OK432 (Picibanil) in the Treatment of Lymphatic Malformations

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.

• OK432 (Drug), also known as Picibanil: OK432 will be injected at dosage of 0.01 to 0.05 mg/mL 6-12 weeks apart up to 4 injections total.

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 6 Months to 17 Years, accepts healthy volunteers

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)

Participant flow

Outcome results

• Number of Participants With Clinical Success at 1 to 6 Months Post-Therapy as Assessed by Imaging (Primary), Count of participants, Participants: OK-432 57
• Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging (Secondary), Count of participants, Participants: OK-432 43
• Number of Participants With Investigator-Evaluated Overall Response (Secondary), Count of participants, Participants: OK-432 80
• Change From Baseline in Lesion Volume (Secondary), Mean, percent change: OK-432 -44.92 +/- 110.561

Adverse events

Time frame: Nonserious AEs (Subject Diary): Up to 14 days after each injection Treatment Emergent SAEs: Day 1 to 35 days after last injection All Cause Mortality: Day 1 to study completion ie, 2 years after treatment completion (All-Cause Mortality) Note: Results presented 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.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Results are based on a retrospective analysis of source-verified data that include subjects enrolled in the open label study. This study was conducted to provide patients with continued access to OK-432 on a compassionate use basis. Response data were not well documented for everyone. Subjects with missing data included those who were lost to follow up, had incomplete or missing CRFs or imaging studies.

• Study Protocol and Statistical Analysis Plan (PDF, 2021-04-07)

• Richard JH Smith, MD, Principal investigator, University of Iowa