Intradermal Injection of Anti-CTLA-4 in Patients With Stage I/II Melanoma

Study Overview
=================
Brief Summary
-----------------
This study evaluates the clinical safety and tolerability, and the immunological effects of local intradermal injection of tremelimumab in patients with clinical stage I/II melanoma patients undergoing a sentinel node biopsy (SNB). Patients will be treated by local intradermal injections around the excision site of the primary tumor with escalating doses of 2, 5, 10 or 20 mg tremelimumab.

Detailed Description
-----------------
Although of limited therapeutic value, the SLN procedure has proven a useful prognostic tool for the assessment of melanoma relapse and mortality risk. Moreover, the SLN is of great value for the assessment of immunological interventions for melanoma. Since early melanoma development is accompanied by impaired immune effector functions primarily in the SLN, there is a strong rationale for therapeutic immune modulation of the SLN aimed at strengthening cellular immune functions. The investigator now propose a phase I dose escalation study to administer intradermally a single clinical dose of tremelimumab/anti-CTLA-4 locally at the primary tumor excision site of patients with clinical stage I/II melanoma. Such a single local administration aimed at conditioning of the SLN should allow for the use of relatively low anti-CTLA-4 dosages without excess risk of autoimmune effects.

Official Title
-----------------
Releasing the Brakes on CD8+ T Cells in the Melanoma Sentinel Lymph Node by Pre-operative Local Administration of Low-dose Anti-CTLA-4 (Tremelimumab)

Conditions
-----------------
Cutaneous Melanoma

Intervention / Treatment
-----------------
* Drug: Tremelimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Clinical stage I/II melanoma patients, planned to undergo a sentinel lymph node biopsy (SNB) ECOG performance status 0 or 1 White blood count (WBC) ≥ 3 x10^9/L Platelet count ≥ 100 x10^9/L Hemoglobin ≥ 6.5 mmol/L Serum creatinine ≤ 2.5 x ULN Total serum bilirubin, AST, ALT and LDH ≤ 2x ULN Exclusion Criteria: Non-oncology vaccine therapy used for prevention of infectious diseases (up-to) 4 weeks prior and/r 8 weeks after any dose of tremelimumab Prior treatment with a CD137 agonist or CTLA-4 inhibitor or agonist Uncontrolled infectious disease including negative testing for HIV, HBV, HCV Autoimmune disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Seven days before undergoing a SNB, clinical stage I/II melanoma patients will be treated with an intradermal injection of tremelimumab, around the excision site of the primary tumor. Escalating doses of 2, 5, 10, or 20 mg of tremelimumab will be given (3 patients per dose level with an expansion at the optimal dose level with an additional 5 patients).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tremelimumab<br>Intradermal injection of tremelimumab at the primary melanoma excision site, 7 days prior to sentinel node biopsy (SNB), with escalating doses of 2, 5, 10 or 20 mg tremelimumab (3 patients per dose level with an expansion at the optimal dose level with an additional 5 patients). | Drug: Tremelimumab<br>* Intradermal injection of tremelimumab 7 days prior to sentinel node biopsy, with escalating doses of 2, 5, 10 or 20 mg tremelimumab (3 patients per dose level with an expansion at the optimal dose level with an additional 5 patients).<br>* Other names: Anti-CTLA-4;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events as assessed by CTCAE V3.0 | The descriptions and grading scales of CTCAE V 3.0 will be utilized for all toxicity reporting | From the time of injection until 28 days after injection of tremelimumab | 
| Change in frequency of immune cell populations (compared to baseline) assessed by immune monitoring through flow cytometry, | Blood samples and sentinel lymph node material will be collected and then analyzed by flow cytometry. Changes in frequency of tumor-specific T-cells, Tregs and dendritic subsets will be assesess and compared to baseline (time of the injection of the intradermal injection) | 7 days after the intradermal injection of tremelimumab | 
| Change in activation status of immune cell populations (compared to baseline) assessed by immune monitoring through flow cytometry, | Blood samples and sentinel lymph node material will be collected and then analyzed by flow cytometry. Changes in expression level of surface antigens for tumor-specific T-cells, Tregs and dendritic subsets are analyzed and compared to baseline (time of injection of tremelimumab) | 7 days after the intradermal injection of tremelimumab | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stage I-II melanoma, Anti-CTLA-4, Immunotherapy, Neoadjuvant