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

Tracking Information
First Submitted Date ICMJE	November 12, 2009
First Posted Date ICMJE	November 13, 2009
Results First Submitted Date	January 26, 2017
Results First Posted Date	July 14, 2017
Last Update Posted Date	July 14, 2017
Study Start Date ICMJE	November 2009
Actual Primary Completion Date	September 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: July 13, 2017)	Progression-free Survival [ Time Frame: 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 ]; 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.
Original Primary Outcome Measures ICMJE; (submitted: November 12, 2009)	Duration of progression-free survival
Change History	Complete list of historical versions of study NCT01012297 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: July 13, 2017)	Overall Survival [ Time Frame: Up to 5 years ]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.; Frequency and Severity of Adverse Effects as Assessed by the CTCAE Version 4.0 [ Time Frame: Up to 5 years ]Count of participants with Adverse events (AEs) that are CTCAE Grade 3 or worse. Please refer to the adverse event reporting for more detail.; Objective Response Rate as Measured by RECIST 1.1 Criteria [ Time Frame: Up to 5 years ]"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.
Original Secondary Outcome Measures ICMJE; (submitted: November 12, 2009)	Duration of overall survival and response as assessed by RECIST 1.1 criteria; Frequency and severity of adverse effects as assessed by NCI CTCAE v3.0
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Gemcitabine Hydrochloride and Docetaxel With or Without Bevacizumab in Treating Patients With Advanced or Recurrent Uterine Leiomyosarcoma
Official Title ICMJE	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
Brief Summary	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	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.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	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 ICMJE	Biological: Bevacizumab Given IV Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF; Drug: Docetaxel Given IV Other Names: RP56976 Taxotere Taxotere Injection Concentrate; Biological: Filgrastim Given SC Other Names: Filgrastim XM02 G-CSF Neupogen r-metHuG-CSF Recombinant Methionyl Human Granulocyte Colony Stimulating Factor rG-CSF Tbo-filgrastim Tevagrastim; Drug: Gemcitabine Hydrochloride Given IV Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride Gemzar LY-188011; Biological: Pegfilgrastim Given SC Other Names: Filgrastim SD-01 filgrastim-SD/01 Neulasta SD-01 SD-01 sustained duration G-CSF; Other: Placebo Given IV Other Names: placebo therapy PLCB sham therapy
Study Arms	Experimental: Arm I Gem+Doce+Placebo 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. Interventions: Drug: Docetaxel Biological: Filgrastim Drug: Gemcitabine Hydrochloride Biological: Pegfilgrastim Other: Placebo; Experimental: Arm II Gem+Doce+Bev 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. Interventions: Biological: Bevacizumab Drug: Docetaxel Biological: Filgrastim Drug: Gemcitabine Hydrochloride Biological: Pegfilgrastim
Publications *	Hensley ML, Miller A, O'Malley DM, Mannel RS, Behbakht K, Bakkum-Gamez JN, Michael H. Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2015 Apr 1;33(10):1180-5. doi: 10.1200/JCO.2014.58.3781. Epub 2015 Feb 23.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Terminated
Actual Enrollment ICMJE; (submitted: July 13, 2017)	107
Original Estimated Enrollment ICMJE; (submitted: November 12, 2009)	130
Actual Study Completion Date	September 2015
Actual Primary Completion Date	September 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: Female
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01012297
Other Study ID Numbers ICMJE	NCI-2010-01738; NCI-2010-01738 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000659024; GOG-0250; GOG-0250 ( Other Identifier: NRG Oncology ); GOG-0250 ( Other Identifier: CTEP ); U10CA027469 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Cancer Institute (NCI)
Study Sponsor ICMJE	National Cancer Institute (NCI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Martee Hensley NRG Oncology
PRS Account	National Cancer Institute (NCI)
Verification Date	July 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP