Soft Tissue Sarcoma
Conditions
Keywords
Sarcoma, Intratumoral injection, Dendritic cells, Neo-adjuvant treatment, Immunotherapy, Pheresis, Radiation
Brief summary
This is a Phase II study using a combination of external beam radiation with intratumoral injection of dendritic cells (white blood cells) as neo-adjuvant treatment for patients with high-risk soft tissue sarcoma. The purpose was to determine if an injection of the patient's own immune related white blood cells into their tumor would strengthen the immune system to fight against their cancer.
Detailed description
Patients were treated with external beam radiation therapy (EBRT) combined with experimental intratumoral injection of dendritic cell (DC). Patients received 5,040 centigray (cGy) EBRT in 28 equal fractions. Radiation was delivered 5 days per week (Monday-Friday). DCs (10\^7 cells) were injected intratumorally three times on the second, third, and fourth Friday during the course of radiation. One additional DC injection was given several days before surgery to assess DC migration. Tumors were surgically resected 3-6 weeks after the completion of EBRT.
Interventions
BIOLOGICALDendritic Cell (DC) Injections
* DCs (10\^7 cells) were injected intratumorally three times on the second, third, and fourth Friday during the course of radiation. * One additional DC injection was given before surgery to assess DC migration * Patients were assigned to one of three cohorts: Group 1 - DC injection # 4 given 24 hours prior to surgery Group 2 - DC injection # 4 given 48 hours prior to surgery Group 3 - DC injection # 4 given 72 hours prior to surgery
PROCEDURERadiation therapy
Radiation was delivered 5 days per week (Monday-Friday).
PROCEDUREComplete Resection - Surgery for tumor removal
Tumors were surgically resected 3-6 weeks after the completion of EBRT.
Sponsors
Cancer Treatment Research Foundation
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Intermediate or high grade sarcoma as determined by pathology review * Musculoskeletal tumor in extremities, trunk or chest wall. * Primary tumor or isolated locally recurrent tumor greater than 5 cm in diameter. * Clinical Stage T2N0M0 (AJCC 6th edition) * Patient is not a candidate for neoadjuvant chemotherapy. * Performance status Eastern Cooperative Oncology Group (ECOG) 0 or 1. * No steroid therapy within 4 weeks of first dendritic cell administration. * No coagulation disorder. * Patient's written informed consent. * No contraindication to resection. * Adequate organ function (measured within a week of beginning treatment). * White blood count (WBC) \> 3,000/mm to the third power and absolute neutrophil count (ANC) \>1500/mm to the third power * Platelets \> 100,000/mm to the third power * Hematocrit \> 25% * Bilirubin \< 2.0 mg/dL * Creatinine \< 2.0 mg/dL, or creatinine clearance \> 60 mL/min * Radiation Oncologist must confirm that a 2-3 cm strip of skin can be spared from radiation.
