Stage III Cutaneous Melanoma AJCC v7, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Metastatic Melanoma
Conditions
Brief summary
This phase II trial studies how well tumor-infiltrating lymphocytes (TIL) after combination chemotherapy works in treating patients with melanoma that has spread to other places in the body. Biological therapies, such as TIL, may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving TIL after combination chemotherapy may kill more tumor cells.
Detailed description
OUTLINE: Patients receive cyclophosphamide intravenously (IV) on days -7 to -6 and fludarabine phosphate IV on days -5 to -1. Patients undergo TIL infusion over 30-60 minutes on day 0 and receive aldesleukin IV every 8 hours on days 1-5 for up to a maximum of 14 doses. After completion of study treatment, patients are followed up at 6, 12, and 24 weeks.
Interventions
BIOLOGICALAldesleukin
Given IV
DRUGCyclophosphamide
Given IV
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
Undergo TIL infusion
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
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
Step I Inclusion Criteria: * Stage IV melanoma or stage III melanoma that is unlikely to be cured by surgery * Able to tolerate high-dose cyclophosphamide, fludarabine and high-dose IL-2 * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * Patients must have a magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) of the brain within 2 months before consenting if known history of brain metastasis or if clinically indicated; if new lesions are present, principal investigator (PI) or designee should make final determination regarding enrollment * Patients must have a site of metastatic disease that can be safely resected or biopsied for tissue sufficient for TIL harvest Step II Inclusion Criteria: * Patients must have measurable metastatic melanoma * Able to tolerate high-dose cyclophosphamide, fludarabine, and high-dose IL-2 * ECOG performance status of 0-1 * Patients must have brain imaging by MRI, CT or PET within 30 days prior to lymphodepletion; patients may have asymptomatic brain lesions that are =\< 1 cm each, lesions that are \> 1 cm that have been irradiated and in the opinion of the investigator no longer represents active disease will also be allowed * A functional cardiac test (e.g., stress treadmill, stress thallium, multigated acquisition scan (MUGA), dobutamine echocardiogram) to rule out cardiac ischemia within 4 months prior to lymphodepletion is required for all patients * Pulmonary function tests (PFTs) are required of all patients within 4 months prior to lymphodepletion; forced expiratory volume (FEV)1 and forced vital capacity (FVC) must be \>= 65% predicted and diffusion lung capacity for carbon monoxide (DLCO) must be \>= 50% predicted * Patients must have their tumor sent for v-Raf murine sarcoma viral oncogene homolog B1(BRAF) mutational analysis * Patients must have adequate TIL (at least 40 x 10\^6 cells at the pre-expansion stage)
Exclusion criteria
Step I
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Each Clinical Response Category | Up to 24 weeks post infusion | Assessed using Response Evaluation Criteria in Solid Tumors 1.1 definitions for complete response, partial response, stable disease, and progressive disease. Clinical response will be determined at 6 weeks, 12 weeks and 24 weeks based on RECIST version 1.137 definitions for Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD). Response reported is best response per participant. A complete response will be defined as total regression of all tumors, a PR as 30% or greater decrease in the sum of the longest diameter of target lesions compared to baseline and PD as 20% increase in the sum of the longest diameter of target lesions compared to the smallest prior diameter (RECIST v1.1 criteria). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced in Vivo Persistence of Adoptively Transferred T Cells Following TIL Infusion | Up to 24 months | Whole exome and RNA sequencing of tumor cells and normal tissue was performed to identify non synonymous missense mutations, which was then used to generate peptide pools to identify neoantigen-reactive T cells. T-Cell Receptor (TCR) sequencing of T cell clonotypes in blood at time of treatment, 10 months and 24 months was performed and used to assess the persistence of a tumor antigen specific clonotype infused in the TIL product. |
| Count of Participants Who Experienced Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Adverse events will be collected through 4 weeks after T cell infusion. Beginning 4 weeks after the T cell infusion, only study-related toxicities will be collected for up to 1 year following T cell infusion. | — |
| A Count of Participants With Biomarker Expression Above Threshold | Up to 24 weeks | Several biomarkers, CXCL13+ CD4 cells, CXCL13+ CD8+ cells, and regulatory cells were evaluated to assess correlation with clinical responses to TIL therapy. |
Countries
United States
Participant flow
Pre-assignment details
A patient counts as enrolled on this study when they sign treatment consent on the study. 11 patients signed treatment consent, however 1 patient did not move on to treatment due to increased edema and bleeding at brain metastasis. 10 patients were treated on study.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) Patients receive cyclophosphamide IV on days -7 to -6 and fludarabine phosphate IV on days -5 to -1. Patients undergo TIL infusion over 30-60 minutes on day 0 and receive aldesleukin IV every 8 hours on days 1-5 for up to a maximum of 14 doses.
