Bevacizumab Plus Ixabepilone to Treat Patients With Advanced Kidney Cancer
Verified August 2013 by National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
First received: June 17, 2009
Last updated: March 14, 2014
Last verified: August 2013
- Bevacizumab (Avastin) belongs to a class of drugs that interferes with the formation of new blood vessels. As tumors grow, they need to supply themselves with blood in order to survive and grow. Bevacizumab can reduce the amount of new blood vessels being formed to supply nutrients to tumors, and has demonstrated a significant activity in kidney cancer.
- Ixabepilone is a member of the class of drugs called epothilones. These drugs interfere with the ability of cancer cells to replicate. They have a similar mechanism of action to taxanes, another class of drugs that includes the drug Taxol, which is used to treat a variety of cancers.
- Ixabepilone can work in cells that are resistant to Taxol and has been approved to treat breast cancer that has spread beyond the breast to other parts of the body.
- To determine whether the combination of ixabepilone and bevacizumab is effective for treating kidney cancer.
- Patients 18 years of age or older with advanced kidney cancer that does not respond to standard treatments.
- Patients receive bevacizumab intravenously (through a vein) on day 1 of each 21-day treatment cycle. Ixabepilone is infused over 60 minutes on days 1-5 of each cycle. The number of cycles patients receive depends on their response to the treatment.
- Patients have CT scans and other tests before starting treatment and then at every other treatment cycle to determine the response of the tumor to treatment.
- Patients who can undergo a tumor biopsy (removal of a sample of tumor tissue) are asked to have a biopsy done before starting treatment with the study drugs and again after the first treatment cycle is completed and before the second cycle begins. This procedure is optional.
- Patients have routine and research blood tests and MRI scans.
Renal Cell Carcinoma
Drug: Ixempra (Ixbepilone [BMS-247550]
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Phase II Multi-Center Study of Bevacizumab in Combination With Ixabepilone in Subjects With Advanced Renal Cell Carcinoma
Primary Outcome Measures:
- Response rate per RECIST.
Secondary Outcome Measures:
- Biomarkers, imaging studies.
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||November 2014 (Final data collection date for primary outcome measure)
Drug: Ixempra (Ixbepilone [BMS-247550]
- Substantial preclinical antitumor synergy supports the exploration of the combination of antiangiogenic compounds (including sunitinib and bevacizumab) plus ixabepilone. In Vivo, synergistic activity between ixabepilone and bevacizumab has been demonstrated using the 151-B human renal carcinoma xenograft model and this synergy compares favorably with other antiangiogenic inhibitors (i.e. sunitinib).
- Combination therapies of bevacizumab with chemotherapy demonstrated improved benefit compared with single-agent cytotoxics in multiple animal models and in humans.
- Clinical activity of both compounds used as single agents has been demonstrated in a broad spectrum of solid tumors. Bevacizumab and ixabepilone, when used as a single agent, have demonstrated substantial activity in renal cell carcinoma. Ixabepilone is currently being evaluated in a Phase II study (CCR/NCI, Tito Fojo MD, PhD, PI) in stage IV renal carcinoma, with encouraging preliminary activity.
- Phase II studies with bevacizumab and ixabepilone suggest the absence of overlapping toxicities.
- Development of a well-tolerated and active bevacizumab/ixabepilone combination has the potential to further improve the treatment of metastatic renal cell carcinoma (mRCC), and could represent a second-line option after sunitinib or sorafenib are no longer of benefit or are intolerable.
- Determine the objective response rate of the combination of ixabepilone and bevacizumab in patients with relapsed or refractory mRCC.
- Determine progression-free survival.
- Characterize the toxicity of the combination of ixabepilone and bevacizumab in patients with mRCC.
- Determine changes in biomarkers and evaluate correlation with clinical outcomes.
- Pathologic confirmation of renal cell carcinoma (clear cell histology) by the Laboratory of Pathology, NCI or the Medical University of South Carolina..
- Presence of metastatic renal carcinoma, after progression or intolerance to VEGFR inhibitors (sunitinib and/or sorafenib).
- Adequate organ and bone marrow function.
- Multi-center, open labeled phase II study
- Following a Simon two-stage optimal design, a maximum of 58 patients with metastatic RCC will be accrued.
- Ixabepilone will be administered daily as a one hour infusion on five successive days (daily x 5), every three weeks (one cycle equals 3 weeks or 21 days). The starting dose will be a daily dose of 6 mg/m(2)/day, for a total per cycle dose of 30 mg/m(2).
- In addition, 15 mg/kg bevacizumab will be administered intravenously on day 1 of each cycle. The first infusion of bevacizumab will be 90 minutes in duration, the second 60 minutes in duration, and in all subsequent cycles bevacizumab will be infused over 30 minutes if prior infusions are well tolerated.
|Ages Eligible for Study:
||18 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
Subjects meeting all of the following criteria will be considered for enrollment into the study:
- Pathologic confirmation of metastatic or unsectable renal cell carcinoma with predominant clear cell histology (greater than 70%) by the Laboratory of Pathology, NCI or the Medical University of South Carolina..
- Progression on or after stopping treatment with an agent approved by the FDA for the treatment of RCC. Patients must have received at least one FDA approved agent (axitinib, sunitinib, sorafenib, pazopanib, temsirolimus, IL-2, interferon or everolimus). Patients must be off prior IL-2 or interferon for 4 weeks prior to entry. They must be off sunitinib, sorafenib, pazopanib, axitinib, temsirolimus or everolimus or other TKIs for 2 weeks prior to entry.
- Eighteen years of age or older.
- ECOG performance status less than or equal to 2.
- Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE v.3.0 through 12/31/10 and version 4.0 beginning 1/1/11 grade less than or equal to 1 and to baseline laboratory values as defined in inclusion criterion # 6.
Adequate organ and bone marrow function as evidenced by:
- hemoglobin greater than or equal to 9.0 g/dL
- absolute neutrophil count greater than or equal to 1.5 x 10(9)/L
- platelet count greater than or equal to 100 x 10(9)/L
- creatinine less than or equal to 1.5 times the ULN, OR measured creatinine clearance greater than or equal to 40 ml/min
- urine proteinuria less than 20mg/dL on randon protein creatinine ratio urine samples or a 24-hour urine protein less than 500 mg. NOTE: If on a random protein creatinine ratio the urine protein is greater that or equal to 20mg/dL, then obtain a 24 hour urine collection to accurately demonstrate that the 24 hour total is less than 500 mg/24 hours.
- AST/SGOT and ALT/SGPT less than or equal to 2.5 times the ULN (or less than or equal to 5 times the ULN if liver function abnormalities due to underlying malignancy)
- total bilirubin less than or equal to 1.5 times the ULN
- Subjects must be postmenopausal, surgically sterile, or using effective contraception. All female subjects of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days prior to enrollment. Effective contraception includes hormonal or barrier methods.
- No other invasive malignancies within the past two years (with the exception of nonmelanoma skin cancers, non-invasive bladder cancer, stage I endometrial cancer or cervical cancer).
- Subjects must agree to sign and date an Institutional Review Board (IRB)-approved subject informed consent form.
- Subjects must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
- Patients must have measurable disease either by conventional imaging or clinical examination.
Subjects presenting with any of the following will not be included in the study:
Invasive procedures defined as follows:
- Major surgical procedure, open biopsy or significant traumatic injury within 6 weeks prior to Day 1 therapy
- Anticipation of need for major surgical procedures during the course of the study
- Minor surgery, such as port-a-cath placement, and dental procedures, within 2 weeks.
- (There will be no delay for percutaneous core biopsies or PICC/IJ line placement)
- Cumulative radiation therapy to greater than 25% of the total bone marrow.
- History of uncontrolled or labile hypertension, defined as blood pressure greater than 160/90 mm Hg (NCI CTCAE v.3.0 through 12/31/10 and version 4.0 beginning 1/1/11 grade greater than or equal to 2), on at least 2 repeated determinations on separate days within 15 days prior to study enrollment.
- Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure; cerebrovascular accident or transient ischemic attack, grade greater than or equal to 2 peripheral neuropathy, peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, or other thromboembolic event.
- Symptomatic spinal cord compression.
- Evidence of clinically significant bleeding diathesis or underlying coagulopathy.
- Antiretroviral therapy for HIV disease.
- Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy.
- Other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the subject s safety, 18 inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.
- Prior therapy with bevacizumab
- Prior therapy with ixabepilone.
- Patients on anticoagulant therapy will be evaluated on a case by case basis for inclusion.
- Serious or non-healing wound, ulcer or bone fracture
- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1
- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
Known CNS disease except for treated brain metastasis.
-Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (MRI or CT). (Stable dose of anticonvulsants are allowed). Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
- Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies
- Patients receiving CYP3A4 inhibitors in section 3.6 that cannot be discontinued.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00923130
|National Institutes of Health Clinical Center, 9000 Rockville Pike
|Bethesda, Maryland, United States, 20892 |
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937 |
|University of South Carolina
|Charlestown, South Carolina, United States, 29425 |
||Antonio T Fojo, M.D.
||National Cancer Institute (NCI)
||National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
History of Changes
|Other Study ID Numbers:
|Study First Received:
||June 17, 2009
||March 14, 2014
||United States: Federal Government
Keywords provided by National Institutes of Health Clinical Center (CC):
Renal Cell Carcinoma
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on July 20, 2014
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms by Site
Angiogenesis Modulating Agents
Physiological Effects of Drugs