Exclusion criteria
* Retroperitoneal location. * Gastrointestinal stromal tumor (GIST). * Demonstrated metastatic disease. * Prior radiation therapy if the current tumor is locally recurrent after prior resection. * Concurrent treatment with any anticancer agent other than radiation as dictated by the protocol. * Bleeding disorder. * H.I.V. infection or other primary immunodeficiency disorder. * Ongoing systemic therapy with immunosuppressant drugs (e.g. corticosteroids, azathioprine, cyclosporin, methotrexate). * Any serious ongoing 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). * ECOG performance status of 2, 3 or 4.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 3 years | Immune responses in patients treated with EBRT and DCs: Transient immune response = response detected at only one time point; Robust immune response = response detected at least at two time points. An individual patient was considered a responder to tumor cell lysates (TCL) or survivin if at any time point the response in the interferon gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay was higher than 30 spots per 2 X 10\^5 cells and in the proliferation assay higher than 3,000 counts per minute (CPM) and the response in IFN-γ ELISPOT or proliferation assays to TCL or Ad-surv was more than 2 standard deviations (SD) higher than the response to the corresponding control lysate or Ad-c at the same time point and 2 SD higher than the response to the same stimuli before start of the treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Significant (>/= Grade 2) Toxicity | Up to 3 years | Toxicity assessment during combination external beam radiation therapy (EBRT)/DC neoadjuvant treatment. Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. |
| Occurrence of Postoperative Wound Complications | Up to 3 years | Postoperative wound complications were defined using NCI Common Toxicity Criteria (CTC). |
| Participants With No Evidence of Disease at Follow-up | 3 years | Participants who had no evidence of the disease for at least one year after the start of the treatment (time of follow-up); for at least 2 years, and for at least 3 years. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Increase in Level of Radioactivity at Excision Per Cohort | Up to 3 years | To identify the nodes to be excised, an injection with Indium 111 (radio active dye) labeled dendritic cells (of vaccine #4) was performed 1 to 3 days prior to surgery. Patients were evenly divided to be assigned to one of three cohorts: Cohort 1, 1 day before surgery; Cohort 2, 2 days before surgery; Cohort 3, 3 days before surgery. Vaccine #4 was labeled in order to evaluate how long dendritic cells need to travel to regional draining lymphatics. Tumor resection was not delayed by this. |
Countries
United States
Participant flow
Recruitment details
Patients with histologically confirmed large high grade soft-tissue sarcomas (STS) of the extremity/trunk/chest wall were enrolled to the study from 5/18/2006 to 2/19/2009. These patients had clinical stage T2N0M0 with a significant (\>50%) risk of progressing to distant metastases.
Participants by arm
| Arm | Count |
|---|---|
| COHORT 1: EBRT + DC Injection + Resection Single Arm: EBRT + DC Injection + Resection. Prior to the fourth DC Injection, participants were assigned to 3 cohorts for that injection only.
Dendritic Cell (DC) Injections: DCs (10\^7 cells) were injected intratumorally three times on the second, third, and fourth Friday during the course of radiation. One additional DC injection was given before surgery to assess DC migration. Patients were assigned to one of three cohorts: Group 1 - DC injection # 4 given 24 hours prior to surgery, Group 2 - DC injection # 4 given 48 hours prior to surgery, Group 3 - DC injection # 4 given 72 hours prior to surgery.
Radiation was delivered 5 days per week (Monday-Friday).
Complete Resection - Surgery for tumor removal: Tumors were surgically resected 3-6 weeks after the completion of EBRT. | 5 |
| COHORT 2: EBRT + DC Injection + Resection Single Arm: EBRT + DC Injection + Resection. Prior to the fourth DC Injection, participants were assigned to 3 cohorts for that injection only.
Dendritic Cell (DC) Injections: DCs (10\^7 cells) were injected intratumorally three times on the second, third, and fourth Friday during the course of radiation. One additional DC injection was given before surgery to assess DC migration. Patients were assigned to one of three cohorts: Group 1 - DC injection # 4 given 24 hours prior to surgery, Group 2 - DC injection # 4 given 48 hours prior to surgery, Group 3 - DC injection # 4 given 72 hours prior to surgery.
Radiation was delivered 5 days per week (Monday-Friday).
Complete Resection - Surgery for tumor removal: Tumors were surgically resected 3-6 weeks after the completion of EBRT. | 6 |
| COHORT 3: EBRT + DC Injection + Resection Single Arm: EBRT + DC Injection + Resection. Prior to the fourth DC Injection, participants were assigned to 3 cohorts for that injection only.
Dendritic Cell (DC) Injections: DCs (10\^7 cells) were injected intratumorally three times on the second, third, and fourth Friday during the course of radiation. One additional DC injection was given before surgery to assess DC migration. Patients were assigned to one of three cohorts: Group 1 - DC injection # 4 given 24 hours prior to surgery, Group 2 - DC injection # 4 given 48 hours prior to surgery, Group 3 - DC injection # 4 given 72 hours prior to surgery.
Radiation was delivered 5 days per week (Monday-Friday).
