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

• Sponsor: Barbara Ann Karmanos Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00514215
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 8
• Location: 1
• Arm: 1
• Duration (Months): 49.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Kidney Cancer; Lung Cancer; Metastatic Cancer; Unspecified Adult Solid Tumor, Protocol Specific	Biological: sargramostim; Other: flow cytometry; Other: immunoenzyme technique; Procedure: biopsy; Procedure: cryosurgery	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Percutaneous Cryotherapy and Aerosolized GM-CSF for Pulmonary Metastases and Primary Lung Cancer
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sargramostim, Flow Cytometry, Biopsy. Cryosurgery 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; 250 μg, inhaled, two times a day, on days 4-10 and days 36-42; Other Names: GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor) Leukine ; Other: flow cytometry; Days 1 & 32; Other: immunoenzyme technique; Days 1 & 32; Procedure: biopsy; CT guided biopsy on days 1 & 32; Procedure: cryosurgery; Days 1 and 32

Outcome Measures

Primary Outcome Measures

1. Immunologic Response as Measured by ELISPOT Assay and Flow Cytometry [Days 1 & 32]

   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.

Secondary Outcome Measures

1. Clinical Response as Measured by CT Criteria [Days 1 & 32]

   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.

2. Toxicity of Grade 1 or Higher [Days 11, 32, 43, & 63]

   Number of Participants with Toxicity of Grade 1 or Higher as defined by CTCAE v2

3. Immune Function and Cancer-specific Response [Days 1 & 63]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379

Sponsors and Collaborators

• Barbara Ann Karmanos Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Study Chair: Peter J. Littrup, MD, Barbara Ann Karmanos Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical trial summary from the National Cancer Institute's PDQ® database

Publications

None provided.

• Responsible Party: Peter Littrup, Principal Investigator, Barbara Ann Karmanos Cancer Institute
• ClinicalTrials.gov Identifier: NCT00514215
• Other Study ID Numbers: CDR0000559667; P30CA022453; WSU-C-2795; WSU-HIC-050304M1(R)F
• First Posted: Aug 9, 2007
• Last Update Posted: Mar 5, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Peter Littrup, Principal Investigator, Barbara Ann Karmanos Cancer Institute: 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
• Additional relevant MeSH terms: Lung Neoplasms; Neoplasm Metastasis; Kidney Neoplasms; Molgramostim; Sargramostim

Study Results

Participant Flow

Arm/Group Title	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
Arm/Group Description	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 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 biopsy: CT guided biopsy on days 1 & 32 cryosurgery: Days 1 and 32
Period Title: Overall Study
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
Arm/Group Description	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 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 biopsy: CT guided biopsy on days 1 & 32 cryosurgery: Days 1 and 32
Overall Participants	8
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55
Sex: Female, Male (Count of Participants)
Female	2 25%
Male	6 75%
Region of Enrollment (participants) [Number]
United States	8 100%

Outcome Measures

1. Primary Outcome

Title	Immunologic Response as Measured by ELISPOT Assay and Flow Cytometry
Description	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.
Time Frame	Days 1 & 32

Outcome Measure Data

Analysis Population Description

Patients who had metastatic Renal Cell carcinoma

Arm/Group Title	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
Arm/Group Description	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 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 biopsy: CT guided biopsy on days 1 & 32 cryosurgery: Days 1 and 32
Measure Participants	6
Complete Response	1 12.5%
Partial Response	3 37.5%
Progressive Disease	2 25%

2. Secondary Outcome

Title	Clinical Response as Measured by CT Criteria
Description	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.
Time Frame	Days 1 & 32

Outcome Measure Data

Analysis Population Description

only those with metastatic Renal Cell carcinoma

Arm/Group Title	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
Arm/Group Description	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 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 biopsy: CT guided biopsy on days 1 & 32 cryosurgery: Days 1 and 32
Measure Participants	6
Complete Response	1 12.5%
Partial Response	3 37.5%
Progressive Disease	2 25%

