COLOMBE is a multicenter, single arm, phase 1/2 trial designed to evaluate the safety and efficacy of imiquimod cream with IV low dose nivolumab in primary resectable vulvar squamous cell carcinoma patients prior to surgery, leveraging the preoperative "window of opportunity" period, an unavoidable interval due to surgical scheduling.
At least 1 lesion that can be measured in at least 1 dimension with ≥ 10 mm in largest diameter
Clinically stage FIGO I-III (2021 FIGO staging)
Eligible for primary tumour surgery
Surgical complexity due to either bulky tumors > 4 cm OR multifocal tumor (defined as the presence of two or more foci of cancer on the vulva), the largest lesion must be ≥ 10 mm and all lesions ≥ 10 mm are designated as "target" lesion(s) for all subsequent tumor evaluations OR any tumor for which a surgical excision would have anatomical or functional consequences deemed significant by the treating surgeon
Major surgery: 2 weeks
Live vaccines: 4 weeks
Systemic corticosteroids (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy: 1 week
Single group
Imiquimod 5% cream
DrugAt the starting dose (DL1) : 5 consecutive days per week for 4 weeks At DL-1: 3 consecutive days per week for 4 weeks
Nivolumab
DrugAt DL1 and DL-1: Administration IV at a dose of 40 mg, every two weeks for 6 weeks (3 doses)
Phase I Safety run-in: Dose-limiting toxicity (DLT) related to imiquimod and/or nivolumab, occurring during the induction period (first 6 weeks of treatment)
Dose-limiting toxicity (DLT) defined as any adverse event (AE) related to imiquimod and/or nivolumab, occurring during the induction period (first 6 weeks of treatment, i.e., DLT period) and graded according to the NCI-CTCAE V6.0 classification: * Grade 4 non-laboratory AE including skin toxicity; * Grade 3 non-laboratory AE lasting \>14 days despite optimal supportive care with the following exceptions: Influenza-like symptoms and application site reaction related to imiquimod * Any grade 3 or grade 4 laboratory value with clinical symptoms requiring medical intervention or hospitalization, and persisting for more than 14 days; * Any imiquimod site application AE or nivolumab related AE postponing the surgery of at least 14 days * Any other AE evaluated as clinically significant by investigator and sponsor, for instance delaying the nivolumab administration for more than 14 days * Any toxic death, grade 5 AE
Phase II: To evaluate the clinical efficacy of imiquimod and nivolumab combination in adult patients with resectable primary VSCC
Clinical ORR (objective response rate) as per RECIST 1.1 category documented by calipers using standardized digital photography with reference ruler at the time of surgery
Evaluation of the Pathological Response
The pathological tumor response (pTR) is defined as the presence of tumor cell necrosis and keratinous debris with giant cell/histiocytic reaction, quantified as a percentage of the overall tumor bed (area pathologic response/area pathologic response plus viable tumor): pTR-0 (\<10%), pTR-1 (10%-49%), pTR-2 (≥50%), pTR-3 (100%, complete response). The pTR will be quantified in increments of 10%.
Rate of positive margin
Rate of patients with positive margin defined as \<8mm
Rate of positive Sentinel Lymph Node
Rate of patients with positive Sentinel Lymph Node (SLN)
Rate of patients undergoing RT
Rate of patients undergoing radiotherapy
To study the impact of the treatment on the Tumour Microenvironment (TME) immune profile : Changes in CD8 infiltrate
Exploratory analyses in pretreatment tumour biopsies versus surgical specimen will be performed in an effort to understand the impact of the treatment by nivolumab and imiquimod combination on the Tumor Microenvironment (TME) immune profile. Exploratory data will be summarized using descriptive statistics (e.g. N, medians, inter-quartile range, and mean, standard deviation, minimum and maximum for continuous variables and frequency counts and percentages for categorical variables). The relationship between TME immune profile and efficacy variables will be assessed using appropriate multivariate models. The exploratory analyses will include the following : changes in CD8 infiltrate
To study the impact of the treatment on the Tumour Microenvironment (TME) immune profile: CD8/FOXP3 ratio
Exploratory analyses in pretreatment tumour biopsies versus surgical specimen will be performed in an effort to understand the impact of the treatment by nivolumab and imiquimod combination on the Tumor Microenvironment (TME) immune profile. Exploratory data will be summarized using descriptive statistics (e.g. N, medians, inter-quartile range, and mean, standard deviation, minimum and maximum for continuous variables and frequency counts and percentages for categorical variables). The relationship between TME immune profile and efficacy variables will be assessed using appropriate multivariate models. The exploratory analyses will include the following : CD8/FOXP3 ratio
To study the impact of the treatment on the Tumour Microenvironment (TME) immune profile : T effector memory cells
Exploratory analyses in pretreatment tumour biopsies versus surgical specimen will be performed in an effort to understand the impact of the treatment by nivolumab and imiquimod combination on the Tumor Microenvironment (TME) immune profile. Exploratory data will be summarized using descriptive statistics (e.g. N, medians, inter-quartile range, and mean, standard deviation, minimum and maximum for continuous variables and frequency counts and percentages for categorical variables). The relationship between TME immune profile and efficacy variables will be assessed using appropriate multivariate models. The exploratory analyses will include the following : T effector memory cells functional analysis (cytokine production of interferon gamma)
To study the impact of the treatment on the Tumour Microenvironment (TME) immune profile: immune checkpoints expression (PD-1, TIGIT, TIM3, CTLA4, CD39)
Exploratory analyses in pretreatment tumour biopsies versus surgical specimen will be performed in an effort to understand the impact of the treatment by nivolumab and imiquimod combination on the Tumor Microenvironment (TME) immune profile. Exploratory data will be summarized using descriptive statistics (e.g. N, medians, inter-quartile range, and mean, standard deviation, minimum and maximum for continuous variables and frequency counts and percentages for categorical variables). The relationship between TME immune profile and efficacy variables will be assessed using appropriate multivariate models. The exploratory analyses will include the following : immune checkpoints expression (PD-1, TIGIT, TIM3, CTLA4, CD39)
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