (1)

St. Justine 's Hospital

Montreal, Quebec, H3T1C5, Canada

Location

MeSH Terms

Interventions

Denosumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Pierre Teira, MD

  St. Justine's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, MSc

Study Record Dates

• First Submitted: February 2, 2016
• First Posted: February 9, 2016
• Study Start: December 1, 2016
• Primary Completion: September 4, 2018
• Study Completion: September 4, 2018
• Last Updated: September 6, 2018

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)