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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
At the starting dose (DL1) : 5 consecutive days per week for 4 weeks At DL-1: 3 consecutive days per week for 4 weeks
At DL1 and DL-1: Administration IV at a dose of 40 mg, every two weeks for 6 weeks (3 doses)
Groupe Hospitalier Mutualiste de Grenoble
Grenoble, France
Centre Léon Bérard
Lyon, France
CHU de Saint Etienne
Saint-Priest-en-Jarez, France
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
Time frame: From Cycle 1 Day 1 to week 6
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
Time frame: From Cycle 1 Day 1 to surgery (up to 3 cycles - each cycle is 14 days)
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%.
Time frame: At time of surgery
Rate of positive margin
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Rate of patients with positive margin defined as \<8mm
Time frame: At time of surgery
Rate of positive Sentinel Lymph Node
Rate of patients with positive Sentinel Lymph Node (SLN)
Time frame: Through study completion, up to 3 years
Rate of patients undergoing RT
Rate of patients undergoing radiotherapy
Time frame: Through study completion, up to 3 years
Evaluation of Overall Survival (OS)
Overall survival defined as the time between treatment initiation (C1D1) and death from any cause. Patients still alive at the time of analysis will be censored at the date of last news they are known to be alive.
Time frame: From Cycle 1 Day 1 to the date of death from any cause (assessed up to 3 years)
Recurrence Free Survival (RFS)
Recurrence Free Survival (RFS): defined as the time from C1D1 to the first documented disease recurrence or death from any cause, whichever occurs first. Patients who are alive and without evidence of recurrence at the time of analysis will be censored at the date of their last disease assessment.
Time frame: From Cycle 1 Day 1 to the date of first documented disease recurrence or death (assessed up to 3 years)
Evaluation of surgical complications
The frequency of surgical complications: * The percentage of wound breakdown (dehiscence) in the vulva defined as larger than one third of the length of excision. * The percentage of wound breakdown (dehiscence) in the groins defined as larger than one third of the length of excision. * The percentage of wound infection in the vulva defined as a clinical infection (e.g. the presence of a purulent exudate and/or a positive culture with the presence of erythema, oedema, and localized pain involving skin and subcutaneous tissue) which requires antibiotic therapy * The percentage of wound infection in the groins defined as a clinical infection (e.g. the presence of a purulent exudate and/or a positive culture with the presence of erythema, oedema, and localized pain involving skin and subcutaneous tissue) which requires antibiotic therapy. * The percentage of patients with lymphocyst formation defined by greater than 4 cm in diameter and confirmed by puncture or ultrasound
Time frame: From surgery to short term safety visit (occuring 30 days after surgery)
To assess the impact of the proposed induction treatment on patient QoL
To assess the impact of the proposed induction treatment on patient QoL with Quality of Life questionnaires: * EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30): scores range from 0 to 100, with higher scores indicating better functioning/global health status but worse symptoms * EORTC QLQ-VU34 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Vulva Cancer module with 34 questions): scores range from 0 to 100, with higher scores indicating better functioning/global health status but worse symptoms
Time frame: From enrollment to Short Term Safety Visit (STSV) (assesed up to 30 days following surgery)
To define the tolerability of the proposed therapeutic strategy
Incidence and severity of AE according to NCI CTCAE V6.0
Time frame: Through study completion, up to 3 years