Peginterferon and TIL Therapy for Metastatic Melanoma

Study Overview
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Brief Summary
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Adoptive T cell therapy with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. The TILs are isolated from the patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 are administered to support T cell activation and proliferation in vivo. In this trial the therapy is combined with peginterferon (the pegylated form of interferon alpha 2b). Interferon alpha has immunomodulatory effects and is known to upregulate HLA expression on melanoma cells and are hypothesized to synergize with TIL therapy.

Official Title
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T Cell Therapy in Combination With Peginterferon for Patients With Metastatic Melanoma

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: TIL infusion
* Drug: Interleukin-2
* Drug: Peginterferon alfa-2b


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed unresectable stage III or stage IV metastatic melanoma Metastasis available for surgical resection (about 2 cm3) and residual measurable disease after resection ECOG performance status 0-1 Life expectancy ≥ 3 months No significant toxicity from prior treatments Adequate renal, hepatic and hematologic function Women of childbearing potential (WOCBP) and men in a sexual relationship with a WOCBP must be using an effective method of contraception during treatment and for at least 6 months after completion af treatment. Able to comprehend the information given and willing to sign informed consent - Exclusion Criteria: Other Malignancies, unless followed for ≥ 5 years with no sign of disease, except squamous cell carcinoma or adequately treated carcinoma in situ colli uteri. Cerebral metastasis. Patients with previously treated CNS metastases can participate if CNS metastases are surgically removed or treated with stereotactic radiosurgery and stable ≥ 28 days after treatment measured by MRI. Patients with asymptomatic, stable and untreated CNS metastasis can in be included according to investigators and sponsors decision. Patients with ocular melanoma Severe allergies, history of anaphylaxis or known allergies to the administered drugs. Serious medical or psychiatric comorbidity Creatinine clearance < 70 ml/min Acute or chronic infection with e.g. HIV, hepatitis, tuberculosis Severe and active autoimmune disease Pregnant and nursing women Need for immunosuppressive treatment, e.g. corticosteroids or methotrexate Concomitant treatment with other experimental drugs Patients with uncontrolled hypercalcemia Less than four weeks since prior systemic antineoplastic treatment at the time of treatment. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>All patients receive the same treatment. All patients are hospitalized during treatment (approximately 3 weeks) and receive treatment only once. The patients are admitted to hospital day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) on day -7 to day -1. The TILs are infused on day 0 and Interleukin-2 therapy are administered on day 0 to day 5. Interleukin-2 are administered in an i.v. continuous decrescendo regimen starting approximately 6 hours after TIL infusion with a duration of approximately 5 days Subcutaneous injections of peginterferon alpha 2b are administered three time (day -2, day 7 and day 14) | Drug: Cyclophosphamide<br>* Cyclophosphamide 60 mg/kg are administered i.v on day -7 and -6<br>Drug: Fludarabine<br>* Fludarabine 25 mg/m2 are administered i.v on day -5 to -1<br>* Other names: Fludara;Biological: TIL infusion<br>* The maximum number of expanded TILs are infused over 30-45 min on day 0<br>* Other names: T cell infusion;Drug: Interleukin-2<br>* Interleukin-2 are administered as a continuous i.v. infusion in a decrescendo regimen (18 MIU/m2 IL-2 over 6 hours, 18 MIU/m2 IL-2 over 12 hours, 18 MIU IL-2 over 24 hours followed by 4.5 MIU/m2 IL-2 over another 24 hours for three days)<br>* Other names: Proleukin;Drug: Peginterferon alfa-2b<br>* Peginterferon alpha-2b, 3 microgram/kg are administered as subcutaneous injection on day -2, day 7 and day 14.<br>* Other names: PegIntron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events/Serious Adverse Events | Determine the safety of the administration of peginterferon in combination with TIL therapy including lymphodepleting chemotherapy and Interleukin-2 by reporting adverse events according to CTCAE v. 4.0 | 0-24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Related Immune Responses | Number of participants with detectable in vitro immune responses in the TIL infusion product using intracellular flow cytometry. | Up to 12 months | 
| Objective Response Rate | Clinical responses will be evaluated by RECIST 1.1 (Response Criteria In Solid Tumors Criteria version 1.1) and assessed by CT scan. Complete response (CR), disapperance of all lesions; Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective response (OR) = CR + PR | Up to 36 months | 
| Overall Survival | Overall survival (OS), defined as time from treatment initiation to death, described using the Kaplan Meier method | Up to 36 months | 
| Progression Free Survival | Progression free survival (PFS), defined as the time from treatment initiation to disease progression, relapse or death due to any cause, which ever comes first, will be described with the Kaplan Meier method. | Up to 36 months |