PEG-Interferon Alfa-2b and Sorafenib in Treating Patients With Unresectable or Metastatic Kidney Cancer

Phase 1

Terminated

Conditions: Kidney Cancer

Interventions: Biological: PEG-interferon alfa-2b
Drug: Sorafenib
Genetic: gene expression analysis
Genetic: polymerase chain reaction
Genetic: reverse transcriptase-polymerase chain reaction
Other: flow cytometry
Other: immunoenzyme technique
Other: laboratory biomarker analysis

Registration Number: NCT00589550

Lead Sponsor: Thomas Olencki

Brief Summary: RATIONALE: PEG-interferon alfa-2b may interfere with the growth of tumor cells. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also stop the growth of kidney cancer by blocking blood flow to the tumor. Giving PEG-interferon alfa-2b together with sorafenib may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of PEG-interferon alfa-2b and sorafenib in treating patients with unresectable or metastatic kidney cancer.

Detailed Description: OBJECTIVES:

Primary

* To determine the maximum tolerated dose and toxicity of PEG-interferon alfa-2b and sorafenib tosylate in patients with unresectable or metastatic clear cell renal cell carcinoma.

Secondary

* To determine the progression-free survival of patients treated with this regimen.

* To evaluate, in a preliminary manner, the response rate and overall survival of patients treated with this regimen.

* To evaluate the activation of interferon-induced transcription factors in immune cell subsets (including regulatory T cells \[T regs\]) using a novel flow cytometric assay and correlate this information with clinical outcome.

* To measure circulating levels of IFN-γ and IL-5 for determination of Th1/Th2 status and CD4+, CD25+, and FoxP3 cell number (T regs) in peripheral blood.

OUTLINE: Patients receive PEG-interferon alfa-2b subcutaneously on days 1, 8, 15, 22, 29, 36, 43, and 50. Patients also receive oral sorafenib tosylate 2-3 times daily on days 15-56 of course 1 and on days 1-56 of all subsequent courses. Courses repeat every 56 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for correlative laboratory studies. Peripheral blood mononuclear cells are analyzed for STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5) and CD4+, CD25+, and FoxP3 regulatory T cells by flow cytometric assays. Samples are also analyzed for the presence of VEGF, VEGFR, IFN-γ, and IL-5 by ELISA assays; baseline expression of Jak-STAT signaling intermediates (Jak1, Tyk2, IFNAR, and IRF9) by immunoblot analysis; and interferon-stimulated gene expression by real time PCR and RT-PCR analysis.

After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

Inclusion Criteria

Must have histologically or cytologically confirmed clear cell renal cell carcinoma (RCC)
Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension and is ≥ 1.0 cm by spiral CT scan
No prior treatment except

PATIENT CHARACTERISTICS:

ECOG performance status 0-1
Life expectancy > 6 months
Good/intermediate Motzer prognostic status
ANC ≥ 1,000/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 10.0 g/dL
Total bilirubin ≤ 2.0 mg/dL
AST and ALT < 2.5 times normal
Creatinine ≤ 1.8 mg/dL OR creatinine clearance > 50 mL/min
Calcium < 12 mg/dL (when corrected for serum albumin)
INR < 1.5 times upper limit of normal
Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% by 2D echo
Pulse oximetry ≥ 90% at rest on room air
Not pregnant
Negative pregnancy test
Fertile patients must use effective contraception
No evidence of bleeding diathesis
No uncontrolled coagulation disorders
No active infections requiring IV antibiotics
No known HIV, hepatitis C, or hepatitis B
No autoimmune disease requiring ongoing therapy
No requirement for adrenal replacement
No angina (controlled or uncontrolled)
No uncontrolled hypertension
No history of other major medical illnesses including, but not limited to, any of the following:
- Cardiac ischemia
- Myocardial infarction
- Major cardiac arrhythmias
- Inflammatory bowel disorders
No other prior malignancy except for previously treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 3 years
No significant psychiatric disease that, in the opinion of the principal investigator, would preclude giving adequate informed consent or render immunotherapy unsafe

PRIOR CONCURRENT THERAPY:

No prior treatment for RCC except sunitinib malate
- Patients may have progressed or have been intolerant to sunitinib malate
No prior systemic treatment for metastatic disease (other than sunitinib malate)
No prior organ allografts
At least 2 weeks since prior laparoscopic/robotic surgery
At least 4 weeks since prior open nephrectomy
More than 4 weeks since prior and no concurrent radiotherapy or other surgery
More than 4 weeks since prior systemic steroids
More than 2 weeks since prior topical, injected, or inhaled steroids
No concurrent steroid therapy
No concurrent Hypericum perforatum (St. John's wort)

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Peginterferon alfa-2b	reverse transcriptase-polymerase chain reaction	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.
Peginterferon alfa-2b	polymerase chain reaction	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.
Peginterferon alfa-2b	laboratory biomarker analysis	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.
Peginterferon alfa-2b	gene expression analysis	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.
Peginterferon alfa-2b	immunoenzyme technique	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.
Peginterferon alfa-2b	PEG-interferon alfa-2b	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.
Peginterferon alfa-2b	flow cytometry	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.
Peginterferon alfa-2b	Sorafenib	Peginterferon alfa-2b will be administered SC on day 1 of each week of therapy. This will most likely be a Monday or a Tuesday. Sorafenib will be initiated on day 15 (start of week 3) of the first course and continued daily without breaks.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose of PEG-interferon Alfa-2b and Sorafenib Tosylate	up to 2 months
Characterize the Toxicity of Peginterferon Alfa-2b and Sorafenib in Patients With Metastatic or Unresectable Clear Cell Renal Cell Carcinoma.	up to 2 months

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival of Patients Receiving Peginterferon Alfa-2b and Sorafenib.	up to 1 year
Response Rate of Patients Receiving Peginterferon Alfa-2b and Sorafenib.	up to 1 year
Overall Survival	up to 1 year
Activation of Interferon-induced Transcription Factors in Immune Cell Subsets by Flow Cytometry and Correlation of This Information With Clinical Outcome	up to 1 year
Circulating Levels of IFN-γ and IL-5 for Determination of Th1/Th2 Status and CD4+, CD25+, and FoxP3 Cell Number (T Regs) in Peripheral Blood	Up to 1 year