Vaccine Therapy, Tretinoin, and Cyclophosphamide in Treating Patients With Metastatic Lung Cancer

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00601796
• Collaborator: National Cancer Institute (NCI) (NIH), National Institutes of Health (NIH) (NIH)
• Enrollment: 24
• Location: 1
• Arm: 1
• Duration (Months): 68
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects (good and/or bad) a tumor vaccine used in combination with two drugs (ATRA and cytoxan) have on the patient and their cancer. We also want to find out if the vaccine and the drugs can boost the patient's immune system and how their immune system reacts, both before and after the vaccine treatment.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Biological: Vaccine Treatment; Drug: Cyclophosphamide; Drug: All-trans retinoic acid (ATRA)	Phase 2

Detailed Description

This protocol describes a phase II study involving patients with stage IV adenocarcinoma of the lung. Treatment will consist of Cyclophosphamide (300 mg/m²) to be given IV on day 1 and day 57. On day 4 immunization with intradermal vaccine injections at 4 separate sites (bilateral upper arms and bilateral upper thighs will be repeated every 14 days times 2 followed by every 28 days times 3 (day 4, 18, 32, 60, 88, and 116). Decavac (tetanus shot) 0.5 cc intramuscular (IM) will be given after the first vaccine. ATRA (150 mg/m2/day) oral three times daily (TID) dosing administered after the first and fourth vaccines (day 5-7 & day 61-63). Those patients achieving stable disease (SD), partial response (PR), or complete response (CR) at restaging after the initial 6 vaccines will receive additional vaccines every 3 months until disease progression. The vaccine will consist of GM.CD40L bystander cells admixed with an equivalent number of the 2 allogeneic tumor cell lines. There will be a +/- 7 day window for all study related exams, tests, and procedures.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Combination Immunotherapy for Lung Cancer
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combination Immunotherapy Vaccine + Cytoxan + ATRA as outlined in Detailed Description

Biological: Vaccine Treatment; We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3.; Other Names: Allogeneic Tumor Cell-Based Vaccines ; Drug: Cyclophosphamide; Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.; Other Names: cytoxan ; Drug: All-trans retinoic acid (ATRA); All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation.; Other Names: Vesanoid® tretinoin all trans retinoic acid ATRA

Outcome Measures

Primary Outcome Measures

1. Number of Evaluable Participants With Tumor Response [3 years]

   Number of participants with evaluable peripheral blood mononuclear cells (PBMCs) who demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival.

Secondary Outcome Measures

1. Median Time to Progression (TTP) [3 years]

   Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier.

2. Median Overall Survival (OS) [3 years]

   Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier.

3. Number of Participants With Serious Adverse Events (SAEs) [3 years]

   Toxicity will be assessed using the NCI Common Terminology Criteria for Adverse Criteria (CTAE-3),Version 3.0 (www.ctep.cancer.gov). Particular attention will assess the presence of symptomatic lymphadenopathy or any local skin / soft tissue reaction at the vaccine site. Blood tests for ANA and rheumatoid factor will be performed on any patient who develops evidence of autoimmune phenomena.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed metastatic adenocarcinoma of the lung

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1

• No radiation therapy within 2 weeks of first vaccine administration

• No chemotherapy within 4 weeks of first vaccine administration

• No steroid therapy within 4 weeks of first vaccine administration

• Patient's written informed consent

• Adequate organ function (measured within a week of beginning treatment)

• Patients will be tested for human leukocyte antigen A0201 (HLA-A0201) as determined by flow cytometry followed by molecular analysis of a peripheral blood specimen, however this result will not be an inclusion criterion.

• Measurable metastatic tumor as defined by standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Lesions must be accurately measured in at least one dimension with the longest diameter greater than or equal 20mm. With spiral computer tomography (CT) scan, lesion must be greater than or equal to 10 mm at least one dimension.

• Patient's must have received, and completed first line chemotherapy.

