Clinical trial NCT04274816: Intradermal Injection of Anti-CTLA-4 in Patients With Stage I/II Melanoma
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cutaneous Melanoma
Keywords: Stage I-II melanoma
Anti-CTLA-4
Immunotherapy
Neoadjuvant
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2020-02-18
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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).
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of participants with adverse events as assessed by CTCAE V3.0
timeFrame: From the time of injection until 28 days after injection of tremelimumab
measure: Change in frequency of immune cell populations (compared to baseline) assessed by immune monitoring through flow cytometry,
timeFrame: 7 days after the intradermal injection of tremelimumab
measure: Change in activation status of immune cell populations (compared to baseline) assessed by immune monitoring through flow cytometry,
timeFrame: 7 days after the intradermal injection of tremelimumab
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Tanja D de Gruijl
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam UMC, location VUmc
name: Alfons JM van den Eertwegh
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Pul KM, Notohardjo JCL, Fransen MF, Koster BD, Stam AGM, Chondronasiou D, Lougheed SM, Bakker J, Kandiah V, van den Tol MP, Jooss K, Vuylsteke RJCLM, van den Eertwegh AJM, de Gruijl TD. Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic Treg reduction and effector T cell activation. Sci Immunol. 2022 Jul 15;7(73):eabn8097. doi: 10.1126/sciimmunol.abn8097. Epub 2022 Jul 15.