3. Secondary Outcome

Title	Toxicity of Grade 1 or Higher
Description	Number of Participants with Toxicity of Grade 1 or Higher as defined by CTCAE v2
Time Frame	Days 11, 32, 43, & 63

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
Arm/Group Description	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 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 biopsy: CT guided biopsy on days 1 & 32 cryosurgery: Days 1 and 32
Measure Participants	8
Alergic Reaction	1 12.5%
Allergic rhinitis	2 25%
Anemia	1 12.5%
Anorexia	1 12.5%
Atelectasis	1 12.5%
Bronchospasm, wheezing	1 12.5%
Chest Pain (noncardiac, nonpleuritic)	1 12.5%
Chest wall pain	6 75%
Cough	7 87.5%
Decreased platelets	1 12.5%
Dizziness	1 12.5%
Dyspnea	4 50%
Fatigue	4 50%
Hemoptysis	1 12.5%
Hemorrhage, pulmonary lung (hemoptysis)	4 50%
Hyperglycemia	1 12.5%
Low grade fever	1 12.5%
Lymphopenia	2 25%
Nausea	1 12.5%
Pain at incision site	1 12.5%
Pain-upper resp. throat	2 25%
Platelets Low	1 12.5%
Pneumothorax	4 50%
Sensory Neuropathy	1 12.5%
Shortness of Breath	1 12.5%
Sweating	1 12.5%
Thrombocytopenia	1 12.5%
Vomiting	1 12.5%

4. Secondary Outcome

Title	Immune Function and Cancer-specific Response
Description	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.
Time Frame	Days 1 & 63

Outcome Measure Data

Analysis Population Description

only those with metastatic Renal Cell carcinoma

Arm/Group Title	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
Arm/Group Description	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 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 biopsy: CT guided biopsy on days 1 & 32 cryosurgery: Days 1 and 32
Measure Participants	6
increase of IFN gamma secreting T cells	4 50%
elevated antibody levels	4 50%
Increased anti-RC-2+KCI-18 serum antibodies	4 50%

Adverse Events

Arm/Group Title	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
Arm/Group Description	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 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 biopsy: CT guided biopsy on days 1 & 32 cryosurgery: Days 1 and 32
All Cause Mortality
	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Sargramostim, Flow Cytometry, Biopsy. Cryosurgery
	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)
Blood and lymphatic system disorders
Anemia	1/8 (12.5%)	1
Decreased Platelets ( thrombocytopenia)	1/8 (12.5%)	1
Gastrointestinal disorders
Nausea	1/8 (12.5%)	1
General disorders
Chest Pain (noncardiac, nonpleuritic)	1/8 (12.5%)	1
Fatigue	4/8 (50%)	4
Low grade fever	1/8 (12.5%)	1
Pain at incision site	1/8 (12.5%)	1
Immune system disorders
Allergic Reaction	1/8 (12.5%)	1
Investigations
Lymphopenia (low lever of lymphocytes)	2/8 (25%)	2
Platelets (low count, thrombocytopenia)	2/8 (25%)	2
Metabolism and nutrition disorders
Anorexia	1/8 (12.5%)	1
Hyperglycemia	1/8 (12.5%)	1
Musculoskeletal and connective tissue disorders
Chest Wall Pain	6/8 (75%)	12
Nervous system disorders
Dizziness	1/8 (12.5%)	1
Sensory Neuropathy	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Allergic Rhinitis	2/8 (25%)	2
Atelectasis	1/8 (12.5%)	1
Bronchospasm, wheezing	1/8 (12.5%)	1
Cough	7/8 (87.5%)	12
Dyspnea	4/8 (50%)	5
Hemoptysis	1/8 (12.5%)	1
Hemorrhage, pulmonary lung (hemoptysis)	4/8 (50%)	5
Pain - Upper Respiratory throat	2/8 (25%)	2
Pneumothorax	4/8 (50%)	6
Shortness of Breath	1/8 (12.5%)	2
Skin and subcutaneous tissue disorders
Sweating	1/8 (12.5%)	1

Limitations/Caveats

Small sample size.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.