Doxorubicin Hydrochloride, Cisplatin, and Paclitaxel or Carboplatin and Paclitaxel in Treating Patients With Stage III-IV or Recurrent Endometrial Cancer

Study Overview
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Brief Summary
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This randomized phase III trial compares how well two different combination chemotherapy regimens (doxorubicin hydrochloride, cisplatin, and paclitaxel versus carboplatin and paclitaxel) work in treating patients with endometrial cancer that is stage III-IV or has come back (recurrent). Drugs used in chemotherapy such as doxorubicin hydrochloride, cisplatin, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known which combination chemotherapy regimen is more effective in treating endometrial cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if the combination of carboplatin and paclitaxel (TC) chemotherapy is therapeutically equivalent to the combination of doxorubicin (doxorubicin hydrochloride), cisplatin and paclitaxel (TAP) chemotherapy with regards to survival. II. To determine if estrogen/progesterone receptor status provides prognostic information in patients treated with chemotherapy. III. To assess whether combination TC chemotherapy is superior to combination TAP chemotherapy with regards to toxicity profile, specifically neurotoxicity and infection. IV. To measure differences in patient-reported neurotoxicity and quality of life (QOL) among the regimens. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients with left ventricular ejection fraction < 50% at randomization who are initially randomized to Arm I are immediately crossed over to Arm II. ARM I: Patients receive doxorubicin hydrochloride intravenously (IV) over approximately 15-30 minutes on day 1, cisplatin IV over 60-90 minutes on day 1, paclitaxel IV over 3 hours on day 2, and filgrastim subcutaneously (SC) on days 3-12 or pegfilgrastim SC on day 3. ARM II: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30-60 minutes on day 1. In both arms, treatment repeats every 21 days for 7 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
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Randomized Phase III Trial of Doxorubicin/Cisplatin/Paclitaxel and G-CSF Versus Carboplatin/Paclitaxel in Patients With Stage III &Amp; IV or Recurrent Endometrial Cancer

Conditions
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Recurrent Uterine Corpus Carcinoma, Stage IIIA Uterine Corpus Cancer AJCC v7, Stage IIIB Uterine Corpus Cancer AJCC v7, Stage IIIC Uterine Corpus Cancer AJCC v7, Stage IVA Uterine Corpus Cancer AJCC v7, Stage IVB Uterine Corpus Cancer AJCC v7

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Doxorubicin Hydrochloride
* Biological: Filgrastim
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Biological: Pegfilgrastim
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have primary stage III or stage IV or recurrent endometrial carcinoma whose potential for cure by radiation therapy or surgery alone or in combination is very poor; pathological confirmation and estrogen receptor (ER)/progesterone receptor (PR) status of the primary tumor is mandatory; however, the results do not need to be available prior to registration Patients may not have received prior cytotoxic chemotherapy, including chemotherapy used for radiation sensitization; patients may have received prior radiation therapy, hormonal therapy, or therapy with biologic agents, but such therapies must be discontinued prior to entry on this study Patients in whom both radiation and chemotherapy is planned must receive radiation prior to entry on this study; at least four weeks should have elapsed since completion of radiation therapy (RT) involving the whole pelvis or over 50% of the spine Platelets >= 100,000/mcl Granulocytes (absolute neutrophil count [ANC]) >= 1,500/mcl Creatinine =< upper limit of normal (ULN) (Common Toxicity Criteria [CTC] grade 0) or calculated creatinine clearance (Jeliffe Formula) >= 60 ml/min Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limits of normal Bilirubin =< institutional upper limits of normal Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2 Patients must have met the pre-entry requirements Patients must have signed an approved informed consent and authorization permitting release of personal health information Exclusion Criteria: Patients with a concomitant malignancy other than non-melanoma skin cancer; with the exception of non-melanoma skin cancer, patients with a prior invasive malignancy who have been disease-free for < 5 years or who received prior chemotherapy for that malignancy Patients in whom pathological confirmation and estrogen receptor (ER)/progesterone receptor (PR) status of the tumor is not obtainable Patients for whom radiation therapy is planned during or after study chemotherapy prior to demonstrated progression Patients with concomitant medical illness such as serious uncontrolled infection, uncontrolled angina, or serious peripheral neuropathy, which, in the opinion of the treating physician, make the treatments prescribed on this study unreasonably hazardous for the patient Patients with third degree or complete heart block are not eligible unless a pacemaker is in place; patients on medications which alter cardiac conduction, such as digitalis, beta-blockers, or calcium channel blockers, or who have other conduction abnormalities or cardiac dysfunction may be placed on study at the discretion of the investigator Patients with history of myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure or symptoms suspicious for congestive heart failure are not eligible unless a left ventricular ejection fraction in the past 6 months is documented to be 50% or greater; patients who have had a left ventricular ejection fraction (LVEF) (performed for any reason) of less than 50% in the past 6 months are ineligible Patients whose circumstances will not permit study completion or adequate follow-up Patients who are sensitive to E. coli-derived drug preparations Patients with uterine carcinosarcoma or other non-epithelial uterine malignancies

