Carboplatin-Paclitaxel Adjuvant Chemotherapy in the Treatment of Locally Advanced Cervical Cancer

Study Overview
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Brief Summary
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This is a mutlicentric, open-label non-randomized, national, 2-stage phase II trial to assess efficacy and safety of a weekly Carboplatin-Paclitaxel adjuvant chemotherapy after intensity modulated extended-field chemoradiation in patient suffering from of locally advanced cervical cancer with para-aortic positive nodes.

Detailed Description
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This is a mutlicentric, open-label non-randomized, national, 2-stage phase II trial to assess efficacy and safety of a weekly Carboplatin-Paclitaxel adjuvant chemotherapy after intensity modulated extended-field chemoradiation in patient suffering from of locally advanced cervical cancer with para-aortic positive nodes. Patients will be registered in the first part of the study at diagnosis and will receive a first part of treatment corresponding to a standard of care (standard concomitant radio-chemotherapy, Part 1 of the study). will be included in the second part of the study for the second part of treatment (experimental adjuvant chemotherapy, Part 2 of the study), providing they fulfill eligibility criteria at this stage (no progression during Part 1 of the study and no medical contra-indication to the study treatment). The primary objective is to evaluate the efficacy of adjuvant chemotherapy with Carboplatin-Paclitaxel administrated in adjuvant situation after concomitant radio-chemotherapy in terms of Progression Free Survival (PFS) in patients treated for a locally advanced cervical cancer presenting positive lombo-aortic lymph nodes.

Official Title
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Phase II Trial of Weekly Carboplatin-Paclitaxel Adjuvant Chemotherapy After Intensity Modulated Extended-field Chemoradiation in the Treatment of Locally Advanced Cervical Cancer With Para-aortic Positive Nodes

Conditions
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Locally Advanced Cancer, Cervical Cancer

Intervention / Treatment
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* Drug: Carboplatin-Paclitaxel adjuvant chemotherapy


Participation Criteria
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Eligibility Criteria
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PART 1: Inclusion Criteria: Female patient aged more than 18 years old Histological diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous cell carcinoma of the cervix With locally advanced cervical cancer (FIGO stage IIIC2) With para-aortic or iliac common nodes positive on PET-scan or after laparoscopic surgical staging if PET-scan negative ECOG Performance Status ≤ 2 Adequate hematologic function: Absolute Neutrophil Count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 10g/dL Adequate renal function: creatinine clearance (estimated according to MDRD formula) ≥ 60ml/min/1.73m² Adequate hepatic function: Aspartate aminotransferase (ALT)/ Alanine aminotransferase (ALT) ≤ 2.5 × upper normal limit (UNL); Total bilirubin ≤ 1.5 x UNL (except in case of Gilbert's disease) Negative serum pregnancy test within 7 days prior to treatment for women of childbearing potential. For non-menopaused women, if not surgically sterilized, willing to accept the use of an effective contraceptive regimen during the treatment period and at least 6 months after the end of treatment Absence of contraindication to receive the products used in this study (products used in concomitant/ adjuvant chemotherapy) according to the most recent SmPC of these products (available at http://base-donnees-publique.medicaments.gouv.fr/) Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up Patient covered by the French Social Security regime Signed informed consent form Exclusion Criteria: Histological diagnosis of sarcoma Previous hysterectomy or planned hysterectomy as part of their initial cervix cancer therapy, Presence of distant metastases other than lombo-aortic lymph nodes Patient with other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of the other cancer present within the last 5 years Patient with bilateral hydronephrosis unless at least one side has been stented Prior diagnosis of Crohn's disease or ulcerative colitis or sclerodermia Other uncontrolled intercurrent disease including, but not limited to: active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation Pregnant or breastfeeding woman, Participation in another therapeutic trial with an experimental molecule for the current disease Psychiatric illness or social situation that would limit compliance with study requirement, substantially increase the risk of side effects, or compromise the ability of the patient to give written informed consent Inability to comply with medical follow-up of the trial (geographical, social or psychic reasons) Person under guardianship or curatorship PART 2: Inclusion Criteria: Maintained consent Adequate hematologic function: Absolute Neutrophil Count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 10g/dL Adequate renal function: creatinine clearance (estimated according to MDRD formula) ≥ 60ml/min/1.73m2 Adequate hepatic function: Aspartate aminotransferase (ALT)/ Alanine aminotransferase (ALT) ≤ 2.5 × upper normal limit (UNL); Total bilirubin ≤ 1.5 x UNL (except in case of Gilbert's disease) Patient having received curative intent chemo-radiation therapy with the following recommendations: extended field CT-RT delivered by IMRT: 45-50Gy according the dosimetry limitation histogram dose volume (HDV) in whole pelvis and Para Aortic volumes + concomitant boost on macroscopic nodes defined as PET-positive associated with weekly Cisplatin (40mg/m²) followed by image guided brachytherapy. Patient will be eligible even in case of temporary stop of radiation therapy, provided she has received a total dose of 45Gy and a concomitant boost. Patient should have received at least 3 injections of Cisplatin 40mg/m² during radiation therapy. Exclusion Criteria: Progression during Part 1, Contraindication for one of the study drug in particular the residual toxicity of Part 1 (radio-chemotherapy) such as: Renal failure (defined as creatinine clearance according to MDRD formula < 60 mL/ min/1.73m2), Any clinical residual toxicity (including peripheral neuropathy) ≥ grade 2 (as per CTCAE v5), Radiation therapy prematurely stopped (total dose on whole pelvis and on nodes not received) Cumulative dose of Cisplatin received less than 120 mg/m².