Complete Resection - Surgery for tumor removal: Tumors were surgically resected 3-6 weeks after the completion of EBRT. | 6 |
| Total | 17 |
Baseline characteristics
| Characteristic | COHORT 2: EBRT + DC Injection + Resection | COHORT 3: EBRT + DC Injection + Resection | COHORT 1: EBRT + DC Injection + Resection | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 0 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 5 Participants | 11 Participants |
| Age, Continuous | 61 years | 68 years | 35 years | 53 years |
| Region of Enrollment United States | 6 participants | 6 participants | 5 participants | 17 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 5 / 17 |
Outcome results
Primary
Overall Response Rate (ORR)
Immune responses in patients treated with EBRT and DCs: Transient immune response = response detected at only one time point; Robust immune response = response detected at least at two time points. An individual patient was considered a responder to tumor cell lysates (TCL) or survivin if at any time point the response in the interferon gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay was higher than 30 spots per 2 X 10\^5 cells and in the proliferation assay higher than 3,000 counts per minute (CPM) and the response in IFN-γ ELISPOT or proliferation assays to TCL or Ad-surv was more than 2 standard deviations (SD) higher than the response to the corresponding control lysate or Ad-c at the same time point and 2 SD higher than the response to the same stimuli before start of the treatment.
Time frame: Up to 3 years
Population: All evaluable participants available for follow-up at time of analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EBRT + DC Injection + Resection | Overall Response Rate (ORR) | Robust Response | 6 participants |
| EBRT + DC Injection + Resection | Overall Response Rate (ORR) | Developed Tumor Specific Response | 9 participants |
| EBRT + DC Injection + Resection | Overall Response Rate (ORR) | Transient Response | 3 participants |
Secondary
Occurrence of Postoperative Wound Complications
Postoperative wound complications were defined using NCI Common Toxicity Criteria (CTC).
Time frame: Up to 3 years
Population: All evaluable participants available for follow-up at time of analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EBRT + DC Injection + Resection | Occurrence of Postoperative Wound Complications | 5 participants |
Secondary
Occurrence of Significant (>/= Grade 2) Toxicity
Toxicity assessment during combination external beam radiation therapy (EBRT)/DC neoadjuvant treatment. Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria.
Time frame: Up to 3 years
Population: All evaluable participants available for follow-up at time of analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EBRT + DC Injection + Resection | Occurrence of Significant (>/= Grade 2) Toxicity | 0 participants |
Secondary
Participants With No Evidence of Disease at Follow-up
Participants who had no evidence of the disease for at least one year after the start of the treatment (time of follow-up); for at least 2 years, and for at least 3 years.
Time frame: 3 years
Population: All evaluable participants available for follow-up at time of analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EBRT + DC Injection + Resection | Participants With No Evidence of Disease at Follow-up | At One Year Follow-up | 12 participants |
| EBRT + DC Injection + Resection | Participants With No Evidence of Disease at Follow-up | At Two Year Follow-up | 6 participants |
| EBRT + DC Injection + Resection | Participants With No Evidence of Disease at Follow-up | At Three Year Follow-up | 4 participants |
Other Pre-specified
Number of Participants With Increase in Level of Radioactivity at Excision Per Cohort
To identify the nodes to be excised, an injection with Indium 111 (radio active dye) labeled dendritic cells (of vaccine #4) was performed 1 to 3 days prior to surgery. Patients were evenly divided to be assigned to one of three cohorts: Cohort 1, 1 day before surgery; Cohort 2, 2 days before surgery; Cohort 3, 3 days before surgery. Vaccine #4 was labeled in order to evaluate how long dendritic cells need to travel to regional draining lymphatics. Tumor resection was not delayed by this.
Time frame: Up to 3 years
Population: Participants evaluable for this measure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EBRT + DC Injection + Resection | Number of Participants With Increase in Level of Radioactivity at Excision Per Cohort | 0 participants |
| Single Arm - Cohort 2 | Number of Participants With Increase in Level of Radioactivity at Excision Per Cohort | 4 participants |
| Single Arm - Cohort 3 | Number of Participants With Increase in Level of Radioactivity at Excision Per Cohort | 6 participants |