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

Phase 3

Terminated

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

Interventions: Biological: Bevacizumab
Drug: Docetaxel
Drug: Gemcitabine Hydrochloride
Biological: Filgrastim
Biological: Pegfilgrastim
Other: Placebo

Registration Number: NCT01012297

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 107

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I Gem+Doce+Placebo	Gemcitabine Hydrochloride	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 Gem+Doce+Bev	Gemcitabine Hydrochloride	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.
Arm II Gem+Doce+Bev	Pegfilgrastim	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.
Arm II Gem+Doce+Bev	Filgrastim	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.
Arm I Gem+Doce+Placebo	Pegfilgrastim	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 I Gem+Doce+Placebo	Filgrastim	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 I Gem+Doce+Placebo	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.
Arm II Gem+Doce+Bev	Bevacizumab	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.
Arm I Gem+Doce+Placebo	Docetaxel	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 Gem+Doce+Bev	Docetaxel	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	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	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	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.

Trial Locations

Locations (200): Saint Joseph's Hospital and Medical Center
🇺🇸
Phoenix, Arizona, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
🇺🇸
Burbank, California, United States
John Muir Medical Center-Concord Campus
🇺🇸
Concord, California, United States
UC San Diego Moores Cancer Center
🇺🇸
La Jolla, California, United States
Kaiser Permanente Los Angeles Medical Center
🇺🇸
Los Angeles, California, United States
Los Angeles County-USC Medical Center
🇺🇸
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
UCLA / Jonsson Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
Palo Alto Medical Foundation-Gynecologic Oncology
🇺🇸
Mountain View, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
🇺🇸
Orange, California, United States
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Saint Joseph's Hospital and Medical Center
🇺🇸Phoenix, Arizona, United States