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CompletedNCT03427619Updated Nov 23, 2021Results posted

OK432 (Picibanil) in the Treatment of Lymphatic Malformations

A Phase 2 interventional study of OK432 in Lymphatic Malformations, sponsored by Richard JH Smith. Completed at 14 sites in United States. Open to participants aged 6 Months to 17 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-11-23.

Sponsored by Richard JH Smith · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
275
Allocation
Not applicable
Ages
6 Months to 17 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Lymphatic Malformations
03

Who can participate

Ages eligible
6 Months to 17 Years
Sexes eligible
All
Accepts 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

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)
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
275 participants (actual)

Study arms

  • Experimental
    OK432 (Picibanil)

    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

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.

    Also known as: Picibanil

05

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

06

Results

Posted Oct 28, 2021
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.

Participant flow

The study was conducted in 14 centers across the United States between September 2005 and November 2017.

Participant flow — Overall Study
MilestoneOK-432
Started275
Safety population275
Modified intention to treat population143
Completed209
Not completed66
Withdrew: Physician decision3
Withdrew: Withdrawal by subject4
Withdrew: Lost to follow-up5
Withdrew: Administrative4
Withdrew: Other2
Withdrew: Unknown or missing completion status48

Outcome measures

PrimaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Clinical Success at 1 to 6 Months Post-Therapy as Assessed by Imaging
ParticipantsOK-432
Number of Participants With Clinical Success at 1 to 6 Months Post-Therapy as Assessed by Imaging57
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Clinical Response 1 to 6 Months Post-Therapy as Assessed by Imaging
ParticipantsOK-432
Number of subjects who achieved a complete response43
Number of subjects who achieved a substantial response14
Number of subjects who achieved an intermediate response5
Number of subjects who achieved no response16
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Investigator-Evaluated Overall Response
ParticipantsOK-432
Number of Participants With Investigator-Evaluated Overall Response80
SecondaryChange 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
Reported as:
Mean · percent change
Change From Baseline in Lesion Volume
percent changeOK-432
Change From Baseline in Lesion Volume-44.92 ± 110.561

Adverse events

Collected over 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.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
OK-4320/275 (0%)11/275 (4%)112/114 (98.2%)
Most frequent serious events
Showing 10 of 20
Most frequent serious events
EventOK-432
PyrexiaGeneral disorders5/275
VomitingGastrointestinal disorders3/275
Injection site swellingGeneral disorders2/275
SwellingGeneral disorders2/275
DehydrationMetabolism and nutrition disorders2/275
Decreased appetiteMetabolism and nutrition disorders1/275
HypophagiaMetabolism and nutrition disorders1/275
OdynophagiaGastrointestinal disorders1/275
FuruncleInfections and infestations1/275
Infected cystInfections and infestations1/275
Most frequent other events
Showing 10 of 11
Most frequent other events
EventOK-432
SwellingGeneral disorders112/114
PainGeneral disorders112/114
RednessGeneral disorders110/114
FeverGeneral disorders72/114
FatigueGeneral disorders66/114
Decreased appetiteGeneral disorders63/114
Nausea/vomitingGeneral disorders35/114
HeadacheGeneral disorders32/114
ChillsGeneral disorders21/114
Joint painGeneral disorders18/114

Baseline characteristics

The Safety Population included all enrolled subjects that have been treated with at least one injection of OK-432. Results were based on a retrospective analysis of source-verified data and only non-missing data is presented. Therefore there are differences in the number of subjects for different analyses.

Age, Continuous
Age, Continuous(years)OK-432
Mean5.481 ± 6.6382
Sex: Female, Male
Sex: Female, Male(Participants)OK-432
Female151
Male123
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)OK-432
Hispanic or Latino36
American Indian or Alaska Native2
White191
Black or African American29
Asian10
Other7
Region of Enrollment
Region of Enrollment(participants)OK-432
United States275
07

Study locations

14 sites
  • Rady Children's Hospital & Health Center San Diego
    San Diego, California 92123, United States
  • The Children's Hospital of Denver
    Denver, Colorado 80218, United States
  • Children's National Medical Center
    Washington, District of Columbia 20010, United States
  • All Children's Hospital
    Saint Petersburg, Florida 33701, United States
  • Richard Smith, MD
    Iowa City, Iowa 52242, United States
  • Spectrum Health-SHMG Ear, Nose, & Throat
    Grand Rapids, Michigan 49546, United States
  • Children's Hospitals & Clinics of Minnesota - Minneapolis
    Minneapolis, Minnesota 55404, United States
  • SUNY Health Science Center
    Syracuse, New York 13210, United States
  • Oregon Health Sciences University
    Portland, Oregon 97239, United States
  • Vanderbilt University Hospital
    Nashville, Tennessee 37232, United States
  • Children's ENT of Houston
    Houston, Texas 77030, United States
  • Children's Hospital of the Kings Daughter
    Norfolk, Virginia 23507, United States
  • University of Wisconsin Hospital & Clinic
    Madison, Wisconsin 53279, United States
  • Children's Hospital of Wisconsin
    Milwaukee, Wisconsin 53226, United States
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Apr 7, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03427619
Lead sponsor
Richard JH Smith
Responsible party
Richard JH Smith (Principal Investigator, University of Iowa) — Sponsor-investigator
First posted
Feb 9, 2018
Start date
Oct 5, 2005
Primary completion
Apr 30, 2018
Completion
Apr 30, 2018
Results posted
Oct 28, 2021
Last update
Nov 23, 2021

Study contacts

Richard JH Smith, MD
principal investigator · University of Iowa

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Oct 2021. You cannot join it, but the record below documents what was studied.

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