Gemcitabine Hydrochloride and Docetaxel With or Without Bevacizumab in Treating Patients With Advanced or Recurrent Uterine Leiomyosarcoma

Study Overview
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Brief Summary
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This randomized phase III trial is studying gemcitabine hydrochloride, docetaxel, and bevacizumab to see how well they work compared with gemcitabine hydrochloride, docetaxel, and a placebo in treating patients with advanced or recurrent uterine leiomyosarcoma. Drugs used in chemotherapy, such as gemcitabine hydrochloride and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether gemcitabine hydrochloride and docetaxel are more effective when given with or without bevacizumab in treating uterine leiomyosarcoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether the addition of bevacizumab to fixed-dose rate gemcitabine-docetaxel reduces the progression-free survival (PFS) event rate when compared to gemcitabine-docetaxel plus placebo in patients with advanced or recurrent uterine leiomyosarcoma (LMS). SECONDARY OBJECTIVES: I. To determine the objective response rate, as measured by RECIST, of patients treated with fixed-dose rate gemcitabine-docetaxel with bevacizumab, compared with the objective response rate of patients treated with fixed-dose rate gemcitabine-docetaxel with placebo. II. To determine if the addition of bevacizumab to the combination of gemcitabine and docetaxel increases overall survival in patients with advanced or recurrent uterine LMS. III. To determine the toxicity profile of fixed-dose rate gemcitabine-docetaxel with and without bevacizumab in this patient population. IV. To bank formalin-fixed and paraffin-embedded (FFPE) tumor tissue for research. OUTLINE: This is a multicenter study. Patients are stratified according to prior whole-pelvic radiotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive a placebo IV over 30-90 minutes on day 1, gemcitabine hydrochloride IV over 90 minutes on days 1 and 8, and docetaxel IV over 60 minutes on day 8. Patients also receive filgrastim subcutaneously (SC) on days 9-15 or pegfilgrastim SC on day 9 or 10. ARM II: Patients receive bevacizumab IV over 30-90 minutes on day 1, gemcitabine hydrochloride IV over 90 minutes on days 1 and 8, and docetaxel IV over 60 minutes on day 8. Patients also receive filgrastim SC on days 9-15 or pegfilgrastim SC on day 9 or 10. In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Randomized Phase III Evaluation of Docetaxel (NSC #628503) and Gemcitabine (NSC #613327) Plus G-CSF With Bevacizumab (NSC #704865) Versus Docetaxel (NSC #628503) and Gemcitabine (NSC #613327) Plus G-CSF With Placebo in the Treatment of Recurrent or Advanced Leiomyosarcoma of the Uterus

Conditions
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Recurrent Uterine Corpus Sarcoma, Stage IIIA Uterine Sarcoma, Stage IIIB Uterine Sarcoma, Stage IIIC Uterine Sarcoma, Stage IVA Uterine Sarcoma, Stage IVB Uterine Sarcoma, Uterine Corpus Leiomyosarcoma

