Colorectal Cancer, Metastatic Cancer
Conditions
Keywords
liver metastases, adenocarcinoma of the colon, recurrent colon cancer, stage IV colon cancer, adenocarcinoma of the rectum, recurrent rectal cancer, stage IV rectal cancer, lung metastases
Brief summary
RATIONALE: Vaccines made from a gene-modified virus and a person's white blood cells may make the body build an effective immune response to kill tumor cells. Biological therapies, such as Granulocyte-macrophage colony-stimulating factor (GM-CSF), may stimulate the immune system in different ways and stop tumor cells from growing. Combining different types of biological therapies may kill more tumor cells. PURPOSE: This randomized phase II trial is studying giving vaccine therapy together with dendritic cells to see how well it works compared to giving vaccine therapy together with GM-CSF in treating patients with liver or lung metastases from colorectal cancer removed by surgery.
Detailed description
OBJECTIVES: Primary * Compare 2-year disease-free survival of patients with completely resected hepatic or pulmonary metastases secondary to colorectal cancer treated with adjuvant vaccine therapy comprising vaccinia-Carcinoembryonic antigen (CEA)-mucin 1 (MUC-1)- Triad of costimulatory molecules TRICOM vaccine (PANVAC-V) and fowlpox-CEA-MUC-1-TRICOM vaccine (PANVAC-F) administered with autologous dendritic cells or with sargramostim (GM-CSF). Secondary * Compare the rate and magnitude of immune response, as determined by enzyme-linked immunosorbent spot (ELISpot), in patients treated with these regimens. OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients undergo leukapheresis to obtain leukocytes for generation of autologous dendritic cells (DC). Patients then receive autologous DC loaded with vaccinia-CEA-MUC-1-TRICOM (PANVAC-V) vaccine subcutaneously (SC) and intradermally (ID) on day 1 and autologous DC loaded with fowlpox-CEA-MUC-1-TRICOM (PANVAC-F) vaccine subcutaneously (SC) and intradermally (ID) on days 28, 56, and 84. * Arm II: Patients receive PANVAC-V SC on day 1 and PANVAC-F SC on days 28, 56, and 84. Patients also receive sargramostim (GM-CSF) SC into the same injection site once daily on days 0-3, 28-31, 56-59, and 84-87. After completion of study treatment, patients are followed for 2 years. PROJECTED ACCRUAL: A total of 72 patients (36 per treatment arm) will be accrued for this study within 2 years.
Interventions
BIOLOGICALfalimarev
Given subcutaneously and intradermally
BIOLOGICALinalimarev
Given subcutaneously and intradermally
BIOLOGICALsargramostim
Given subcutaneously
BIOLOGICALtherapeutic autologous dendritic cells
Given subcutaneously and intradermally
Sponsors
National Cancer Institute (NCI)
Michael Morse, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed hepatic or pulmonary metastases secondary to adenocarcinoma of the colon and rectum * Must have undergone complete resection of hepatic or pulmonary metastases with curative intent * No evidence of gross residual disease after surgery * One or more resected and ablated lesions allowed provided all gross residual tumor was destroyed by ablation * Repeated resections of hepatic metastatic disease or resections of extrahepatic metastases prior to resection of the hepatic metastases allowed provided the most recent hepatic metastatic resection included total disease resection and/or ablation * Must have received at least 2 months of perioperative systemic chemotherapy (including preoperative and/or postoperative chemotherapy) that was completed at least 1 month ago PATIENT CHARACTERISTICS: Age * At least 18 Performance status * Karnofsky 70-100% Life expectancy * At least 6 months Hematopoietic * Platelet count ≥ 75,000/mm\^3 * Hemoglobin ≥ 8.5 g/dL (transfusion or epoetin alfa allowed) Hepatic * Bilirubin ≤ 2.0 mg/dL * Hepatitis B surface antigen negative * Hepatitis C antibody negative * No other serious chronic or acute hepatic disease Renal * Creatinine ≤ 1.5 mg/dL OR * Creatinine clearance \> 60 mL/min Cardiovascular * No New York Heart Association class III or IV cardiac disease * No other serious chronic or acute cardiac disease Pulmonary * No asthma * No chronic obstructive pulmonary disease * No other serious chronic or acute pulmonary disease Immunologic * No history of autoimmune disease, including, but not limited to, any of the following: * Inflammatory bowel disease * Systemic lupus erythematosus * Ankylosing spondylitis * Scleroderma * Multiple sclerosis * No human immunodeficiency virus (HIV) infection by enzyme-linked immunosorbent assay (ELISA) and western blot * Not immunocompromised (by disease or therapy) * No allergy to eggs or any component of the study vaccine * No history of allergy or untoward reaction to prior vaccinia (smallpox) vaccination * No allergy or untoward reaction to sargramostim (GM-CSF) * No active acute or chronic infection, including urinary tract infection within the past 72 hours * No inflammatory bowel conditions, including, but not limited to, the following: * Active infectious enteritis * Eosinophilic enteritis * No acute, chronic, or exfoliative skin disorders, including any of the following: * Extensive psoriasis * Burns * Impetigo * Disseminated zoster * Varicella zoster * Severe acne * Other open rashes or wounds Other * Not pregnant or nursing * Fertile patients must use effective contraception * Able to avoid close contact or household contact for 3 weeks after each vaccination with the following individuals: * Children under 5 years of age * Pregnant or nursing women * Individuals with prior or concurrent extensive eczema, other eczematoid skin disorders, or other acute or chronic skin conditions * Immunosuppressed or immunodeficient individuals * No medical or psychological condition that would preclude study compliance * No extensive eczema * No other serious chronic or acute illness that would preclude study participation * No other malignancy within the past 5 years except nonmelanoma skin cancer, controlled superficial bladder cancer, or previously treated carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy * No other concurrent immunotherapy Chemotherapy * See Disease Characteristics * No concurrent chemotherapy Endocrine therapy * More than 6 weeks since prior and no concurrent steroid therapy Radiotherapy * No concurrent radiotherapy Surgery * See Disease Characteristics Other * No other concurrent immunosuppressants (e.g., azathioprine or cyclosporine)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free Survival at 2 Years | 2 years | Recurrence-free survival for randomized patients receiving dendritic cells (DC) loaded with PANVAC or PANVAC plus Granulocyte-macrophage colony-stimulating factor (GM-CSF) measured from the date of metastasectomy, with relapse defined as documented disease recurrence at any site. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive Immune Response as Measured by (Enzyme-linked Immunosorbent Spot) ELISpot Assay | 13 weeks | CEA-Specific Immune Responders by enzyme-linked immunosorbent spot (ELISpot). The ELISPOT assay is considered positive for a subject if the mean number of spots with CEA exceeds the number of spots with control by a magnitude of 10 and the difference between CEA and control is statistically significant at a level of p=0.05 by the t-test. |
Countries
United States
Participant flow
Recruitment details
This was a 7 site study where patients were recruited from medical clinics and the patient's primary oncologist and study team approached the patient about the study. Patients were recruited for this study from January 2005 and September 2009.
