Hemangioma
Conditions
Keywords
hemangioma, steroid, prednisolone, vincristine
Brief summary
The goal of this study is to determine the safety and efficacy of Prednisolone and Vincristine for treatment of large, complicated infantile hemangiomas. The diagnostic, therapeutic and response criteria experimentally determined in this study will be used as a framework for future infantile hemangioma studies.
Detailed description
Infants with large hemangiomas are often treated systemically with oral steroids (Prednisolone) to prevent complications. The best treatment for hemangiomas is not known and there are no medications approved by the FDA for treatment of hemangiomas. Also, the best method to measure the response of hemangioma to treatment is not known. Patients enrolling on this study will be randomly assigned to receive either daily Prednisolone by mouth or weekly Vincristine in a vein. Response to treatment will be monitored by clinical exams every two weeks and by an MRI at study entry and six and twelve weeks later. Patients with evidence of progressive disease (larger hemangiomas) on the week 6 MRI will be switched to the other drug to complete a total of 12 weeks of therapy. Side effects of each medication will be monitored closely determined from histories, physical exams, blood tests and other studies as necessary. Participation in this study will last up to 12 weeks and follow up for protocol.
Interventions
DRUGVincristine
Vincristine (0.05 mg/kg/dose) will be administered into a vein (PICC line) every week for 12 weeks. If assigned to receive Vincristine, a PICC line will be placed by a doctor who is a specialist in this procedure, an interventional radiologist. This will require sedation and when possible, will be coordinated with sedation for the MRI.
DRUGPrednisone
Prednisolone given at 3 mg/kg/day by mouth for 12 week
Sponsors
FDA Office of Orphan Products Development
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Months
Healthy volunteers
No
Inclusion criteria
* Children age 0-6 months old. * Infants with infantile hemangiomas with complications that require systemic therapy to control their growth. To be eligible for enrollment infants must have clear indications for systemic treatment. * Clinical diagnosis of infantile hemangioma confirmed by tissue biopsy positive for GLUT-1 Immunohistochemical staining. If the risk of bleeding or permanent disfigurement from biopsy is believed to be too great then clinical and radiological characteristics may be used to establish the diagnosis after discussion with the study PI. Patients with GLUT-1 negative vascular tumors such as Kaposiform hemangioendothelioma, tufted angioma, and angiosarcoma are not eligible. * Hemangiomas must be greater than or equal to 50 cm2 clinically measured by taking the product of the two largest perpendicular diameters and have one of the following complications: ulceration, impairment of vision, impairment of hearing, obstruction of the airway, high output cardiac failure, bleeding, abdominal distention and/or compartment syndrome, compression of the spinal cord, or high risk of permanent disfigurement. * Adequate liver function defined as: * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and * SGPT(serum glutamate pyruvate transaminase) (ALT) \< 2.5 x upper limit of normal (ULN) for age. * Patients who have received topical or intralesional corticosteroids are eligible to be enrolled. A washout of one week is required prior to study enrollment. Patients who have undergone surgical resection are eligible if they meet all inclusion criteria after surgery. * All patients' parents or legal guardians must sign a written informed consent. All institutional and FDA requirements for human studies must be met.
Exclusion criteria
* Children greater then 6 months old. * Contraindications to Vincristine: previously diagnosed neuropathy including sensory neuropathy type 1, Charcot- Marie-Tooth or childhood poliomyelitis. * Hemangioma involving the central nervous system (CNS) as Vincristine has poor CNS penetration. * Infants who have received prior systemic therapy with corticosteroids (oral or intravenous), interferon or Vincristine are not eligible for enrollment. * Patients receiving Vincristine who concomitantly require oral steroids for treatment of non-hemangioma indications such as asthma or atopic dermatitis will be removed from study. * A life-threatening intercurrent infection. * Infants with an underlying illness that would require use of general anesthesia (as opposed to sedation) for the MRI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response of Hemangioma (IH) to Treatment | 6 weeks | Response of IH not confined to the dermis will be coded using the following criteria: Progressive disease: \>40% increase in volume by MRI, Partial response: \>65% reduction in volume by MRI, Complete response: no visual or radiographic evidence of disease, Stable disease: none of the above or \<40% increase or \<65% decrease in volume by MRI. Response of superficial IH will be coded using the following criteria (based on RECIST): Progressive disease: \>30% increase in IH size, Partial response: \>30% reduction in size, Complete response: no evidence of disease, Stable disease: none of the above. Our first 3 patients showed limits to using MRI volume to measure IH size/response to therapy. Unlike other solid tumors, the superficial distribution of some IH made getting volume by MRI difficult, resulting in smaller tumor estimation compared to clinical assessment. Based on these observations, we amended the protocol to report response based on RECIST criteria instead of change in IH volume. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity to Medications | Initial visit, 2, 4, 6, 10 and 12 weeks of therapy | Adverse events were closely monitored and recorded at weekly visits during treatment period and for two years after treatment ceased. Laboratory values were taken every other week during the treatment period. Please see Adverse Events module for more details. |
Countries
United States
Participant flow
Recruitment details
Study participants were recruited from the Pediatric Dermatology clinic at Children's Hospital of Wisconsin between. Study enrollment period extended from 2008-2009.