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Docetaxel
* Biological: Filgrastim
* Drug: Gemcitabine Hydrochloride
* Biological: Pegfilgrastim
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have advanced or recurrent uterine leiomyosarcoma with documented disease progression; histologic confirmation of the original primary tumor is required All patients must have measurable disease as defined by RECIST 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI Patient must have at least one target lesion to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy Patients must have a GOG Performance Status of 0, 1, or 2 Patients must have recovered from effects of recent surgery, radiotherapy or other therapy Patients should be free of active infection requiring antibiotics (with the exception of an uncomplicated UTI) Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to first day of study treatment; continuation of hormone replacement therapy is permitted Platelet count greater than or equal to 100,000/mm^3 ANC count greater than or equal to 1,500/mm^3 Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN), per NCI CTCAE Version 4.0 Grade 1 Bilirubin within normal range (CTCAE Version 4 Grade 0) SGOT and alkaline phosphatase less than or equal to 2.5 x ULN, per the CTCAE Version 4.0 Grade 1) SGOT less than or equal to 2.5 x ULN, per the CTCAE Version 4.0 Grade 1 Alkaline phosphatase less than or equal to 2.5 x ULN, per the CTCAE Version 4.0 Grade 1 Neuropathy (sensory and motor) less than or equal to Grade 1 per the CTCAE Version 4.0. No history of transient ischemic attack (TIA) or stroke or CNS hemorrhage within the past 6 months Urine protein creatinine (UPC) ratio must be < 1.0 gm; if UPC ratio >= 1, collection of 24-hour urine measurement of urine protein is recommended PT such that international normalized ratio (INR) is =< 1.5 and a PTT =< 1.5 times the institutional upper limit of normal (or an in-therapeutic-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) Patients must have signed an approved informed consent and authorization permitting release of personal health information Patients must meet pre-entry requirements Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing an effective form of contraception Exclusion Criteria: Patients who have received prior cytotoxic chemotherapy for management of uterine sarcoma; patients who have received prior VEGF-pathway targeted agent such as bevacizumab, PTK787, VEGF-trap, or who have received prior treatment with a multi-kinase inhibitor such as sorafenib or sunitinib are not eligible Patients who have had prior therapy with docetaxel or gemcitabine or bevacizumab Patients with a history of other invasive malignancies, with the exceptions of non-melanoma skin cancer, carcinoma in situ of the cervix, and ductal carcinoma in situ of the breast, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels; (necessary use of warfarin or low molecular weight heparin is permitted, provided the INR is maintained in the therapeutic range of approximately 2-3) Patients with major surgery or significant traumatic injury within 28 days prior to study entry Patients with a history of abdominal fistula or perforation within the past 12 months Patients with a current, serious, non-healing wound, ulcer, or bone fracture Patients with history or evidence upon physical examination of CNS disease, including history of primary brain tumor, or any history of brain metastases, or seizures not controlled with standard medical therapy Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies Cardiovascular function; specifically, patient may not have: Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 100 mm Hg in a patient with no history of hypertension; patients with a history of hypertension before enrollment on study are permitted, but such patients must have BP less than or equal to 140/90 mmHg; use of blood pressure medications to achieve and maintain blood pressure control is permitted Myocardial infarction or unstable angina within 6 months of the first date of bevacizumab/placebo therapy New York Heart Association (NYHA) Grade II or greater congestive heart failure or serious cardiac arrhythmia requiring medication; women who have received prior treatment with an anthracycline (including doxorubicin and/or liposomal doxorubicin) and have an ejection fraction < 50% will be excluded from the study Grade 1, Category 2 or greater, peripheral vascular disease; patient cannot have anything worse than mild, symptomatic claudication with exercise History of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of bevacizumab/placebo therapy History of pulmonary embolism or deep vein thrombosis in the past 6 months Patients with, or with anticipation of, invasive procedures as defined below: Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to the first date of bevacizumab/placebo therapy Major surgical procedure anticipated during the course of the study. Minor surgical procedures (i.e., mediport insertion), fine needle aspirates, or core biopsies within 7 days prior to the first date of bevacizumab/placebo therapy Patients who are pregnant or nursing

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 |
| --- | --- |
| Experimental: Arm I Gem+Doce+Placebo<br>Patients receive a placebo IV over 30-90 minutes on day 1, gemcitabine hydrochloride IV over 90 minutes on days 1 and 8, and docetaxel IV over 60 minutes on day 8. Patients also receive filgrastim subcutaneously (SC) on days 9-15 or pegfilgrastim SC on day 9 or 10. | Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY-188011;Biological: Pegfilgrastim<br>* Given SC<br>* Other names: SD-01 sustained duration G-CSF;Other: Placebo<br>* Given IV<br>* Other names: sham therapy;|
| Experimental: Arm II Gem+Doce+Bev<br>Patients receive bevacizumab IV over 30-90 minutes on day 1, gemcitabine hydrochloride IV over 90 minutes on days 1 and 8, and docetaxel IV over 60 minutes on day 8. Patients also receive filgrastim SC on days 9-15 or pegfilgrastim SC on day 9 or 10. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY-188011;Biological: Pegfilgrastim<br>* Given SC<br>* Other names: SD-01 sustained duration G-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan. Assessed with a log-rank test stratified by whether the patient had whole pelvic radiotherapy prior to starting the study treatment. The product-limit method will be used to estimate the cumulative distribution of PFS for the patients assigned to each treatment group. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) was defined as the number of months between study enrollment and death from any cause. Patients still alive at the last followup were censored on the date of last CT Scan. The product-limit method will be used to estimate the cumulative distribution of overall survival times for the patients assigned to each treatment group. | Up to 5 years | 
| Frequency and Severity of Adverse Effects as Assessed by the CTCAE Version 4.0 | Count of participants with Adverse events (AEs) that are CTCAE Grade 3 or worse. Please refer to the adverse event reporting for more detail. | Up to 5 years | 
| Objective Response Rate as Measured by RECIST 1.1 Criteria | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 5 years |