EWOC-1 Trial: Carboplatin +/- Paclitaxel in Vulnerable Elderly Patients With Stage III-IV Advanced Ovarian Cancer

Study Overview
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Brief Summary
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The current standard of first-line chemotherapy in advanced ovarian cancer is the combination of carboplatin AUC 5mg/mL/min and paclitaxel 175 mg.m-². This combination is feasible in selected elderly patients such as those included in prospective trials. These trials, however, include a minority of the elderly population. In wider selection of patients >70 years old, the standard carboplatin-paclitaxel regimen has been shown to induce an excess of toxicity and premature treatment stopping. For elderly patients thought to be vulnerable and at high risk of toxicity with the standard 3-weekly carboplatin-paclitaxel regimen, other options are used in routine practice. One option is to delete paclitaxel and treat elderly patients with carboplatin as a single agent. An alternative is to use the carboplatin-paclitaxel regimen in a weekly schedule for both drugs such as reported by the MITO (Multicentre Italian Trial in Ovarian Cancer). To date, there is no randomized trial which could give us some evidence of how to select patients who could benefit most of one or the other regimen described above. The 4th Ovarian Cancer Consensus Conference has indeed recognised the medical unmet need of adapted therapy for elderly patients with ovarian cancer and the necessity of additional research in this population. Recently, GINECO has described a Geriatric Vulnerability Score (GVS) in a population of elderly patients with advanced ovarian cancer included in a specific multicenter phase II trial. The best proportional hazard model fitting for overall survival identified the following geriatric covariates score as being poor survival risk factors: ADL score <6, IADL score <25, HADS score >14, albuminemia <35g/L and , lymphopenia <1G/L. GVS is the sum of these risk factors for each patient. Using a cut off of 3, the GVS identified a group of patients at high risk of severe toxicity, early cessation of treatment, unplanned hospitalization and adverse outcomes. This international multicentre randomized phase II trial will compare the success rate of delivering 6 courses of chemotherapy with evidence of efficacy and without premature termination for progression, death or unacceptable toxicity of three different chemotherapy regimens in a selected population of elderly patients with a GVS ≥ 3: Arm A: Paclitaxel 175mg/m²/3 hours, I.V. and carboplatin AUC 5, I.V. every 3 weeks Arm B: Carboplatin monotherapy AUC 5 or 6 every 3 weeks Arm C: Weekly paclitaxel 60 mg/m²/1 hour and weekly carboplatin AUC 2 (d1, d8, d15 every 4 weeks) The total number of patients to be enrolled is 240, ie 22 in each arm (total = 66) at the first step, then 58 more by arm (total=174) after interim analysis.

Official Title
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EWOC-1 Trial: Multicenter, Randomized Trial of Carboplatin +/- Paclitaxel in Vulnerable Elderly Patients With Stage III-IV Advanced Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Paclitaxel + Carboplatin every 3 weeks
* Drug: Carboplatin monotherapy every 3 weeks
* Drug: Weekly Paclitaxel and Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Woman >70 year old Histologically or cytologically proven FIGO stage III to IV epithelial ovarian cancer or peritoneal primary or fallopian tube. A cytological proof is accepted if associated with a ratio of CA125/CEA >25 and a radiological pelvic mass. GVS (Geriatric Vulnerability Score) >3. Adequate bone marrow function including the following: Neutrophils ≥ 1.5 x 109/L , platelets ≥100 x 109/L and hemoglobin ≥9 g/dL. Adequate glomerular filtration rate >40 ml/min (estimates based on MDRD or Chatelut formula are sufficient) No icterus. Life expectancy > 3 months. Written informed consent obtained. Covered by a Health System where applicable Exclusion Criteria: Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer. Prior history of chemotherapy. Prior history of radiotherapy which may affect patient tolerability to chemotherapy. Major perturbations of liver biology: Bilirubin > 2 fold the upper normal limit (UNL), SGOT-SGPT > 3 fold UNL. Patient unable to be regularly followed for any reason (geographic, familial, social, psychologic). Any mental or physical handicap at risk of interfering with the appropriate treatment. Known allergy to Cremophor ® EL -containing drugs. Any administrative or legal supervision where applicable

