Bevacizumab Plus Ixabepilone to Treat Patients With Advanced Kidney Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00923130
First received: June 17, 2009
Last updated: August 22, 2014
Last verified: July 2014
  Purpose

Background:

  • 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.

Primary Objective:

  • 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.

Eligibility:

  • 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.

Design:

  • 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 over a period of 24 months.
  • 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.

Condition Intervention Phase
Renal Cell Carcinoma
Drug: Bevacizumab
Drug: Ixabepilone
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Multi-Center Study of Bevacizumab in Combination With Ixabepilone in Subjects With Advanced Renal Cell Carcinoma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Response rate per RECIST. [ Time Frame: Two Years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine progression-free survival [ Time Frame: Two Years ] [ Designated as safety issue: No ]
  • Characterize the toxicity of the combination of ixabepilone and bevacizumab in patients with mRCC [ Time Frame: Two Years ] [ Designated as safety issue: Yes ]
  • Determine changes in biomarkers and evaluate correlation with clinical outcomes [ Time Frame: Two Years ] [ Designated as safety issue: No ]

Estimated Enrollment: 58
Study Start Date: December 2008
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m2/day
Drug: Bevacizumab
Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg.
Drug: Ixabepilone
Ixabepilone will be given on a days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m2/day on five successive days.

Detailed Description:

Background:

  • 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.

Primary Objective:

  • 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.

Eligibility:

  • 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.

Design:

  • 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 over a period of 24 months.
  • 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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Subjects meeting all of the following criteria will be considered for enrollment into the study:

  1. 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..
  2. 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.
  3. Eighteen years of age or older.
  4. ECOG performance status less than or equal to 2.
  5. 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.
  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
  7. 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.
  8. 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).
  9. Subjects must agree to sign and date an Institutional Review Board (IRB)-approved subject informed consent form.
  10. Subjects must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
  11. Patients must have measurable disease either by conventional imaging or clinical examination.

EXCLUSION CRITERIA:

Subjects presenting with any of the following will not be included in the study:

  1. 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)
  2. Cumulative radiation therapy to greater than 25% of the total bone marrow.
  3. 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.
  4. 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.
  5. Symptomatic spinal cord compression.
  6. Evidence of clinically significant bleeding diathesis or underlying coagulopathy.
  7. Antiretroviral therapy for HIV disease.
  8. 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.
  9. 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.
  10. Prior therapy with bevacizumab
  11. Prior therapy with ixabepilone.
  12. Patients on anticoagulant therapy will be evaluated on a case by case basis for inclusion.
  13. Serious or non-healing wound, ulcer or bone fracture
  14. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1
  15. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
  16. 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.

  17. Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies
  18. Patients receiving CYP3A4 inhibitors in section 3.6 that cannot be discontinued.
  Contacts and Locations
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

Contacts
Contact: Maureen E Edgerly, R.N. (301) 435-5604 edgerlym@pbmac.nci.nih.gov
Contact: Antonio T Fojo, M.D. (301) 496-2831 fojot@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
United States, South Carolina
University of South Carolina Recruiting
Charlestown, South Carolina, United States, 29425
Sponsors and Collaborators
Investigators
Principal Investigator: Antonio T Fojo, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00923130     History of Changes
Obsolete Identifiers: NCT00820209
Other Study ID Numbers: 090057, 09-C-0057
Study First Received: June 17, 2009
Last Updated: August 22, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Renal Cell Carcinoma
Bevacizumab
Ixabepilone
Phase II

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Bevacizumab
Epothilones
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014