Exclusion Criteria:

• Symptomatic brain metastasis

• Any acute medical problems requiring active intervention

• Current corticosteroid (other than replacement doses in patients who are hypoadrenal) or other immunosuppressive therapy

• Any other pre-existing immunodeficiency condition (including known HIV infection)

• Pregnant or lactating women -- Patients in reproductive age must agree to use contraceptive methods for the duration of the study (*A pregnancy test will be obtained before treatment).

• Eastern Cooperative Oncology Group (ECOG) performance status of 2, 3 or 4

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612-9497

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• National Cancer Institute (NCI)
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Alberto Chiappori, MD, H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00601796
• Other Study ID Numbers: MCC-14744; P30CA076292; NIH-OBA-0608-801
• First Posted: Jan 28, 2008
• Last Update Posted: May 24, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: adenocarcinoma of the lung; stage IV non-small cell lung cancer
• Additional relevant MeSH terms: Lung Neoplasms; Cyclophosphamide; Tretinoin; Vaccines

Study Results

Participant Flow

Recruitment Details	24 participants were accrued at a single center from 10/2006 to 6/2008.

Arm/Group Title	Combination Immunotherapy
Arm/Group Description	Vaccine + Cytoxan + ATRA as outlined in Detailed Description Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3. All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Cyclophosphamide : Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
Period Title: Overall Study
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Combination Immunotherapy
Arm/Group Description	Vaccine + Cytoxan + ATRA as outlined in Detailed Description Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3. All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Cyclophosphamide : Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 50%
>=65 years	12 50%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	12 50%
Male	12 50%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Number of Evaluable Participants With Tumor Response
Description	Number of participants with evaluable peripheral blood mononuclear cells (PBMCs) who demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

14 participants with evaluable PBMCs

Arm/Group Title	Combination Immunotherapy
Arm/Group Description	Vaccine + Cytoxan + ATRA as outlined in Detailed Description Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3. All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Cyclophosphamide : Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
Measure Participants	14
Number [participants]	5 20.8%

2. Secondary Outcome

Title	Median Time to Progression (TTP)
Description	Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Combination Immunotherapy
Arm/Group Description	Vaccine + Cytoxan + ATRA as outlined in Detailed Description Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3. All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Cyclophosphamide : Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
Measure Participants	24
Median (95% Confidence Interval) [months]	2.4

3. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Combination Immunotherapy
Arm/Group Description	Vaccine + Cytoxan + ATRA as outlined in Detailed Description Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3. All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Cyclophosphamide : Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
Measure Participants	24
Median (95% Confidence Interval) [months]	8

4. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	Toxicity will be assessed using the NCI Common Terminology Criteria for Adverse Criteria (CTAE-3),Version 3.0 (www.ctep.cancer.gov). Particular attention will assess the presence of symptomatic lymphadenopathy or any local skin / soft tissue reaction at the vaccine site. Blood tests for ANA and rheumatoid factor will be performed on any patient who develops evidence of autoimmune phenomena.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Combination Immunotherapy
Arm/Group Description	Vaccine + Cytoxan + ATRA as outlined in Detailed Description Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3. All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Cyclophosphamide : Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
Measure Participants	24
Number [participants]	11 45.8%

