Cryotherapy and GM-CSF in Treating Patients With Lung Metastases or Primary Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Cryotherapy kills tumor cells by freezing them. Giving an injection of GM-CSF before cryotherapy and inhaling GM-CSF after cryotherapy may interfere with the growth of tumor cells and shrink the tumor. Giving cryotherapy together with GM-CSF may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cryotherapy together with GM-CSF works in treating patients with lung metastases or primary lung cancer.

Detailed Description
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OBJECTIVES: Primary Determine whether percutaneous cryotherapy in combination with aerosolized sargramostim (GM-CSF) has any demonstrable immunologic effect in patients with pulmonary metastases or primary lung cancer. Determine whether any systemic immune response is detectable by the combination of cryotherapy as the antigen presentation source and GM-CSF as the immunologic adjuvant. Determine whether low morbidities will be maintained in patients treated with this regimen. Determine whether effective immunization is associated with a drop in CD4+, CD25+, LTP(TGF-β1)+, Tr cells as measured by flow cytometry or ELISPOT assay for TGF-β1-secreting cells. Secondary Determine clinical response (i.e., tumor control in the dominant masses undergoing cryotherapy or in other metastatic sites) as measured by CT criteria. Determine the toxicity of this regimen in these patients. OUTLINE: Patients undergo CT-guided core biopsy of a dominant lung mass and placement of at least 2 cryoprobes. Prior to initiating the freeze, patients receive an interstitial injection of sargramostim (GM-CSF) near the tumor. Patients then undergo percutaneous cryotherapy over 2 hours utilizing a freeze-thaw-freeze cycle. Beginning within 3 days of cryotherapy, patients receive aerosolized GM-CSF twice daily for 1 week. Beginning on day 32, patients may elect to undergo a second course of treatment as described above in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tumor tissue collection at baseline and periodically during study for immunological correlative studies. Peripheral blood mononuclear cells isolated from blood samples are analyzed for antigen-specific CD4-positive or CD8-positive T-cell response by flow cytometry or by TGF-β1 ELISPOT assay to measure TGF-β1- secreting cells. Tumor cell lysates extracted from tumor samples are pulsed with autologous dendritic cells and analyzed by ELISPOT assay to measure T-cell reactivity in tumor specimens. After completion of study therapy, patients are followed at 6 and 12 months.

Official Title
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Percutaneous Cryotherapy and Aerosolized GM-CSF for Pulmonary Metastases and Primary Lung Cancer

