Protocol Number: 09-C-0057

Title:

A Phase II Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma

Number:

09-C-0057

Summary:

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 patient 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.

-Presence of metastatic renal carcinoma, after progression or intolerance to VEGFR inhibitors (sunitinib and/or sorafenib).

-Adequate organ and bone marrow function.

Design:

-Single-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.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility 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.

2. Progression on or after stopping treatment with a VEGF receptor tyrosine kinase inhibitor (sunitinib and/or sorafenib). Patients must have received one or both agents (sunitinib and/or sorafenib). Prior IL-2, interferon treatment and/or m-TOR treatment is allowed, but not manditory. Patients must be off of prior therapy for at least 4 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 grade less than or equal to 1 and to baseline laboratory values as defined in inclusion criterion # 6. Beva & Ixa in RCC Version date10/31/08 CTEP 8277:17

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 x ULN, and proteinuria less than or equal to 500 mg/24 hours

-AST/SGOT and ALT/SGPT less than or equal to 2.5 x ULN (or less than or equal to 5 x ULN if liver function abnormalities due to underlying malignancy)

-total bilirubin less than or equal to 1.5 x 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 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, Beva & Ixa in RCC Version date10/31/08 CTEP 8277:18 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.

13. Patients on anticoagulant therapy will be evaluated on a case by case basis for inclusion.

14. Serious or non-healing wound, ulcer or bone fracture

15. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1

16. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1

17. 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.

18. Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies

19. Patients receiving CYP3A4 inhibitors in section 3.6 that can not be discontinued.

Special Instructions:

Currently Not Provided

Keywords:

Renal Cell Carcinoma

Bevacizumab

Ixabepilone

Phase II

Recruitment Keyword(s):

None

Condition(s):

Renal Cell Carcinoma D002292

Investigational Drug(s):

Bevacizumab

Ixempra (Ixbepilone (BMS-247550)

Investigational Device(s):

None

Intervention(s):

Drug: Bevacizumab

Drug: Ixempra (Ixbepilone (BMS-247550)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Ryan AM, Eppler DB, Hagler KE, Bruner RH, Thomford PJ, Hall RL, Shopp GM, O'Neill CA. Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol. 1999 Jan-Feb;27(1):78-86.

Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, Chisholm V, Hillan KJ, Schwall RH. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med. 1998 Mar;4(3):336-40.

Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, Stalter S, Shak S, Adelman D. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001 Feb 1;19(3):843-50.

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