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (doxorubicin hydrochloride, cisplatin, paclitaxel)<br>Patients receive doxorubicin hydrochloride IV over approximately 15-30 minutes on day 1, cisplatin IV over 60-90 minutes on day 1, paclitaxel IV over 3 hours on day 2, and filgrastim SC on days 3-12 or pegfilgrastim SC on day 3. Treatment repeats every 21 days for 7 courses in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pegfilgrastim<br>* Given SC<br>* Other names: SD-01 sustained duration G-CSF;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm II (paclitaxel, carboplatin)<br>Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 7 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>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;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Alive at Time of Last Follow-up. | The time alive in months from study entry to last contact or death. | Patients were assessed during treatment. Following completion of treatment, follow up was assessed every 3 months for 2 years, then every 6 months for 3 years and annually after for a maximum of 10 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported Neurotoxicity (Ntx) as Measured by the FACT/GOG-Ntx Subscale (Short) | The FACT/GOG-Ntx subscale (short version) contains 4 items measuring sensory neuropathy. Each item is scored using a 5-point Likert scale (0=not at all; 1= a little bit; 2=somewhat; 3=quite a bit; 4=very much). For east item, reversal was performed prior to score calculation so that a large score suggests less symptom. according to the FACIT measurement system, the subscale score was calculated as 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 Ntx subscale score ranges 0-16 with a large subscale score suggests less symptom or better QOL (Quality of Life). | Baseline, 6 weeks post treatment start, 15 weeks post treatment start and 26 weeks post treatment start | 
| Patient Reported Quality of Life as Measured With the Combination of Physical Well-being (PWB) Subscale and Functional Well-being (FWB) Subscale From the FACT-G | The FACT-G contains 4 subscales: Physical Well Being (7 items), Social Well Being (7 items), Emotional Well Being (6 items), Functional Well Being (7 items). The combination (14 items) of the physical well-being (PWB) and functional well-being (FWB) subscales was used to measure the HRQOL (Health Related Quality of Life). Each item is scored using a 5-point Likert scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). for each negative item, reversal was performed prior to score calculation so that a large score suggests better QOL. A subscale score was calculated as 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 answred item scores by the number of items in the subscale. The QOL was measured with the summation of the PWB and FWBsubscale score and ranges 0-56 with a large score suggests better QOL. | Pre-treatment, 6 weeks post starting treatment (prior to cycle 3), 15 weeks post starting treatment (prior to cycle 6), 26 weeks post starting treatment | 
| Number of Participants Alive at Time of Last Follow-up by Estrogen or Progesterone Receptor Status (Positive or Negative) | The time alive in months from study entry to last contact or death. | Patients were assessed during treatment. Following completion of treatment, follow up was assessed every 3 months for 2 years, then every 6 months for 3 years and annually thereafter, for a maximum of 10 years. | 
| Number of Participants With Indicated Severity of CTCAE v2 Graded Neurotoxicity and Infection | Maximum grade of physician assessed neurotoxicity and infection | Assessed throughout the treatment period and for 30 days after discontinuation of treatment. |