Pilot hu14.18-IL2 in Resectable Recurrent Stage III or Stage IV Melanoma

Study Overview
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Brief Summary
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Evaluate the antitumor activity of hu14.18-IL2 in the minimal residual disease setting. Evaluate the time to recurrence and overall survival of patients treated with hu14.18-IL2.

Official Title
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A Pilot Trial of HU14.18-IL2 (EMD273063) in Subjects With Completely Resectable Recurrent Stage III or Stage IV Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: hu14.18-IL2
* Drug: hu14.18-IL2


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Subjects must have recurrent stage III (i.e., recurrent regional metastasis), or stage IV (i.e., any distant metastasis) melanoma for which surgical resection would be clinically recommended, with biopsy proven (current or previous) Stage III or Stage IV disease. Any biopsies obtained to demonstrate recurrent regional metastasis or distant metastasis must be considered clinically appropriate for clinical management and must not be performed solely for meeting eligibility criteria. In addition, subjects must have disease that has not yet been completely excised. Patients must have disease which involves 3 or fewer sites. A nodal basin recurrence will be scored as one site, even if multiple nodes are positive. Clustered subcutaneous and/or cutaneous lesions that can be removed in a single surgical excision will be scored as one site, even if multiple subcutaneous and/or cutaneous lesions are present. The subjects' disease is determined to be completely resectable with uninvolved margins using standard surgical guidelines based on physical exam and radiographic imaging (MRI or CT of the head, and CT or MRI of the chest, abdomen and pelvis). Subjects must have one of the following: a) Stage III melanoma with recurrence after prior surgery, with or without subsequent adjuvant systemic (standard or experimental) and/or radiotherapy management Or b) Stage IV melanoma (cutaneous, ocular, mucosal, or unknown primary) Subjects must be 18 years old or older OR if they are 15 years old or greater, considered to be mature minors, able to give adult informed consent (with parental co-signature), meet all other eligibility criteria, and also weigh at least 45 kg.. Subjects must weigh at least 45 kg in order to safely provide sufficient blood for monitoring studies (see section 7.7 for details). Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Subjects must have adequate bone marrow, liver, and renal function. Subjects with one or more of the following cardiac risk factors must complete a stress radionuclide scan with no evidence of myocardial ischemia or heart failure: (a) a history of cardiac disease, (b) age greater than 65 years old, (c) any clinically significant abnormality found on ECG (required at baseline), or (d) significant risk factors for coronary artery disease (history of significant dyslipidemia; any treatment for dyslipidemia; or two first degree relatives with a documented myocardial infarction prior to age 55). Subjects with significant history of pulmonary disease, shortness of breath at rest, or known Chronic Obstructive Pulmonary Disease (COPD) must have pulmonary function tests within 35% of normal age-predicted values. Subjects must be willing and able to provide informed written consent prior to any study-related procedures. Subjects must have no immediate requirements for palliative chemotherapy, palliative radiotherapy, or palliative hormonal therapy. Subjects must be willing and able to discontinue antihypertensive medications if advised to do so for days of hu14.18-IL2 infusion. Subjects must have slides available from stage III or stage IV melanoma. Paraffin blocks are preferable, but at a minimum, slides documenting melanoma by biopsy (including fine needle cytology) must be available for pathology review, and potential restaining/staining (see Section 7.4, Surgical Pathology Guidelines). Prior histologic demonstration of metastatic melanoma (either stage III or Stage IV) may be utilized if a repeat biopsy is not clinically needed to to establish eligibility. Exclusion criteria Subjects are ineligible if they have received monoclonal antibodies (mAb) during biologic therapy, tumor imaging, purging of autologous marrow/stem cells for re-infusion or for any other reason unless serological testing is performed. If the absence of detectable antibody (over background) to hu14.18 is documented, the subject is eligible for the study. Subjects treated with IL2 in the past that developed intolerable (Grade 4) IL2-related side effects are not eligible. Subjects who have received any (standard or experimental) systemic therapy for stage IV disease