Ages Eligible for Study
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Minimum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A:Paclitaxel + Carboplatin every 3 weeks<br>Patients randomized to the arm A receive 6 courses the following regimen: Paclitaxel 175 mg/m²/3 hours, I.V. and carboplatin AUC 5, I.V. every 3 weeks (1 cycle = 21 days). | Drug: Paclitaxel + Carboplatin every 3 weeks<br>* Patients will receive a premedication of 130mg prednisolone the day before (22 pm) and the morning (7 am). A pretreatment using corticosteroids, antihistamines and H2 antagonists and setrons in accordance with local standards of care will be administered 30 minutes before Paclitaxel administration. At H0, Paclitaxel is administered at 175mg/m² in 3 hours then Carboplatin is administered at AUC 5mg/mL/min.<br>|
| Experimental: B:Carboplatin monotherapy every 3 weeks<br>Patients randomized to the arm B receive 6 courses the following regimen: Carboplatin monotherapy AUC 5 or 6 every 3 weeks (1 cycle = 21 days). | Drug: Carboplatin monotherapy every 3 weeks<br>* A pretreatment using setrons in accordance with local standards of care will be administered 30 minutes before Carboplatin at AUC 5 to 6mg/mL/min in 1 hour.<br>|
| Experimental: C:Weekly Paclitaxel and Carboplatin<br>Patients randomized to the arm C receive 6 courses the following regimen: weekly paclitaxel 60 mg/m²/1 hour and weekly carboplatin AUC 2 (d1, d8, d15 ; d1=d29) (1 cycle = 28 days). | Drug: Weekly Paclitaxel and Carboplatin<br>* A pretreatment using corticosteroids, antihistamines and H2 antagonists and setrons in accordance with local standards of care will be administered 30 minutes before Paclitaxel 60mg/m² in 1 hour followed by Carboplatin at AUC 2mg/mL/min in 1 hour.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment success.Treatment success is defined as the ability to deliver 6 courses of chemotherapy without premature termination for progression, death or unacceptable toxicity | Treatment success is defined as the ability to deliver 6 courses of chemotherapy without premature termination for progression, death or unacceptable toxicity. Unacceptable toxicity is defined as a major adverse event related to chemotherapy or treatment procedure leading either to early treatment stopping, to an unplanned hospital admission or to death or to a dose delay lasting more than 14 days or more than 2 dose reductions. | After 6 courses of chemotherapy i.e 4.5 to 6 months (depending on the arm) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapeutical strategy | Therapeutical strategy will be assessed by measuring the feasibility of performing an optimal surgery and feasibility of performing neoadjuvant chemotherapy and surgery and post operative chemotherapy until 6 courses in case of planned interval debulking surgery. | At the end of treatment (6 courses ), i.e 4.5 to 6 months (depending on the arm) | 
| Overall Survival | Overall survival is defined as the time period from the date of randomization to the date of death. | 2.5 years | 
| Progression-free survival | Progression-free survival is defined as the time period from the date of randomization to the date of disease progression or death whichever occurs first. | 2.5 years | 
| Quality of Life | Quality of life is evaluated using the FACT-O questionnaire | At the end of treatment (6 courses ), i.e 4.5 to 6 months (depending on the arm) | 
| Safety and tolerability | Adverse events are defined using the NCI-CTC AE scale version 4.3 | At the end of treatment (6 courses ), i.e 4.5 to 6 months (depending on the arm) | 
| Aging biomarkers | Aging biomarkers are represented by the expression level of cathelin-related antimicrobial peptide or CRAMP, stathmin, EF-1α, and chitinase | At the end of treatment (6 courses ), i.e 4.5 to 6 months (depending on the arm) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elderly, Vulnerable, Ovarian cancer, Chemotherapy