MITO CERV …3…(?) Phase II study on Carboplatin-Paclitaxel-Pembrolizumab in neoadjuvant treatment of locally advanced cervical cancer

STUDY DESIGN

Study design This is a single arm multicenter phase II trial evaluating the role of Pembrolizumab in combination to Carboplatin-Paclitaxel dose dense chemotherapy in locally advanced cervical cancer patients. Patients with stage IB2-IIB cervical cancer will be treated with 3 cycles of neo- adjuvant dose dense Carboplatin-Paclitaxel chemotherapy (Carboplatin AUC 5 d1 q 21+ Paclitaxel 80 mg/mq d1,8,15 q 21+ Pembrolizumab 200 mg flat dose every 3 weeks) After 3 cycles of neo-adjuvant platinum-based chemotherapy patients non progressing will undergo radical surgery. After surgery, patients presenting with high risk factors (positive lymphnodes, positive parametria, positive surgical margins or at least 2 of the following risk factor between tumor diameter >3 cm, LVSI, stromal infiltration >1/3) will receive 3 cycles of adjuvant dose dense Carboplatin-Paclitaxel chemotherapy in combination and maintenance with pembrolizumab 200 mg every 3 weeks until progression or unacceptable toxicity or patient consent withdrawal for up to 2 years

Objectives Primary: 2-years Progression-free survival (PFS) Secondary: Overall survival (OS) Toxicity Clinical Response rate (per RECIST vers 1.1 and per modified iRecist) Pathologic optimal response (complete response+ partial microscopic response <3 mm stromal invasion) QoL Correlation between PD1-PDL1 as evaluated in immuno-histochemistry and Pembrolizumab pathologic and clinical response  

EXPLORATORY OBJECTIVES To evaluate additional biomarker research to identify factors predicting responsiveness or resistance to Pembrolizumab on tumor biopsy before chemotherapy initiation and after 3 cycles of chemotherapy at surgery. When possible another biopsy will be performed at progression. Assays will include, but are not limited to: Transcriptional Analyses of Gene Expression Signatures To assess the association between anti-tumor activity from Pembrolizumab with several gene expression signatures related to PD-1/PD-L1 signaling. Messenger RNA (mRNA) transcript profiling will be performed to assess gene expression and to evaluate specific gene sets that may correlate with clinical response to Pembrolizumab. Genetic Analysis To assess the association between anti-tumor activity from genetic alterations that may indicate a specific genotype reflective of greater dependency on PD-1/PD-L1 checkpoint function or other immune checkpoint signaling pathways. DNA isolated from blood or tumor tissue will be analyzed in order to identify genetic alterations and to evaluate specific genetic alterations that may correlate with clinical response to Pembrolizumab. These and other additional biomarker or genomic research to identify factors important for Pembrolizumab therapy (for example, HLA genotype) may also be pursued. Lymphocyte population and Cytokines evaluation In order to evaluate the capability of Pembrolizumab to reverse immunosuppression present in locally advanced cervical cancer patients, blood sample will be collected before cycle 1, before cycle 6 and at progression. CD3 cells will be isolated and CD4/CD8 ratio will be evaluated by FACS analyses. Concomitantly, serum levels of IL -2, IL-10; TGF- Beta and IL-6 will be assessed. When technically possible, tumor biopsies at progression will be collected in order to determine the PD-1R infiltrating lymphocyte population before and after treatment. Finally single and dual staining IHC analysis of: OX40-OX40L; ICOS; PD1, PD-L1, PD2, PDL2 and CTLA-4; FOXP3 and CD4; CD95 and CD95L .  

Inclusion Criteria 1. Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of FIGO Stage IB2-IIB cervical cancer will be enrolled in this study. Squamous, adenocarcinoma and adenosquamous histotypes are admitted. 2. Eligible for carboplatin and paclitaxel chemotherapy in accordance with local standards of care 3 Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.4 Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. 5 Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization. 6 Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to the start of study treatment. 7 No previous systemic chemotherapy or radiation therapy for cervical cancer

Exclusion Criteria   1.  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 2. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 3. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 4. Has active autoimmune disease that has required systemic treatment in the past 2 years

Statistical consideration This is a phase II non randomized multicenter trial, aiming at evaluating activity of Pembrolizumab in combination to Carboplatin-Paclitaxel chemotherapy in locally advanced cervical cancer. The control group will be represented by the historical control of locally advanced cervical cancer patient treated with exclusive concomitant chemoradiation or with neoadijuvant chemotherapy followed by surgery. For these patients literature data report 2-year PFS around 60-65% and 2-year OS of 70-75%. 45 patients will be enrolled, if at least 32 patients will be disease free at 2 years the strategy will be considered successful with 70% of patients being disease free at two years (alfa 0.05, beta 80%). The total duration of the study is 3.5 years ( estimated accrual time 1 year, treatment phase 6 months, maintenance phase 2 years). With a possible accrual rate of 4 patients/month, 45 patients will be enrolled in about 11 months.

Administrative Information Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) EC submision planned in October 2018 Planned study start: November 2018 MERCK SUPPORT drug supply, Financial support for drug and study management Insurance provided by Coordinator center Final protocol approved by Merck To join the trial please contact: domenica.lorusso@istitutotumori.mi.it Iolanda.pulice@istitutotumori.mi.it