Neo-adjuvant Pembrolizumab in Vulvar Squamous Cell Carcinoma: a Clinical Proof-of-concept Study — Apollo  

Squamous Cell Cancer Clinical Trial

Official title: Neo-adjuvant Pembrolizumab in Vulvar Squamous Cell Carcinoma: a Clinical Proof-of-concept Study

Status Not yet recruiting

Clinical Trial Summary

Rationale:

Vulvar squamous cell carcinoma (VSCC) is a rare cancer with a rising incidence. Standard treatment comprises wide local excision of the primary tumour and inguinal lymph nodes and sometimes (chemo) radiotherapy. Treatment is associated with impressive and long-lasting morbidity, sexual and psychological dysfunction and wound healing disorders. Recurrent disease develops in up to 40% of all treated patients. The unmet need, therefore, is a less radical and more effective treatment for VSCC.

Hypothesis:

Based on the local immune profile in a large fraction of patients with primary VSCC the investigators hypothesize that neoadjuvant PD-1 checkpoint inhibition may reinvigorate tumor-specific T cells resulting in a reduced tumor load, potentially leading to less radical surgery and reduces the recurrence rate.

The primary objectives of this trial are to study clinical efficacy and immune activation of neoadjuvant PD-1 blockade in VSCC.

Study design: This is a prospective, multicenter phase II non-controlled clinical trial in 40 VSCC patients.

Study population: Clinically diagnosed FIGO I-III primary VSCC patients to be treated with surgery with curative intent.

Intervention (if applicable):

Anti-PD1 antibody pembrolizumab, 200 mg IV Q3W for a total of 2 administrations per patient over a period of 6 weeks prior to surgery.

Main study parameters/endpoints:

The primary endpoints are:

• Clinical efficacy of neoadjuvant PD-1 blockade in VSCC, measured by objective change in tumour size (according to RECIST1.1)

• The activation, proliferation and migration of the CD4+CD39+PD-1+ intratumoral T-cell population.

Clinical Trial Description

Rationale:

Vulvar squamous cell carcinoma (VSCC) is a rare cancer with a rising incidence. Standard treatment comprises wide local excision of the primary tumour and inguinal lymph nodes and sometimes (chemo) radiotherapy. Treatment is associated with impressive and long-lasting morbidity, sexual and psychological dysfunction and wound healing disorders. Recurrent disease develops in up to 40% of all treated patients. The unmet need, therefore, is a less radical and more effective treatment for VSCC.

Hypothesis:

Based on the local immune profile in a large fraction of patients with primary VSCC the investigators hypothesize that neoadjuvant programmed cell death protein 1 (PD-1) checkpoint inhibition may reinvigorate tumor-specific T cells resulting in a reduced tumor load, potentially leading to less radical surgery and reduces the recurrence rate.

The primary objectives of this trial are to study clinical efficacy and immune activation of neoadjuvant PD-1 blockade in VSCC.

Study design: This is a prospective, multicenter phase II non-controlled clinical trial in 40 VSCC patients.

Study population: Clinically diagnosed FIGO I-III primary VSCC patients to be treated with surgery with curative intent.

Intervention (if applicable):

Anti-PD1 antibody pembrolizumab, 200 mg IV Q3W for a total of 2 administrations per patient over a period of 6 weeks prior to surgery.

Main study parameters/endpoints:

The primary endpoints are:

• Clinical efficacy of neoadjuvant PD-1 blockade in VSCC, measured by objective change in tumour size (according to RECIST1.1)

• The activation, proliferation and migration of the CD4+CD39+PD-1+ intratumoral T-cell population.

The secondary endpoints are:

• Pathological complete responses (pCR) at time of surgery

• Feasibility (defined as delay in planned surgery and surgical outcomes), safety according to NCI-CTC version 5.0,

• The activation, proliferation and migration of the CD8+CD103+CD39+PD-1+ intratumoral T-cell population upon PD-1 blockade.

Exploratory endpoints:

• To study the on-treatment effect of neoadjuvant PD-1 blockade on a) Local RNA-based immune signalling; b) The activation, proliferation and migration of CD39-negative T cells; c)The type 1 cytokine polarization of T cells as indicated by the percentage of Tbet+ T cells; d) The myeloid cell component, as determined by multiplex staining for CD68, CD14, CD11c, CD33, HLA-DR and CD163, present in VSCC tumors.

• To study the relation between the T-cell inflamed gene expression profile (GEP) score and PD-1 blockade driven immunological changes in the tumor microenvironment (TME).

• To study the relation between the T-cell infiltration pattern and PD-1 blockade driven immunological changes in TME.

• To study the relation between immune cell changes in the TME and corresponding immune cells in the blood.

• To study immune cell composition in TME post neoadjuvant checkpoint blockade by AURORA flow cytometry on fresh resection material.

• To study PD-L1 expression and molecular subtype (HPV+, p53mut, other) in tumor material.

• To assess quality of life (EORTC QLQ C-30 and QLQ-VU34).

• To study the utility of plasma-derived circulating tumor DNA (ctDNA) as a potential future predictor for minimal residual disease and/or relapse. ;

Related Conditions & MeSH terms

• Carcinoma, Squamous Cell
• Neoplasms, Squamous Cell
• Squamous Cell Cancer
• Vulva Cancer
• Vulvar Neoplasms

• NCT number: NCT05761132
• Study type: Interventional
• Source: Leiden University Medical Center
• Contact: Mariette van Poelgeest, MD PhD
• Phone: 0031 71 5264050
• Email: m.i.e.van_poelgeest@lumc.nl
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 1, 2023
• Completion date: February 1, 2025