Lymphatic Malformations
Conditions
Brief summary
Standard of care for Lymphatic Malformations has been surgical excision. We have been using OK432/Picibanil (generously supplied by Chugai Pharmaceuticals in Japan) since 1992 with great success for macrocystic disease. The objective of the study was to provide OK-432 immunotherapy to subjects with macrocystic or mixed (\> 50% macrocystic) lymphatic malformations (LMs) and investigate the efficacy and safety of OK 432 as a treatment option in subjects with LMs.
Detailed description
Lymphatic malformations are uncommon tumors that represent localized malformations in the development of the lymphatic system. They typically present in children under 2 years of age and in almost 50% of the cases, are diagnosed at birth. There is neither a racial nor a sexual tendency. The malformations can occur anywhere on the body, but typically they are in the head/neck area. Morbidity can be significant. Besides the obvious cosmetic deformity caused by these tumors, there is risk of infection and airway compromise and even obstruction. However, effective therapeutic options are limited. Small lesions can be observed, although spontaneous resolution is unlikely. For larger lesions, surgery has been the traditional form of therapy. In the head and neck, in particular, lymphangiomas typically wrap themselves around major neurovascular structures, making total excision removal difficult, if not impossible, and thus the likelihood of recurrence is quite high. Because of these surgical limitations, alternate therapies have been considered; including cryotherapy, diathermy, and chemical sclerotherapy. The investigators experience with using the drug for macrocystic disease(large cysts) since 1992 in the United States has been very promising compared to traditional surgery. Recurrence rate to date, has been very minimal as well. (\<2%) After the conclusion of the Phase 2 randomized study, all new subjects who presented with an LM and were eligible for treatment were treated under an open-label protocol for continued access to OK-432. This multicenter, open label study enrolled subjects between September 2005 and November 2017.
Interventions
DRUGOK432
OK432 will be injected at dosage of 0.01 to 0.05 mg/mL 6-12 weeks apart up to 4 injections total.
Sponsors
Richard JH Smith
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All eligible participants receive the actual drug.
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
Yes
Inclusion criteria
To be eligible to receive OK432 immunotherapy * Patients must be ages 6 months to 17 years * Patients must have a macrocystic Lymphatic Malformation * Patients may have had surgical treatment for their Lymphatic Malformation * Patients must have an imaging study to confirm the diagnosis of a macrocystic or mixed Lymphatic Malformation An MRI is preferred over a CT scan (an ultrasound may be used between injections if warranted, however an MRI or CT should be done pre and post treatment)
Exclusion criteria
* Penicillin allergy * Women who are pregnant or nursing * Patients who present with a temperature of 100.5 degrees F or greater * Patients with mixed hemangioma-lymphangioma lesions * Patients with a history OR a family history of rheumatic heart disease or post-streptococcal glomerulonephritis * Patients with hemodynamic instability and respiratory failure * Patients with a history OR a family history of obsessive-compulsive, tic disorders, or PANDA (pediatric autoimmune neuro-psychiatric disorder associated with streptococcal infections) * Patients who demonstrate abnormalities in the history, physical examination or laboratory analysis which may indicate significant hepatic, hematologic, or renal disease * Patients who are not in good general health (including patients with congenital disorders, chronic diseases, immunologic dysfunction, transplant recipients)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Success at 1 to 6 Months Post-Therapy as Assessed by Imaging | 1 to 6 Months Post-Therapy | Clinical success was defined as having either a complete (90% 100%) or substantial (60% 89%) reduction in lymphatic malformation (LM) volume after treatment. Response was determined using post treatment imaging studies at approximately 1 to 6 months after completion of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging | 1 to 6 Months Post-Therapy | Number of participants who demonstrated a complete (90%-100% reduction in LM volume), substantial (60%-89% reduction in LM volume), intermediate (20%-59% reduction in LM volume), or no (\< 20% reduction in LM volume) response 1 to 6 months post-therapy as assessed by imaging |
| Number of Participants With Investigator-Evaluated Overall Response | 1 to 6 Months Post-Therapy | Investigator evaluated post-therapy clinical response based on physical exam and/or ultrasound was categorized as Clinical Improvement or No Change in the size of the cyst. |
| Change From Baseline in Lesion Volume | Baseline and 1 to 6 Months Post-Therapy | Percent change from baseline in lesion volume - pre-therapy to post therapy assessed by imaging. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in 14 centers across the United States between September 2005 and November 2017.