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carboplatin-Paclitaxel adjuvant chemotherapy<br>Patients will be registered in the first part of the study at diagnosis and will receive a first part of treatment corresponding to a standard of care (standard concomitant radio-chemotherapy, Part 1 of the study). will be included in the second part of the study for the second part of treatment (experimental adjuvant chemotherapy, Part 2 of the study), providing they fulfill eligibility criteria at this stage (no progression during Part 1 of the study and no medical contra-indication to the study treatment). | Drug: Carboplatin-Paclitaxel adjuvant chemotherapy<br>* Patients will receive a first part of treatment corresponding to a standard of care (standard concomitant radio-chemotherapy, Part 1 of the study). Then, they will be included in the second part of the study for the second part of treatment (experimental adjuvant chemotherapy, Part 2 of the study), providing they fulfill eligibility criteria at this stage. The second part consists in 4 cycles of Carboplatin-Paclitaxel adjuvant chemotherapy (one cycle = 3 weeks of treatment and 1 free-week)<br>* Other names: Carboplatin-Paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival with adjuvant chemotherapy | To evaluate the efficacy of adjuvant chemotherapy with Carboplatin-Paclitaxel administrated in adjuvant situation after concomitant radio-chemotherapy in terms of Progression Free Survival (PFS) in patients treated for a locally advanced cervical cancer presenting positive lombo-aortic lymph nodes. Progression will be based on a MRI scan, done during the usual oncologic follow-up: every 3 months during the 2 first years after radio-chemotherapy, and then every 6 months during 3 years. Progression will be evaluated with RECIST criteria v1.1. The main analysis of this phase II trial will focus on the 2-year PFS rate from inclusion in the Part 2, but the whole curve will be estimated. | From the date of inclusion in the Part 2 of the study until the date of first progression or relapse (local, lymph nodes or metastatic) or death whatever the cause. Assessed up to 64 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival with adjuvant chemotherapy | To evaluate efficacy of adjuvant chemotherapy with Carboplatin-Paclitaxel in terms of Overall Survival (OS) in patients treated for a locally advanced cervical cancer presenting positive lombo-aortic lymph nodes. OS will be estimated with the Kaplan-Meier method. | From the date of inclusion in the Part 2 of the study until the date of death whatever the cause. Assessed up to 64 months. | 
| Metastasis Free Survival with adjuvant chemotherapy | To evaluate efficacy of adjuvant chemotherapy with Carboplatin-Paclitaxel in terms of Metastasis Free Survival (MFS) in patients treated for a locally advanced cervical cancer presenting positive lombo-aortic lymph nodes. Metastatic progressions will be evaluated with the RECIST criteria. | From the date of inclusion in the Part 2 of the study until the date of first metastatic progression or death whatever the cause. Assessed up to 64 months. | 
| Number of Cycles Received of adjuvant chemotherapy | To describe feasibility of adjuvant chemotherapy in terms of number of cycles received, separately for each molecule Carboplatin and Paclitaxel. The number of cycles will be recorded in the data base with the date and doses of injections, allowing the calculation of the Relative Dose Intensity. Reasons of treatment stop or dose modification will also be recorded. | From the date of inclusion in the Part 2 of the study until the date of adjuvant chemotherapy ending or patient study output or death whatever the cause. Up to 4 months. | 
