A Study of INFUSE Bone Graft (BMP-2) in the Treatment of Tibial Pseudarthrosis in Neurofibromatosis Type 1 (NF1)

Inclusion Criteria:

Diagnosis of NF1 using the NIH Consensus Conference criteria. In addition to tibial pseudarthrosis, one or more of the following diagnostic criteria for NF1 must be present:
Six or more cafe'-au-lait spots (≥ 0.5cm prepubertal; ≥ 1.5cm postpubertal)
Freckling in the axilla or groin Optic pathway glioma
Two or more iris Lisch nodules
Two or more neurofibromas or one plexiform neurofibroma
A first-degree relative with NF1
Patients must have tibial pseudarthrosis that has the potential to cause significant morbidity. Radiographic findings (AP & lateral leg radiographs) must support the diagnosis of tibial pseudarthrosis with chronic non-union.
Age between 2 years and 18 years of age at time of study entry.
Performance Level: Karnofsky ≥ 50 percent for patients > 10 years of age and Lansky ≥ 50 percent for patients or ≤ 10 years of age.

Prior Therapy:

Patients who have undergone 1 previous surgery for tibial pseudarthrosis repair will be eligible to enter the study if they have refracture.
Use of BMP-2 in the prior surgery is permitted, however patients with prior exposure must be screened for antibodies to BMP-2, bovine collagen, and rhBMP-2 neutralizing antibodies.
Prior use of BMP-2 is allowed but will be recorded as a possible compounding factor.
Patients who have had 2 or more prior surgeries for pseudarthrosis repair are ineligible

Absence of Tumors:

Patients must undergo thorough physical examination of the leg undergoing surgery. If physical exam is equivocal for presence of tumors, then a normal MRI of the lower extremity will be required before eligibility is met.
If there is evidence of plexiform neurofibroma or nodular neurofibroma of > 3 cm diameter on the ipsilateral leg, then they are ineligible for the study.
Organ Function Requirements

Adequate bone marrow function defined as:

Absolute neutrophil count (ANC) > 1500/
µl Platelet count > 100,000/
µl Hemoglobin ≥ 10.0 gm/dL

Adequate renal function defined as:

maximum serum creatinine of 1.5 mg/dL OR
a creatinine clearance≥70ml/min/1.73m2.

Adequate renal function defined as:

maximum serum creatinine of 1.5 mg/dL OR
a creatinine clearance ≥ 70ml/min/1.73m2.

Adequate liver function defined as:

Total bilirubin < 1.5 X upper limit of normal for age, and SGPT (serum glutamic pyruvic transaminase, ALT) < 2 X upper limit of normal for age
Serum Vitamin D level ≥ 10 ng/ml

Exclusion Criteria:

Lack of documentation for a diagnosis of NF1
Tibial fracture without evidence of pseudarthrosis or tibial dysplasia
Tibial dysplasia/bowing without fracture or pseudarthrosis
Plexiform neurofibroma of any size, or nodular neurofibroma of > 3 cm diameter involving the ipsilateral leg, including the hip
If presence of plexiform is suspected but not certain on physical exam, MRI of the leg may be indicated to rule this out.
History of MPNST (malignant peripheral nerve sheath tumor) or any malignancy other than asymptomatic and stable optic nerve glioma
Optic nerve glioma that has resulted in precocious puberty or visual impairment of any degree
Visual impairment from any cause
Precocious puberty from any cause
Hypertension other than mild essential hypertension controlled with medication
Metastatic disease of any kind
Inadequate neurovascular status in the involved limb that may jeopardize healing
Active or known prior infection at the pseudarthrosis site
Active systemic infection
Other injury or condition that prevents ambulation or completion of study assessments
Two or more prior surgeries for tibial pseudarthrosis
Bilateral tibial dysplasia
Selection of a surgical approach that does not include prescribed surgical intervention, which must include removal of pseudarthrosis tissue, placement of an intramedullary rod using the Williams approach, and autogenous bone graft from the iliac crest distributed at the osteotomy site
Normal ipsilateral fibula without planned fibular osteotomy at time of surgery
Allergy to bone morphogenetic protein
Allergy to bovine collagen products
Positive antibody titers to BMP-2, bovine collagen, or BMP-2 neutralizing antibodies prior to surgery
History of using any of the following medications, regardless of dose, for at least 1 month, within 3 months of enrollment: Anabolic agents, Glucocorticoids (does not include inhaled glucocorticoids), Growth hormone, Parathyroid hormone (PTH)
Need for postoperative medications that could interfere with bone healing of the implant, such as steroids, (but not including low-dose aspirin or routine perioperative anti-inflammatory drugs)
Untreated endocrine abnormality, such as hypothyroidism, parathyroid hormone disorder
Severe Vitamin D deficiency with serum 25-OH (hydroxy) Vitamin D < 10 ng/ml (25 nmol/l) Patients with Vitamin D levels < 10 ng/ml may be treated with Vitamin D and reconsidered for enrollment when levels are sufficient
Females who are sexually active without use of effective contraception
Females who are pregnant or breastfeeding

For more information on this trial, visit clinicaltrials.gov.