Pre-assignment details
The study was designed to treat 72 subjects. Total number of enrollment is 74 because enrollment reflects the number of subjects that signed consent and were randomized to the study but did not necessarily receive study drug or complete study drug.
Participants by arm
| Arm | Count |
|---|---|
| Experimental PANVAC-V + PANVAC-F + DC Patients undergo leukapheresis to obtain leukocytes for generation of autologous dendritic cells (DC). Patients then receive autologous DC loaded with vaccinia-Carcinoembryonic antigen (CEA)-Mucin 1 (MUC-1)-TRIad of COstimulatory Molecules (TRICOM) (PANVAC-V) vaccine subcutaneously (SC) and intradermally (ID) on day 1 and autologous DC loaded with fowlpox-CEA-MUC-1-TRICOM (PANVAC-F) vaccine subcutaneous (SC) and intradermally (ID) on days 28, 56, and 84. | 37 |
| Experimental PANVAC-V + PANVAC-F + GM-CSF Patients receive PANVAC-V SC on day 1 and PANVAC-F SC on days 28, 56, and 84. Patients also receive sargramostim (Granulocyte-macrophage colony-stimulating factor or GM-CSF) subcutaneous (SC) into the same injection site once daily on days 0-3, 28-31, 56-59, and 84-87. | 37 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Progression of disease | 2 | 1 |
Baseline characteristics
| Characteristic | Experimental PANVAC-V + PANVAC-F + DC | Experimental PANVAC-V + PANVAC-F + GM-CSF | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 7 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 30 Participants | 58 Participants |
| Age, Continuous | 53.6 years | 52.0 years | 53.5 years |
| Carcinoembryonic antigen (CEA) | 2.0 mcg/L | 1.8 mcg/L | 1.9 mcg/L |
| Number of nodules 1 nodules | 11 participants | 17 participants | 28 participants |
| Number of nodules 2-4 nodules | 16 participants | 12 participants | 28 participants |
| Number of nodules >4 nodules | 4 participants | 5 participants | 9 participants |
| Number of nodules unknown | 6 participants | 3 participants | 9 participants |
| Region of Enrollment United States | 37 participants | 37 participants | 74 participants |
| Sex: Female, Male Female | 21 Participants | 18 Participants | 39 Participants |
| Sex: Female, Male Male | 16 Participants | 19 Participants | 35 Participants |
| Sites of metastasis Liver | 26 participants | 31 participants | 57 participants |
| Sites of metastasis Lung | 11 participants | 6 participants | 17 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 35 | 35 / 36 |
| serious Total, serious adverse events | 0 / 35 | 0 / 36 |
Outcome results
Primary
Recurrence-free Survival at 2 Years
Recurrence-free survival for randomized patients receiving dendritic cells (DC) loaded with PANVAC or PANVAC plus Granulocyte-macrophage colony-stimulating factor (GM-CSF) measured from the date of metastasectomy, with relapse defined as documented disease recurrence at any site.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PANVAC-V + PANVAC-F + DC | Recurrence-free Survival at 2 Years | 13 participants |
| PANVAC-V + PANVAC-F + GM-CSF | Recurrence-free Survival at 2 Years | 10 participants |
Secondary
Positive Immune Response as Measured by (Enzyme-linked Immunosorbent Spot) ELISpot Assay
CEA-Specific Immune Responders by enzyme-linked immunosorbent spot (ELISpot). The ELISPOT assay is considered positive for a subject if the mean number of spots with CEA exceeds the number of spots with control by a magnitude of 10 and the difference between CEA and control is statistically significant at a level of p=0.05 by the t-test.
Time frame: 13 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PANVAC-V + PANVAC-F + DC | Positive Immune Response as Measured by (Enzyme-linked Immunosorbent Spot) ELISpot Assay | 9 participants |
| PANVAC-V + PANVAC-F + GM-CSF | Positive Immune Response as Measured by (Enzyme-linked Immunosorbent Spot) ELISpot Assay | 4 participants |