are not eligible. Women of childbearing potential will be excluded if they are pregnant, nursing, or not using effective contraception during the treatment period. Subjects with symptoms of ischemic cardiac disease, congestive heart failure, myocardial infarct within the immediate preceding 6 months and/or uncontrolled cardiac rhythm disturbance are ineligible. Subjects with significant psychiatric disabilities or seizure disorders are ineligible. Subjects who have had major surgery within the past 3 weeks are ineligible. Subjects with clinically detectable pleural effusions or ascites are ineligible. Subjects with organ allografts are ineligible. Subjects who require or are likely to require corticosteroid or other immunosuppressive drugs or have used them within 2 weeks of registration are ineligible. Subjects with significant intercurrent illnesses are ineligible. Subjects with active infections or active peptic ulcer unless these conditions are corrected or controlled are ineligible. Subjects with brain metastases, whether active or inactive, are ineligible. A head MRI or head CT scan will be required at baseline to rule out silent metastases. Subjects with active second malignancy other than non-melanoma skin cancer are ineligible. Patients will be considered eligible if they have been continuously disease free for > 5 years prior to the time of enrollment. Subjects who are infected with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBs Ag) carrier state or with clinical evidence of hepatitis are ineligible. Treatment may be initiated before laboratory confirmation of HIV and HBs Ag negativity, but will be stopped if results are positive. Subjects with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade > 2) are ineligible. Subjects with a known hypersensitivity to the study drug, Tween-80® or to human immunoglobulin are ineligible. Patients with a known history of diabetes mellitus that has required systemic therapy within the past 3 months (either oral hypoglycemic agents or insulin) will be excluded, as treatment with hu14.18-IL2 may alter blood glucose levels. Subjects with a legal incapacity or limited legal capacity are ineligible. Subjects with bone metastases are ineligible.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Hu14.18-IL2 -->Resection-->Hu14.18-IL2 | Drug: hu14.18-IL2<br>* 6 mg/m2 hu14.18-IL2 administered via IV on days 1, 2, and 3 of a 28-day course followed by surgery and up to 2 additional courses of hu14.18-IL2<br>|
| Experimental: B<br>Resection -->Hu14.18-IL2-->Hu14.18-IL2 | Drug: hu14.18-IL2<br>* Surgery followed by 3 courses of 6 mg/m2 hu14.18-IL2 administered via IV on days 1, 2, and 3 of a 28-day course<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ganglioside Expressed by Tumor Cells (GD2) | Histological analysis of anti-tumor activity is a primary endpoint. This is measured after surgical resection via staining to indicate GD2 expression. The GD2 results were summarized in terms of positive (GD2 expression high or low/moderate) and negative (GD2 expression undetectable). | up to 1 week | 
| Recurrence Free Survival (RFS) | RFS was defined as the number of days from the day of evaluation following course 2 of immunocytokine treatment to the day the subject experienced an event of recurrence or death, whichever occurred first. Participants who did not experience an event of recurrence or death at the time of analysis were censored at the date of the last evaluation for recurrence. | up to 24 months | 
| Overall Survival (OS) | OS was defined as the number of days from randomization to the date of the participant's death. Participants who did not experience an event of death at the time of analysis were censored at the date of the last follow-up. | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-Reactive Protein (CRP) | CRP measured at baseline, cycle 1 day 3, and cycle 2 day 1. | up to 29 days | 
| Lymphocyte Count | Lymphocyte count measured at baseline, cycle 1 day 3, cycle 1 day 8, and cycle 2 day 1 | up to 29 days | 
| Anti-Idiotypic Antibodies | Detection of anti-idiotypic will be performed on participants' serum obtained approximately 10 minutes prior to initiation of treatment, and serum samples on Days 3, 4, 8, and 29/1 of 3 cycles. | up to 12 weeks | 
| Anti-Fc-IL2 Antibodies | Detection of anti-FcIL2 will be performed on participants' serum obtained approximately 10 minutes prior to initiation of treatment, and serum samples on Days 3, 4, 8, and 29/1, for 3 cycles | up to 12 weeks | 
| In Vitro Soluble Interleukin-2 (IL2) Receptor Alpha Levels | Soluble IL2 receptor α levels will be performed on participants approximately 10 minutes prior to initiation of treatment, and serum samples on Days 3, 4, 8, and 29/1. | up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, hu14.18-IL2