Bevacizumab and Aldesleukin in Treating Patients With Metastatic Clear Cell Carcinoma of the Kidney

Phase II Open Label Trial of rIL-2 and Bevacizumab Combination in Patients With Metastatic Clear Cell Renal Carcinoma

RATIONALE: 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 tumor cells by blocking blood flow to the tumor. Biological therapies, such as aldesleukin, may stimulate the immune system in different ways and stop tumor cells from growing. Giving bevacizumab together with aldesleukin may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving bevacizumab together with aldesleukin works in treating patients with metastatic clear cell carcinoma of the kidney.

Study Overview

• Status: Completed
• Conditions: Kidney Cancer
• Intervention / Treatment: Biological: aldesleukin; Biological: bevacizumab

Detailed Description

OBJECTIVES:

Primary

• To evaluate the effect of the combination of bevacizumab and aldesleukin on progression-free survival of patients with good- or intermediate-risk metastatic clear cell renal cell carcinoma.

Secondary

• To determine the objective response rate in patients receiving this regimen.
• To determine the time to progression in patients receiving this regimen.
• To evaluate immunomodulatory effects of this regimen in patients
• To evaluate the toxicity of this regimen in these patients.

OUTLINE: Patients receive bevacizumab IV over 30-90 minutes on days -14, 1, 15, 29, and 42 and aldesleukin subcutaneously on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Courses repeat every 8 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients achieving complete response after completion of study therapy may receive 1 additional course of therapy.

After completion of study therapy, patients are followed periodically.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed renal cell carcinoma (RCC) of clear cell histology with or without sarcomatoid features

  • Metastatic disease
  • No non-clear cell RCC (i.e., papillary, collecting-duct, or chromophobe)

• Good- or intermediate-risk category as defined by having ≤ 2 of the following factors:

  • No prior nephrectomy
  • Karnofsky performance status < 80%
  • Hemoglobin < 12 g/dL
  • Corrected calcium > 10.0 mg/dL
  • LDH > 1.5 times upper limit of normal (ULN)
• Must have undergone a nephrectomy at least 28 days ago
• Measurable or evaluable disease by RECIST
• No significant effusions and/or ascites
• No prior or concurrent brain or CNS metastasis

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• Life expectancy of ≥ 3 months
• WBC ≥ 3,000/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.5 g/dL
• Creatinine ≤ 2.0 mg/dL
• Total bilirubin ≤ 1.5 mg/dL
• AST ≤ 5.0 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN (≤ 10 times ULN with bone metastasis)
• Calcium ≤ 12 mg/dL
• Urine protein:creatinine ratio ≤ 1.0
• INR ≤ 1.5 (unless receiving warfarin therapy)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled seizure disorder
• No known HIV positivity
• No local or systemic infections requiring IV antibiotics within the past 28 days
• No significant traumatic injury in the past 28 days
• No serious non-healing wound, ulcer, or acute bone fracture
• No evidence of bleeding diathesis or coagulopathy
• No other malignancy except basal cell or squamous cell carcinoma of the skin, carcinoma in-situ of the uterine cervix, or any malignancy treated with curative intent and in complete remission for > 3 years

• No history of serious systemic or severe cardiovascular disease, including any of the following:

  • Arterial thromboembolic event (including transient ischemic attack)
  • Cerebrovascular accident
  • Unstable angina
  • Myocardial infarction within the past 6 months
  • Uncontrolled hypertension (BP > 160/110 mm Hg on medication)
  • Uncontrolled cardiac arrhythmia
  • Congestive heart failure
  • Angina pectoris
  • NYHA class III-IV cardiovascular disease
  • Peripheral vascular disease ≥ grade II
• No history of abdominal fistula and/or bowel or gastric perforation within the past 6 months
• No history of other diseases, metabolic dysfunction, or physical or laboratory examination findings giving reasonable suspicion of a disease or condition that contraindicate the use of investigational drugs, or that might affect the interpretation of study results, or that render patient at high-risk for treatment complications

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior organ allografts
• No prior systemic therapy for metastatic clear cell renal cell carcinoma

