Comparison of Four Combination Chemotherapy Regimens Using Cisplatin in Treating Patients With Stage IVB, Recurrent, or Persistent Cancer of the Cervix

Study Overview
=================
Brief Summary
-----------------
This randomized phase III trial is studying four combination chemotherapy regimens using cisplatin to compare how well they work in treating women with stage IVB, recurrent, or persistent cancer of the cervix. Drugs used in chemotherapy such as cisplatin, paclitaxel, vinorelbine, gemcitabine, and topotecan, use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which combination chemotherapy regimen containing cisplatin is most effective in treating cervical cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Compare the survival and response of patients with stage IVB, recurrent, or persistent carcinoma of the cervix when treated with paclitaxel and cisplatin vs vinorelbine and cisplatin vs gemcitabine and cisplatin vs topotecan and cisplatin. II. Compare the toxic effects of these regimens in these patients. III. Compare the quality of life of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 4 treatment arms. ARM I: Patients receive paclitaxel IV over 24 hours on day 1 and cisplatin IV over 1-4 hours on day 2. ARM II: Patients receive vinorelbine IV over 6-10 minutes on days 1 and 8 and cisplatin IV over 1-4 hours on day 1. ARM III: Patients receive gemcitabine IV over 30-60 minutes on days 1 and 8 and cisplatin as in arm II. ARM IV: Patients receive topotecan IV over 30 minutes on days 1-3 and cisplatin as in arm II. In all arms, treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, before courses 2 and 5, and at 9 months after study entry. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
-----------------
A Randomized Phase III Trial Of Paclitaxel Plus Cisplatin Versus Vinorelbine Plus Cisplatin Versus Gemcitabine Plus Cisplatin Versus Topotecan Plus Cisplatin In Stage IVB, Recurrent Or Persistent Carcinoma of the Cervix

Conditions
-----------------
Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Recurrent Cervical Carcinoma, Stage IVB Cervical Cancer

Intervention / Treatment
-----------------
* Drug: Cisplatin
* Drug: Gemcitabine Hydrochloride
* Drug: Paclitaxel
* Other: Quality-of-Life Assessment
* Drug: Topotecan Hydrochloride
* Drug: Vinorelbine Tartrate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix Stage IVB, recurrent, or persistent disease Not amenable to curative surgery and/or radiotherapy At least 1 unidimensionally measurable lesion At least 20 mm by palpation, plain x-ray, CT scan, or MRI OR at least 10 mm by spiral CT scan Biopsy confirmation required if lesion is less than 30 mm Target lesion must be outside of a previously irradiated field No craniospinal metastases Performance status - GOG 0-1 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 times normal Alkaline phosphatase no greater than 3 times normal AST no greater than 3 times normal Creatinine ≤ 1.2 mg/dL Creatinine > 1.2 mg/dL but < 1.5 mg/dL AND creatinine clearance ≥ 50 mL/min No bilateral hydronephrosis not alleviated by ureteral stents or percutaneous drainage Not pregnant or nursing Fertile patients must use effective contraception No prior or concurrent malignancy within the past 5 years except nonmelanoma skin cancer No prior malignancy whose treatment contraindicates the current study therapy No concurrent clinically significant infection No concurrent cytokines At least 6 weeks since prior chemoradiotherapy and recovered No prior chemotherapy (except when concurrently administered with radiotherapy) At least 3 weeks since prior radiotherapy and recovered Recovered from prior surgery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (paclitaxel, cisplatin)<br>Patients receive paclitaxel IV over 24 hours on day 1 and cisplatin IV over 1-4 hours on day 2. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm II (vinorelbine, cisplatin)<br>Patients receive vinorelbine IV over 6-10 minutes on days 1 and 8 and cisplatin IV over 1-4 hours on day 1. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Vinorelbine Tartrate<br>* Given IV<br>* Other names: Vinorelbine Ditartrate;|
| Experimental: Arm III (gemcitabine, cisplatin)<br>Patients receive gemcitabine IV over 30-60 minutes on days 1 and 8 and cisplatin as in arm II. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Gemcitabine Hydrochloride<br> <br> * Other names: LY-188011;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm IV (topotecan, cisplatin)<br>Patients receive topotecan IV over 30 minutes on days 1-3 and cisplatin as in arm II. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Overall Survival (OS) | Overall survival is defined as the duration of time from study entry to time of death or the date of last contact. | Baseline, every other cycle during treatment, then every 3 months for 2 years, the every 6 months for 3 years (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Response Using RECIST Version 1.0 | RECIST 1.0 defines complete response as the disappearance of all target lesions and non-target lesions and no evidence of new lesions documented by two disease assessments at least 4 weeks apart. Partial response is defined as at least a 30% decrease in the sum of longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD. There can be no unequivocal progression of non-target lesions and no new lesions. Documentation by two disease assessments at least 4 weeks apart is required. In the case where the ONLY target lesion is a solitary pelvic mass measured by physical exam, which is not radiographically measurable, a 50% decrease in the LD is required. These patients will have their response classified according to the definitions stated above. | Baseline, every other cycle during treatment, then every 3 months for 2 years, the every 6 months for 3 years (up to 5 years) | 
| Duration of Progression-free Survival (PFS) | Progression-free survival (PFS) was defined as the period from study entry until disease progression, death, or the last date of contact. Progression is defined according to RECIST v1.0 as at least a 20% increase in the sum of LD target lesions taking as reference the smallest sum LD recorded since study entry, the appearance of one or more new lesions, death due to disease without prior objective documentation of progression, global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression, or unequivocal progression of existing non-target lesions. | Baseline, every other cycle during treatment, then every 3 months for 2 years, the every 6 months for 3 years (up to 5 years) | 
| Patient-reported Quality of Life as Measured by the Functional Assessment of Cancer Therapy (FACT)-Cervical Trial Outcome of Index (FACT-Cx TOI) | The FACT-Cx TOI is a scale for assessing general QOL of cervical cancer patients.consisting of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Cervical Cancer subscale (15 items). Each item in the FACT-Cx TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative statements (or questions), reversal was performed prior to score calculation. According to the FACIT measurement system, a subscale score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the subscale. The score is calculated as the sum of the subscale scores if more than 80% of the FACT-Cx TOI items provide valid answers and all of the component subscales have valid scores. The score ranges 0-116 with a large score suggesting better QOL. | Baseline (pre-cycle 1), Pre-cycle 2, Pre-cycle 5, 9 months post cycle 1 | 
| Pain, Assessed by Brief Pain Inventory | Single item from the Brief Pain Inventory (BPI) assessing worst pain in the past 24 hours, on a 0-10 scale with a higher score indicating more pain than a low score. | Baseline (pre-cycle 1), Pre-cycle 2, Pre-cycle 5, 9 months post cycle 1 | 
| Patient Reported Neurotoxicity Symptoms as Measured With the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity Subscale (Short Version) (FACT/GOG-Ntx Subscale). | The FACT/GOG-Ntx subscale contains 4 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative items, reversal was performed prior to score calculation. According to the FACIT measurement system, the Ntx score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The Ntx score ranges 0-16 with a large score suggests less neurotoxicity. | Baseline (pre-cycle 1), Pre-cycle 2, Pre-cycle 5, 9 months post cycle 1 |