Adverse Events

Time Frame	3 years
Arm/Group Title	Combination Immunotherapy
Arm/Group Description	Vaccine + Cytoxan + ATRA as outlined in Detailed Description Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3. All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m^2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Cyclophosphamide : Cyclophosphamide (300 mg/m^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
All Cause Mortality
	Combination Immunotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Combination Immunotherapy
	Affected / at Risk (%)	# Events
Total	11/24 (45.8%)
Blood and lymphatic system disorders
Hemoglobin	1/24 (4.2%)	3
Cardiac disorders
Supraventricular and nodal arrhythmia - NOS	1/24 (4.2%)	1
Hypotension	1/24 (4.2%)	3
Gastrointestinal disorders
Dehydration	1/24 (4.2%)	2
Diarrhea	1/24 (4.2%)	1
Dysphagia (difficulty swallowing)	1/24 (4.2%)	2
Nausea	1/24 (4.2%)	1
General disorders
Fatigue (asthenia, lethargy, malaise)	1/24 (4.2%)	2
Death not associated with CTCAE term - Disease progression - NOS	1/24 (4.2%)	1
Pain - Abdomen - NOS	1/24 (4.2%)	2
Pain - Tumor pain	2/24 (8.3%)	3
Metabolism and nutrition disorders
Acidosis (metabolic or respiratory)	1/24 (4.2%)	1
Albumin, serum-low (hypoalbuminemia)	1/24 (4.2%)	2
Calcium, serum-low (hypocalcemia)	1/24 (4.2%)	2
Creatinine	1/24 (4.2%)	2
Potassium, serum-low (hypokalemia)	1/24 (4.2%)	2
Sodium, serum-low (hyponatremia)	1/24 (4.2%)	1
Musculoskeletal and connective tissue disorders
Fracture	1/24 (4.2%)	1
Renal and urinary disorders
Pain - Kidney	1/24 (4.2%)	1
Obstruction, GU - Ureter	1/24 (4.2%)	1
Urine color change	1/24 (4.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	3/24 (12.5%)	5
Hypoxia	2/24 (8.3%)	3
Vascular disorders
Vessel injury-vein - SVC	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	Combination Immunotherapy
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
Hemoglobin	9/24 (37.5%)	13
Platelets	2/24 (8.3%)	3
Cardiac disorders
Hypertension	3/24 (12.5%)	3
Gastrointestinal disorders
Nausea	10/24 (41.7%)	14
Anorexia	9/24 (37.5%)	11
Constipation	7/24 (29.2%)	8
Vomiting	4/24 (16.7%)	5
Diarrhea	3/24 (12.5%)	4
General disorders
Fatigue (asthenia, lethargy, malaise)	19/24 (79.2%)	26
Weight loss	5/24 (20.8%)	5
Insomnia	4/24 (16.7%)	4
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 X 10^9/L)	2/24 (8.3%)	2
Rigors/chills	2/24 (8.3%)	2
Pain	19/24 (79.2%)	44
Pain - Head/headache	14/24 (58.3%)	18
Pain - joint	6/24 (25%)	8
Pain - back	5/24 (20.8%)	5
Pain - Abdomen - NOS	3/24 (12.5%)	3
Pain - Chest/thorax - NOS	3/24 (12.5%)	3
Mood alteration - Anxiety	3/24 (12.5%)	4
Immune system disorders
Allergic rhinitis	5/24 (20.8%)	5
Allergy/Immunology - other	4/24 (16.7%)	4
Metabolism and nutrition disorders
Glucose, serum-high (hyperglycemia)	9/24 (37.5%)	9
Alkaline phosphatase	6/24 (25%)	9
Creatinine	6/24 (25%)	7
Metabolic/Laboratory - other	3/24 (12.5%)	3
ALT, SGPT (serum glutamic pyruvic transaminase)	2/24 (8.3%)	2
AST, SGOT (serum glutamic oxaloacetic transaminase)	2/24 (8.3%)	2
Potassium, serum-high (hyperkalemia)	2/24 (8.3%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal/Soft - other	3/24 (12.5%)	3
Nervous system disorders
Neuropathy: sensory	2/24 (8.3%)	2
Respiratory, thoracic and mediastinal disorders
Cough	12/24 (50%)	15
Dyspnea (shortness of breath)	10/24 (41.7%)	11
Skin and subcutaneous tissue disorders
Injection site reaction/extravasation changes	8/24 (33.3%)	9
Dry skin	5/24 (20.8%)	6
Rash: acne/acneiform	3/24 (12.5%)	3

Limitations/Caveats

[Not Specified]

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.