OK432 (Picibanil) in the Treatment of Lymphatic Malformations

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Multicenter, Open Label Study to Evaluate the Efficacy and Safety of OK-432 Immunotherapy in Individuals With Lymphatic Malformations

Conditions
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Lymphatic Malformations

Intervention / Treatment
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* Drug: OK432


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: All eligible participants receive the actual drug.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OK432 (Picibanil)<br>There is no control in this study. All participants will receive the actual drug -OK432. With each injection they may receive 0.01 to 0.05mg/mL 6-12 weeks apart up to 4 injections total. | Drug: OK432<br>* OK432 will be injected at dosage of 0.01 to 0.05 mg/mL 6-12 weeks apart up to 4 injections total.<br>* Other names: Picibanil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 1 to 6 Months Post-Therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 1 to 6 Months Post-Therapy | 
| 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. | 1 to 6 Months Post-Therapy | 
| Change From Baseline in Lesion Volume | Percent change from baseline in lesion volume - pre-therapy to post therapy assessed by imaging. | Baseline and 1 to 6 Months Post-Therapy |