Vorinostat and Bevacizumab in Treating Patients With Unresectable or Metastatic Kidney Cancer

• ClinicalTrials.gov Identifier: NCT00324870
• Recruitment Status: Completed
• First Posted: May 11, 2006
• Results First Posted: September 9, 2015
• Last Update Posted: January 13, 2016
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: May 10, 2006
• First Posted Date: May 11, 2006
• Results First Submitted Date: August 10, 2015
• Results First Posted Date: September 9, 2015
• Last Update Posted Date: January 13, 2016
• Study Start Date: February 2006
• Actual Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 10, 2015)

Progression-free Survival Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) (Phase II) [ Time Frame: At 6 months ]

Estimated by Kaplan-Meier method

• Original Primary Outcome Measures: Not Provided
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: August 10, 2015)

• Maximum Tolerated Dose [ Time Frame: 18 months from first patient dosing ]
  Determine the maximum tolerated dose of SAHA
• Clinical Response Rate of SAHA and Bevacizumab [ Time Frame: 7 years ]
  To determine the clinical response rate of SAHA and Bevacizumab in patients with metastatic renal cell carcinoma.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Vorinostat and Bevacizumab in Treating Patients With Unresectable or Metastatic Kidney Cancer
• Official Title: Phase I/II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With the VEGF Inhibitor Bevacizumab in Patients With Metastatic Renal Cell Carcinoma
• Brief Summary: This phase I/II trial is studying the side effects and best dose of vorinostat when given together with bevacizumab and to see how well they work in treating patients with unresectable or metastatic kidney cancer. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 kidney cancer by blocking blood flow to the tumor. Giving vorinostat together with bevacizumab may kill more tumor cells.

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of vorinostat (SAHA) in combination with bevacizumab in patients with unresectable or metastatic renal cell carcinoma. (Phase I) II. Determine the recommended dosing in patients treated with this regimen. (Phase I) III. Determine the proportion of patients who are progression-free at 6 months after receiving this regimen. (Phase II) IV. Determine the clinical response rate in patients treated with this regimen. (Phase II)

SECONDARY OBJECTIVES:

I. Determine the toxicity of this regimen in these patients. (Phase II) II. Determine time to progression and duration of progression-free and overall survival in patients treated with this regimen. (Phase II) III. Determine the pharmacodynamic effects in peripheral blood mononuclear cells and tumors before and after treatment with this regimen in these patients. (Phase II) IV. Determine the antiproliferative and apoptotic effects of this regimen in these patients. (Phase II) V. Determine the antiangiogenic effects of this regimen in these patients. (Phase II) VI. Determine the modulation of tumor metabolism and tumor blood flow in patients treated with this regimen. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of vorinostat (SAHA) followed by a phase II study.

PHASE I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD.

PHASE II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I.

After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Clear Cell Renal Cell Carcinoma
• Recurrent Renal Cell Cancer
• Stage III Renal Cell Cancer
• Stage IV Renal Cell Cancer

Intervention

• Drug: vorinostat
  Given orally
  Other Names:

  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
• Drug: bevacizumab
  Given IV
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

Study Arms

Experimental: Arm I

Phase I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD.

Phase II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I.

Interventions:

• Drug: vorinostat
• Drug: bevacizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 10, 2015): 37
• Original Enrollment: Not Provided
• Actual Study Completion Date: November 2013
• Actual Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• No known CNS metastasis
• ECOG performance status 0-2
• Life expectancy > 6 months
• LVEF ≥ 45%
• Absolute neutrophil count ≥ 1,500/mm3
• Platelet count ≥ 100,000/mm3
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST/ALT ≤ 2.5 times ULN
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 50 mL/min
• PT/INR ≤ 1.5
• Urine protein < 1+ by urinalysis OR < 1 g by 24-hour urine collection
• Not pregnant
• No nursing during and for 6 months after completion of study treatment
• Negative pregnancy test
• Fertile patients must use effective contraception for 2 weeks prior, during, and for 6 months after completion of study treatment
• No other currently active malignancy defined as > 30% risk of relapse upon completion of anticancer therapy, except nonmelanoma skin cancer
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA)
• No hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• No evidence of bleeding diathesis or coagulopathy
• No active bleeding or pathological conditions that carry high risk of bleeding (i.e., tumor involving major vessels or known varices)
• No ongoing, active infection
• No New York Heart Association class II-IV congestive heart failure
• No angina pectoris requiring nitrate therapy
• No cardiac arrhythmia
• No myocardial infarction within the past 6 months
• No history of cerebrovascular accident within the past 6 months
• No uncontrolled hypertension (defined as systolic blood pressure (BP) > 160 mm Hg and/or diastolic BP > 90 mm Hg on medication)
• No history of peripheral vascular disease
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness
• No serious nonhealing wound, ulcer, or bone fracture
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
• No significant traumatic injury in the past 28 days
• At least 4 weeks since prior major surgery or open biopsy
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• More than 4 weeks since prior radiotherapy
• At least 2 weeks since prior tyrosine kinase inhibitor
• Prior palliative radiotherapy to metastatic lesions allowed provided ≥ 1 measurable and/or evaluable lesion has not been irradiated
• No more than 2 prior systemic treatments for metastatic disease, including immunotherapy, receptor tyrosine kinase inhibitor therapy, chemotherapy, or investigational therapy
• No prior therapy with bevacizumab, vascular endothelial growth factor-trap, or histone deacetylase inhibitors, including valproic acid
• No core biopsy within 1 week prior to day 1 of study treatment
• No planned major surgery during study treatment
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• Concurrent stable-dose prophylactic anticoagulation (i.e., warfarin or low molecular weight heparin) allowed provided requirements for INR are met
• Histologically confirmed renal cell carcinoma, clear cell component, unresectable or metastatic disease (patients with a primary tumor in place who are eligible for surgery are strongly encouraged to undergo a nephrectomy prior to study entry to increase potential survival)
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm with spiral CT scan

• The following histologies are not allowed:

  • Papillary, sarcomatoid carcinoma
  • Chromophobe carcinoma
  • Oncocytoma
  • Collecting duct tumor
  • Transitional cell carcinoma
• WBC ≥ 3,000/mm^3

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00324870
• Other Study ID Numbers: NCI-2009-00093; NCI-2009-00093 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NA 00001107; NCI-6884; JHOC-J0570; CDR0000467800; 6884; JHOC-00001107; J0570; IRB #NA 00001107, SKCCC J0570 ( Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center ); 6884 ( Other Identifier: CTEP ); P30CA006973 ( U.S. NIH Grant/Contract ); U01CA062491 ( U.S. NIH Grant/Contract ); U01CA070095 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Not Provided
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Not Provided

Investigators

• Principal Investigator: Michael Carducci; Johns Hopkins University/Sidney Kimmel Cancer Center

• PRS Account: National Cancer Institute (NCI)
• Verification Date: October 2013