INFUSE Bone Graft in Treating Patients with Tibial Pseudarthrosis and Neurofibromatosis 1 Undergoing Surgery
This randomized phase II trial studies how well INFUSE bone graft works in treating patients with tibial pseudarthrosis and neurofibromatosis 1 undergoing surgery. INFUSE bone graft containing recombinant human bone morphogenetic protein-2 and absorbable collagen sponge may increase the rate of healing of the tibia bone.
Inclusion Criteria
- All patients who do not have a documented NF1 mutation must meet the clinical diagnosis of NF1 using the National Institutes of Health (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 (anterior-posterior [AP] & lateral leg radiographs) must support the diagnosis of tibial pseudarthrosis with chronic non-union
- Karnofsky >= 50% for patients > 10 years of age and Lansky >= 50 for patients =< 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 magnetic resonance imaging (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
- Absolute neutrophil count (ANC) > 1500/ul
- Platelet count > 100,000/ul
- Hemoglobin >= 10.0 gm/dl
- Maximum serum creatinine of 1.5 mg/dL OR a creatinine clearance >= 70 ml/min/1.73m^2
- Total bilirubin < 1.5 x upper limit of normal for age, and
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [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 antiinflammatory drugs)
- Untreated endocrine abnormality, such as hypothyroidism, parathyroid hormone disorder
- Severe vitamin D deficiency with serum 25-OH 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02718131.
PRIMARY OBJECTIVES:
I. To perform a phase 2 single-blind, randomized clinical trial to determine if use of INFUSE (recombinant human [rh] bone morphogenetic protein-2 [BMP-2] on a collagen sponge) applied at time of surgical repair of tibial pseudarthrosis (TPA) in neurofibromatosis type 1 (NF1) patients will result in: improved bone healing rates compared to patients treated without INFUSE, based on radiographic evidence of cortical bone union at 12 months after surgery (Radiograph union score for tibial fractures [RUST] score; primary outcome measure at 12 months); shorter time (months) to objective radiographic union than in patients treated without INFUSE.
II. To evaluate the feasibility and potential toxicities of BMP-2 administration in this population.
III. To collect, process, and preserve biologic specimens at the time of surgery for future studies.
SECONDARY OBJECTIVES:
I. To evaluate quality of life at the time of surgery, and at 6 months and 12 months after surgery.
II. To determine the incidence and timing of re-fracture after surgery.
III. To provide a cohort of patients with NF1 and TPA treated with a standardized surgical protocol, which can be used as a much-needed arm for future clinical trials.
IV. To provide annual long-term follow up of this cohort of patients for up to 10 years after surgery to monitor for rate of refracture and safety issues. (Note: this objective will not be funded by the current funding for the NF Clinical Trials Consortium).
OUTLINE: Patients are randomized to 1 of 2 groups.
GROUP I: Patients undergo placement of INFUSE bone graft comprising of rhBMP-2 on absorbable collagen sponge (ACS) around the bone junction at the tibial osteotomy site at the time of surgery.
GROUP II: Patients undergo surgery according to standard of care.
After completion of study treatment, patients are followed up at 6 and 12 weeks, and 3, 6, 9, and 12 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Alabama at Birmingham Cancer Center
Principal InvestigatorBruce Richard Korf
- Primary IDF150922005
- Secondary IDsNCI-2017-00197
- ClinicalTrials.gov IDNCT02718131