| Progression Free Survival with concomitant chemo-radiotherapy associated to brachytherapy | To evaluate the efficacy of adjuvant chemotherapy with concomitant chemo-radiotherapy associated to brachytherapy in terms of Progression Free Survival (PFS) in patients treated for a locally advanced cervical cancer presenting positive lombo-aortic lymph nodes. Progression will be based on a MRI scan, done during the usual oncologic follow-up: every 3 months during the 2 first years after radio-chemotherapy, and then every 6 months during 3 years. Progression will be evaluated with RECIST criteria v1.1. | From the date of inclusion in the Part 1 of the study until the date of first progression or relapse (local, lymph nodes or metastatic) or death whatever the cause. Assessed up to 67 months. | 
| Overall Survival with concomitant chemo-radiotherapy associated to brachytherapy | To evaluate efficacy of concomitant chemo-radiotherapy associated to brachytherapy in terms of Overall Survival (OS) in patients treated for a locally advanced cervical cancer presenting positive lombo-aortic lymph nodes. OS will be estimated with the Kaplan-Meier method. | From the date of inclusion in the Part 1 of the study until the date of death whatever the cause. Assessed up to 67 months. | 
| Metastasis Free Survival with concomitant chemo-radiotherapy associated to brachytherapy | To evaluate efficacy of concomitant chemo-radiotherapy associated to brachytherapy in terms of Metastasis Free Survival (MFS) in patients treated for a locally advanced cervical cancer presenting positive lombo-aortic lymph nodes. Metastatic progressions will be evaluated with the RECIST criteria. | From the date of inclusion in the Part 1 of the study until the date of first metastatic progression or death whatever the cause. Assessed up to 67 months. | 
| Number of Cycles Received of concomitant chemo-radiotherapy associated to brachytherapy | To describe feasibility of the concomitant chemo-radiotherapy associated to brachytherapy (Part 1 of the study) in terms of number of cycles received. The number of cycles will be recorded in the data base with the date and doses of injections, allowing the calculation of the Relative Dose Intensity. Reasons of treatment stop or dose modification will also be recorded. | From the date of inclusion in the Part 1 of the study until the date of concomitant chemo-radiotherapy associated to brachytherapy ending or patient study output or death whatever the cause. Assessed up to 12 weeks. | 
| Safety of the whole treatment | To describe safety of the whole treatment (part 1 & 2) in terms of Adverse Event. During the first part of the study (concomitant radio-chemotherapy), all AE (Adverse Events) will be reported. AE occurring after end of treatment will not be collected for patients withdrawn from the study at the end of the first part. For the second part of the study (adjuvant chemotherapy), all AE will be reported up to 30 days after the end of adjuvant chemotherapy, until progression if any. Then, only AE possibly related to chemotherapy or radiation therapy will be collected, up to 5 years after the end of radiation therapy or until progression (whichever occurs first). All AE will be graded using the NCI-CTCAE v5.0 and AE of grade >2 will be considered as severe AE. | From the date of inclusion in the Part 1 of the study, up to 5 years after the end of radiation therapy or until progression (whichever occurs first). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adjuvant Chemotherapy, Cervical cancer