Conditions
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Kidney Cancer, Lung Cancer, Metastatic Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Biological: sargramostim
* Other: flow cytometry
* Other: immunoenzyme technique
* Procedure: biopsy
* Procedure: cryosurgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of 1 of the following: Primary non-small cell lung cancer (NSCLC) Any stage nonoperative NSCLC or patient refuses surgery Any cancer with pulmonary metastatic disease (including renal cell cancer) Stage IV disease (any T, any N, M1) Must have 1-10 pulmonary or mediastinal masses meeting the following criteria: At least 1 mass is appropriate for 2 sessions of core biopsy and cryotherapy with relatively easy access/low risk in nonoperative patients (or those refusing surgery) The two dominant masses are defined as either the largest and/or those that may cause imminent morbidity from continued local progression, thereby potentially benefiting from thoracic cryotherapy alone Optimal tumor size > 1.0 cm Dominant masses up to 6 cm in diameter may be considered if thorough cryotherapy coverage can be anticipated with minimal additional treatment morbidity Measurable disease, defined as tridimensional measurements of up to 6 different pulmonary or mediastinal masses ≥ 0.5 cm by CT scan No active pleural effusion that could be related to respiratory infection or requires further work-up No untreated and/or unstable brain metastases PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Life expectancy ≥ 12 weeks Granulocyte count ≥ 1,500/mm³ Platelet count ≥ 50,000/mm³ INR < 1.5 (i.e., normal PT/PTT) Hemoglobin ≥ 8.0 g/dL Bilirubin ≤ 2 times upper limit of normal (ULN) AST ≤ 3 times ULN Satisfactory pulmonary function test as determined by supervising oncologist, thoracic surgeon, or pulmonologist Not pregnant or lactating Negative pregnancy test Fertile patients must use effective contraception No other active malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix Inactive history of cancer allowed if the patient has been disease-free for > 2 years No serious medical or psychiatric illnesses that would preclude informed consent or limit survival to < 12 wks No uncontrollable cough or inability to lie flat No New York Heart Association class III or IV heart disease No known immunodeficiency state No uncontrolled infection No uncontrolled coagulopathy or bleeding diathesis No advance directive that would prevent the investigator from treating the participant in the event of a complication occurring during or after the procedure No medical contraindication or potential problem that would preclude protocol compliance PRIOR CONCURRENT THERAPY: More than 4 weeks since prior biologic therapy More than 4 weeks since prior immunotherapy More than 4 weeks since prior filgrastim (G-CSF) or sargramostim (GM-CSF) More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) More than 4 weeks since prior radiotherapy More than 2 weeks since prior corticosteroids More than 1 week since prior parenteral antibiotics At least 1 week since prior aspirin or aspirin-like medications At least 3 days since prior warfarin, clopidogrel bisulfate, or similar compounds No concurrent GM-CSF other than study drug No concurrent G-CSF No concurrent radiotherapy No concurrent glucocorticosteroids No concurrent parenteral antibiotics No concurrent immunosuppressive agents No concurrent drugs that cause bleeding tendencies No other concurrent biologic therapy, immunotherapy, radiotherapy, or chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sargramostim, Flow Cytometry, Biopsy. Cryosurgery<br>Sargramostim-250 μg, inhaled, two times a day, on days 4-10 and days 36-42 Flow cytometry-Days 1 & 32 Immunoenzyme technique-Days 1 & 32 CT guided biopsy-Days 1 & 32 Cryosurgery-Days 1 and 32 | Biological: sargramostim<br>* 250 μg, inhaled, two times a day, on days 4-10 and days 36-42<br>* Other names: Leukine;Other: flow cytometry<br>* Days 1 & 32<br>Other: immunoenzyme technique<br>* Days 1 & 32<br>Procedure: biopsy<br>* CT guided biopsy on days 1 & 32<br>Procedure: cryosurgery<br>* Days 1 and 32<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunologic Response as Measured by ELISPOT Assay and Flow Cytometry | CT-guided biopsy & Peritumoral GM-CSF. a CR was defined as involution of the prior tumor and/or ablation site to only a thin, non-enhancing scar within the pulmonary parenchyma on enhanced chest CT. A PR was defined as incomplete resolution of an otherwise thoroughly hypovascular resolving ablation zone which had reached a diameter smaller than the original tumor size. Stable disease (SD) reflects no significant change in size of ablation site and/or overall tumor burden, while the standard definition for progressive disease (PD) remains as evidence of neTw or growing tumors. | Days 1 & 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response as Measured by CT Criteria | CT-guided biopsy. a CR was defined as involution of the prior tumor and/or ablation site to only a thin, non-enhancing scar within the pulmonary parenchyma on enhanced chest CT. A PR was defined as incomplete resolution of an otherwise thoroughly hypovascular resolving ablation zone which had reached a diameter smaller than the original tumor size. Stable disease (SD) reflects no significant change in size of ablation site and/or overall tumor burden, while the standard definition for progressive disease (PD) remains as evidence of neTw or growing tumors. | Days 1 & 32 | 
| Toxicity of Grade 1 or Higher | Number of Participants with Toxicity of Grade 1 or Higher as defined by CTCAE v2 | Days 11, 32, 43, & 63 | 
| Immune Function and Cancer-specific Response | Number of Participants with CT-guided biopsy & Peritumoral GM-CSF. The number of IFNγ secreting T-cells was measured by a direct EliSpots at 10:1 E:T ratio to define the kinetics of the CTL responses from pre-CI to day 63 post CI. | Days 1 & 63 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung metastases, stage I non-small cell lung cancer, stage II non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, recurrent non-small cell lung cancer, recurrent renal cell cancer, stage IV renal cell cancer, unspecified adult solid tumor, protocol specific