• At least 4 weeks since prior radiotherapy and recovered

  • Radiotherapy for control of pain from skeletal lesions allowed within the past 28 days
• More than 12 months since prior adjuvant therapy
• More than 7 days since prior fine-needle aspirations or core biopsies
• More than 28 days since prior and no concurrent major surgery requiring general anesthesia or open biopsy
• No concurrent aspirin, corticosteroids (except at replacement doses), barbiturates, or other investigational agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bevacizumab and Aldesleukin	Biological: aldesleukin; SQ Aldesleukin (Days 1-5) Monday through Friday for six weeks followed by a two-week break.; Other Names: Proleukin®; rIL-2 (NSC3773364); Chiron; Biological: bevacizumab; Bevacizumab will be administered on day -14, then on day 1 and every 2 weeks thereafter (days 1, 15, 29, and 42) in a continuous manner.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression free survival is defined as the time between registration and progression of disease as defined by the RECIST criteria where there is a 20% increase in the diameter of the tumor and at least a 5mm absolute increase in diameter.	From baseline (day -14) to disease progression (reported at 2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (Complete and Partial Response)	Objective response rate to be assigned a status of PR or CR per RECIST criteria, with Complete Response (CR) referring to the disappearance of all target lesions, Partial Response (PR) referring to at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met.	4 weeks after end of treatment
Percentage of Patients With Constitutional Adverse Events	Toxicity Criteria: The NCI graded common clinical toxicity scale (NCI Version 2.0) will be employed to grade observed toxicity of fatigue and fever/chills	From start of treatment to 30 days after treatment
Percentage of Patients With Neutropenia	Toxicity Criteria: The NCI graded common clinical toxicity scale (NCI Version 2.0) will be employed to grade observed toxicity of neutropenia	From start of treatment to 30 days after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral Blood CD1c+ Myeloid Dendritic Cells	Peripheral blood mononuclear cells (PBMC) and plasma were separated by centrifugation. Targeted cells were isolated by a magnetic labeling system. Total RNA was isolated and then amplified by (Polymerase Chain Reactions) PCR to measure levels of the immune parameter.	Baseline (day -14), Beginning and end of cycle 1 (day 1, 57)
CD303+ Plasmacytoid Dendritic Cells	Peripheral blood mononuclear cells (PBMC) and plasma were separated by centrifugation. Targeted cells were isolated by a magnetic labeling system. Total RNA was isolated and then amplified by (Polymerase Chain Reactions) PCR to measure levels of the immune parameter.	Baseline (day -14), beginning and end of cycle 1 (day 1, 57)
IL-8 Levels	Peripheral blood mononuclear cells (PBMC) and plasma were separated by centrifugation. Targeted cells were isolated by a magnetic labeling system. Total RNA was isolated and then amplified by (Polymerase Chain Reactions) PCR to measure levels of the immune parameter.	Baseline (day -14), beginning and end of cycle 1 (day 1, 57)
CD4+ Treg Cells	Peripheral blood mononuclear cells (PBMC) and plasma were separated by centrifugation. Targeted cells were isolated by a magnetic labeling system. Total RNA was isolated and then amplified by (Polymerase Chain Reactions) PCR to measure levels of the immune parameter.	Baseline (day -14), beginning and end of cycle 1 (day 1, 57)
CD25+ Treg Cells	Peripheral blood mononuclear cells (PBMC) and plasma were separated by centrifugation. Targeted cells were isolated by a magnetic labeling system. Total RNA was isolated and then amplified by (Polymerase Chain Reactions) PCR to measure levels of the immune parameter.	Baseline (day -14), beginning and end of cycle 1 (day 1, 57)
T-helper Cells (Type 1,2)	Peripheral blood mononuclear cells (PBMC) and plasma were separated by centrifugation. Targeted cells were isolated by a magnetic labeling system. Total RNA was isolated and then amplified by (Polymerase Chain Reactions) PCR to measure levels of the immune parameter.	Baseline (day -14), beginning and end of cycle 1 (day 1, 57)

Collaborators and Investigators

• Sponsor: Jorge A. Garcia, MD
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jorge A. Garcia, MD, Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: February 26, 2009
• First Submitted That Met QC Criteria: February 26, 2009
• First Posted (Estimate): February 27, 2009

Study Record Updates

• Last Update Posted (Actual): June 5, 2019
• Last Update Submitted That Met QC Criteria: May 23, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: stage IV renal cell cancer; recurrent renal cell cancer; clear cell renal cell carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aldesleukin; Bevacizumab
• Other Study ID Numbers: CASE8804 (Other Identifier: Case Comprehensive Cancer Center); P30CA043703 (U.S. NIH Grant/Contract); 7493 (Cleveland Clinic IRB)