Pre-assignment details
Subjects meeting eligibility criteria including diagnosis and lesional size criteria were enrolled in the study. Subjects who had received topical or intralesional corticosteroids were eligible following a 1 week wash-out period.
Participants by arm
| Arm | Count |
|---|---|
| Vincristine Treatment Group Vincristine is a drug that has been used to treat cancers in children (including infants). It has been effective in treating a small number of infants with hemangiomas, most of whom failed previous therapies including steroids. Vincristine must be administered into a vein. Given the encouraging response data and documented safety record, Vincristine is a good choice for a clinical trial treating infants with complicated hemangiomas.
Vincristine : Vincristine (0.05 mg/kg/dose) will be administered into a vein (PICC line) every week for 12 weeks. If assigned to receive Vincristine, a PICC line will be placed by a doctor who is a specialist in this procedure, an interventional radiologist. This will require sedation and when possible, will be coordinated with sedation for the MRI. | 4 |
| Oral Steroid Treatment Group The standard treatment for hemangioma at most centers is oral steroids (Prednisolone). Prednisolone has been used to stop the growth of infantile hemangiomas that are life threatening, that could harm important functions, or are likely to result in severe disfigurement (scarring) without treatment.
Prednisone : Prednisolone given at 3 mg/kg/day by mouth for 12 week | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Oral Steroid Treatment Group | Vincristine Treatment Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 0.11 years STANDARD_DEVIATION 0.05 | 0.18 years STANDARD_DEVIATION 0.05 | 0.15 years STANDARD_DEVIATION 0.06 |
| Region of Enrollment United States | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 4 | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Response of Hemangioma (IH) to Treatment
Response of IH not confined to the dermis will be coded using the following criteria: Progressive disease: \>40% increase in volume by MRI, Partial response: \>65% reduction in volume by MRI, Complete response: no visual or radiographic evidence of disease, Stable disease: none of the above or \<40% increase or \<65% decrease in volume by MRI. Response of superficial IH will be coded using the following criteria (based on RECIST): Progressive disease: \>30% increase in IH size, Partial response: \>30% reduction in size, Complete response: no evidence of disease, Stable disease: none of the above. Our first 3 patients showed limits to using MRI volume to measure IH size/response to therapy. Unlike other solid tumors, the superficial distribution of some IH made getting volume by MRI difficult, resulting in smaller tumor estimation compared to clinical assessment. Based on these observations, we amended the protocol to report response based on RECIST criteria instead of change in IH volume.
Time frame: 6 weeks
Population: Per protocol, all participants were analyzed, no matter the treatment arm or treatment success.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vincristine Treatment Group | Response of Hemangioma (IH) to Treatment | Progressive Disease | 0 participants |
| Vincristine Treatment Group | Response of Hemangioma (IH) to Treatment | Partial Response | 2 participants |
| Vincristine Treatment Group | Response of Hemangioma (IH) to Treatment | Complete Response | 0 participants |
| Vincristine Treatment Group | Response of Hemangioma (IH) to Treatment | Stable Disease | 2 participants |
| Oral Steroid Treatment Group | Response of Hemangioma (IH) to Treatment | Stable Disease | 2 participants |
| Oral Steroid Treatment Group | Response of Hemangioma (IH) to Treatment | Progressive Disease | 1 participants |
| Oral Steroid Treatment Group | Response of Hemangioma (IH) to Treatment | Complete Response | 0 participants |
| Oral Steroid Treatment Group | Response of Hemangioma (IH) to Treatment | Partial Response | 0 participants |
Secondary
Toxicity to Medications
Adverse events were closely monitored and recorded at weekly visits during treatment period and for two years after treatment ceased. Laboratory values were taken every other week during the treatment period. Please see Adverse Events module for more details.
Time frame: Initial visit, 2, 4, 6, 10 and 12 weeks of therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vincristine Treatment Group | Toxicity to Medications | Patients with Serious Adverse Events | 0 participants |
| Vincristine Treatment Group | Toxicity to Medications | Patients with Other Adverse Events | 3 participants |
| Oral Steroid Treatment Group | Toxicity to Medications | Patients with Serious Adverse Events | 0 participants |
| Oral Steroid Treatment Group | Toxicity to Medications | Patients with Other Adverse Events | 0 participants |