Aldesleukin: Given IV
Cyclophosphamide: Given IV
Fludarabine Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies
Therapeutic Tumor Infiltrating Lymphocytes: Undergo TIL infusion | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Moved to hospice care | 1 |
| Overall Study | New therapy | 1 |
Baseline characteristics
| Characteristic | Treatment (TIL, Combination Chemotherapy, Aldesleukin) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 4 / 10 |
Outcome results
Primary
Number of Participants in Each Clinical Response Category
Assessed using Response Evaluation Criteria in Solid Tumors 1.1 definitions for complete response, partial response, stable disease, and progressive disease. Clinical response will be determined at 6 weeks, 12 weeks and 24 weeks based on RECIST version 1.137 definitions for Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD). Response reported is best response per participant. A complete response will be defined as total regression of all tumors, a PR as 30% or greater decrease in the sum of the longest diameter of target lesions compared to baseline and PD as 20% increase in the sum of the longest diameter of target lesions compared to the smallest prior diameter (RECIST v1.1 criteria).
Time frame: Up to 24 weeks post infusion
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Number of Participants in Each Clinical Response Category | Complete Response | 2 Participants |
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Number of Participants in Each Clinical Response Category | Partial Response | 2 Participants |
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Number of Participants in Each Clinical Response Category | Progressive Disease | 2 Participants |
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Number of Participants in Each Clinical Response Category | Stable Disease | 4 Participants |
Secondary
A Count of Participants With Biomarker Expression Above Threshold
Several biomarkers, CXCL13+ CD4 cells, CXCL13+ CD8+ cells, and regulatory cells were evaluated to assess correlation with clinical responses to TIL therapy.
Time frame: Up to 24 weeks
Population: Samples from 6 patients were evaluated in depth. Biomarker studies were not performed in all patients due to funding constraints.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | A Count of Participants With Biomarker Expression Above Threshold | CXCL13+ as % of CD4 T Cell (40% Threshold) | 2 Participants |
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | A Count of Participants With Biomarker Expression Above Threshold | Treg as % of CD4 T Cell (40% Threshold) | 3 Participants |
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | A Count of Participants With Biomarker Expression Above Threshold | CXCL13+ as % of CD8 T Cell (40% Threshold) | 6 Participants |
Secondary
Count of Participants Who Experienced Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Time frame: Adverse events will be collected through 4 weeks after T cell infusion. Beginning 4 weeks after the T cell infusion, only study-related toxicities will be collected for up to 1 year following T cell infusion.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Count of Participants Who Experienced Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | 10 Participants |
Secondary
Number of Participants Who Experienced in Vivo Persistence of Adoptively Transferred T Cells Following TIL Infusion
Whole exome and RNA sequencing of tumor cells and normal tissue was performed to identify non synonymous missense mutations, which was then used to generate peptide pools to identify neoantigen-reactive T cells. T-Cell Receptor (TCR) sequencing of T cell clonotypes in blood at time of treatment, 10 months and 24 months was performed and used to assess the persistence of a tumor antigen specific clonotype infused in the TIL product.
Time frame: Up to 24 months
Population: Due to the technical challenges and costs of examining persistence of unmodified TIL cells that do not have a unique tag, the persistence has not been performed in the other patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Number of Participants Who Experienced in Vivo Persistence of Adoptively Transferred T Cells Following TIL Infusion | At time of treatment | 1 Participants |
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Number of Participants Who Experienced in Vivo Persistence of Adoptively Transferred T Cells Following TIL Infusion | 10 months post infusion | 1 Participants |
| Treatment (TIL, Combination Chemotherapy, Aldesleukin) | Number of Participants Who Experienced in Vivo Persistence of Adoptively Transferred T Cells Following TIL Infusion | 24 months post infusion | 1 Participants |