Pre-assignment details
After informed consent, subjects who met all eligibility criteria were enrolled into the study. Study completion data was analyzed retrospectively for subjects with observed, non-missing data. Results presented in this report were based on a retrospective analysis of source-verified data and therefore only non-missing data is presented. Therefore there are differences in the number of subjects for different analyses.
Participants by arm
| Arm | Count |
|---|---|
| OK-432 OK 432 is a lyophilized biological preparation for injection containing nonviable cells of Streptococcus pyogenes (A group, type 3) Su strain treated with benzylpenicillin.
OK-432 was administered intracystically at a concentration of 0.01 to 0.05 mg/mL. A 4-dose injection series of OK-432 was planned for all subjects. All injections were spaced approximately 6 to 12 weeks apart | 275 |
| Total | 275 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative | 4 |
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Other | 2 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Unknown or Missing Completion Status | 48 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | OK-432 |
|---|---|
| Age, Continuous | 5.481 years STANDARD_DEVIATION 6.6382 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Asian | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 29 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 36 Participants |
| Race/Ethnicity, Customized Other | 7 Participants |
| Race/Ethnicity, Customized White | 191 Participants |
| Region of Enrollment United States | 275 participants |
| Sex: Female, Male Female | 151 Participants |
| Sex: Female, Male Male | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 275 |
| other Total, other adverse events | 112 / 114 |
| serious Total, serious adverse events | 11 / 275 |
Outcome results
Primary
Number of Participants With Clinical Success at 1 to 6 Months Post-Therapy as Assessed by Imaging
Clinical success was defined as having either a complete (90% 100%) or substantial (60% 89%) reduction in lymphatic malformation (LM) volume after treatment. Response was determined using post treatment imaging studies at approximately 1 to 6 months after completion of treatment
Time frame: 1 to 6 Months Post-Therapy
Population: The modified Intent to Treat (mITT) Population includes all enrolled subjects treated with at least one injection of OK 432 who either have post-therapy imaging assessment data or at least one investigator assessment of overall response throughout the study (N = 148). The efficacy data were presented as observed for subjects with non-missing data in the mITT Population (N = 78).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OK-432 | Number of Participants With Clinical Success at 1 to 6 Months Post-Therapy as Assessed by Imaging | 57 Participants |
Secondary
Change From Baseline in Lesion Volume
Percent change from baseline in lesion volume - pre-therapy to post therapy assessed by imaging.
Time frame: Baseline and 1 to 6 Months Post-Therapy
Population: The mITT includes all enrolled subjects treated with at least one injection of OK 432 who either have post-therapy imaging assessment data or at least one investigator assessment of overall response throughout the study (N = 148). The efficacy data were presented as observed for subjects with non-missing data in the mITT Population (N = 76).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OK-432 | Change From Baseline in Lesion Volume | -44.92 percent change | Standard Deviation 110.561 |
Secondary
Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging
Number of participants who demonstrated a complete (90%-100% reduction in LM volume), substantial (60%-89% reduction in LM volume), intermediate (20%-59% reduction in LM volume), or no (\< 20% reduction in LM volume) response 1 to 6 months post-therapy as assessed by imaging
Time frame: 1 to 6 Months Post-Therapy
Population: The mITT includes all enrolled subjects treated with at least one injection of OK 432 who either have post-therapy imaging assessment data or at least one investigator assessment of overall response throughout the study (N = 148). The efficacy data were presented as observed for subjects with non-missing data in the mITT Population (N = 78).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| OK-432 | Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging | Number of subjects who achieved a complete response | 43 Participants |
| OK-432 | Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging | Number of subjects who achieved a substantial response | 14 Participants |
| OK-432 | Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging | Number of subjects who achieved an intermediate response | 5 Participants |
| OK-432 | Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging | Number of subjects who achieved no response | 16 Participants |
Secondary
Number of Participants With Investigator-Evaluated Overall Response
Investigator evaluated post-therapy clinical response based on physical exam and/or ultrasound was categorized as Clinical Improvement or No Change in the size of the cyst.
Time frame: 1 to 6 Months Post-Therapy
Population: The mITT Population includes all enrolled subjects treated with at least one injection of OK 432 who either have post-therapy imaging assessment data or at least one investigator assessment of overall response throughout the study (N = 148). The investigator assessed response data were presented as observed for subjects with non-missing data in the mITT Population (N = 98).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OK-432 | Number of Participants With Investigator-Evaluated Overall Response | 80 Participants |