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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00324870
First received: May 10, 2006
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Clear Cell Renal Cell Carcinoma
Recurrent Renal Cell Cancer
Stage III Renal Cell Cancer
Stage IV Renal Cell Cancer
Drug: vorinostat
Drug: bevacizumab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • Progression-free survival assessed by Response Evaluation Criteria for Solid Tumors (RECIST) (phase II) [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method

  • Response rate, estimated by the number of confirmed partial or complete responses observed divided by the number of patients who received at least one day of treatment [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to progression assessed by RECIST [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method

  • Overall survival [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method

  • Disease-free survival [ Time Frame: From complete response to disease-progression, up to 4 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method

  • Pharmacodynamic effects assessed by acetylation of histones H3 and H4 in peripheral blood mononuclear cells (PBMC) and tumors [ Time Frame: At baseline and post-therapy ] [ Designated as safety issue: No ]
    Wilcoxon signed-rank tests determine whether or not the data shows evidence of changes from baseline

  • Observed anti-proliferative and apoptotic effects [ Time Frame: At baseline and post-therapy ] [ Designated as safety issue: No ]
    Wilcoxon signed-rank tests determine whether or not the data shows evidence of changes from baseline

  • Antiangiogenic effects assessed by in vitro angiogenesis bioassays [ Time Frame: At baseline and post-therapy ] [ Designated as safety issue: No ]
    Wilcoxon signed-rank tests determine whether or not the data shows evidence of changes from baseline

  • Modulation of tumor metabolism assessed by FDG PET scan [ Time Frame: At baseline and post-therapy ] [ Designated as safety issue: No ]
    Wilcoxon signed-rank tests determine whether or not the data shows evidence of changes from baseline

  • Modulation of tumor blood flow assessed by 15O water PET scan [ Time Frame: At baseline and post-therapy ] [ Designated as safety issue: No ]
    Wilcoxon signed-rank tests determine whether or not the data shows evidence of changes from baseline


Estimated Enrollment: 42
Study Start Date: February 2006
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Drug: vorinostat
Given orally
Drug: bevacizumab
Given IV

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT00324870

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
Peninsula Oncology and Hematology PA
Salisbury, Maryland, United States, 21801
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Investigators
Principal Investigator: Michael Carducci Johns Hopkins University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00324870     History of Changes
Other Study ID Numbers: NCI-2009-00093, NCI-2009-00093, NA 00001107, NCI-6884, JHOC-J0570, CDR0000467800, 6884, JHOC-00001107, J0570, IRB #NA 00001107, SKCCC J0570, 6884, U01CA070095, U01CA062491
Study First Received: May 10, 2006
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 30, 2014