Melanoma
Conditions
Keywords
Melanoma, Cell Therapy, T Cell Therapy, NY-ESO-1, Immuno-oncology, Metastatic, Previously treated, T Cell Receptor
Brief summary
The purpose of this early (phase I/II) clinical trial is to assess the effects (both good and bad) of genetically modified T cells after chemotherapy on your cancer and general health.
Detailed description
Purpose of this study is to evaluate the safety and tolerability of autologous genetically modified T cells. Genetic material is transferred into the subject's previously harvested autologous T cells to redirect them to target melanoma cells rather than their usual target. Study subjects must have histologically or cytologically melanoma stage 3/4 and their tumor must express HLA Class 1 allele HLA-A\*0201 for NY-ESO-1/LAGE. Subjects must also have measureable disease on study entry, as defined by at least one lesion that can be measured in at least one dimension \>= 10mm with spiral CT scan.
Interventions
GENETICAutologous genetically modified T cells, NY-ESO-1ᶜ²⁵⁹T
Cytoreductive chemotherapy followed by infusion of NY-ESO-1ᶜ²⁵⁹T
Sponsors
Adaptimmune
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
* Patients must have histologically or cytologically confirmed melanoma stage III/IV, unresectable * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CT scan * One prior cytotoxic therapy for the treatment of metastatic disease is allowed. Unlimited regimens using biological agents (vaccines), immunotherapy, or targeted agents is permitted. For example, BRAF inhibitors and ipilimumab are permitted. Patients must have fully recovered from the acute toxicities related to any prior therapy. Prior therapy must be completed ≥28 days before the first dose of cyclophosphamide. * Age ≥18 * Life expectancy of greater than 3 months * ECOG performance status ≤ 1 Patients must have normal organ and marrow function as defined below: * Leukocytes ≥ 3,000/mcL * Absolute Neutrophil Count (ANC) ≥ 1,500/mcL * Platelets ≥ 100,000/mcL * Total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal * Creatinine ≤ 2.0 mg/dl Or Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * The patient must express HLA class I allele HLA-A\*0201 for NY-ESO-1/LAGE. * Patient must have proven positive tumor sample for NY-ESO-1 as determined by an H score for immunohistochemistry staining. Positive expression is defined as an H score ≥ 100 where the H score = \[2 x (% cells 2+) + 3 x (% cells 3+)\]. NOTE: The percentages of negative or weakly stained nuclei (i.e. 1+) are not to be included in the calculation of the H score. * Female subjects of childbearing potential must have a negative pregnancy test and both male and female (of childbearing potential) subjects must agree to use reliable methods of contraception during the study. * Ability of the patient (or legally authorized representative if applicable) to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Patients who have had 2 or more regimens containing cytotoxic chemotherapy for metastatic melanoma. * Patients may not be receiving any other investigational agents. * Patients with active brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide or other agents used in the study. * Active infection * Prior malignancy (except non-melanoma skin cancer) within 3 years. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. All patients will undergo a cardiac stress test for evaluation of cardiac function. * Pregnant or nursing females * Active infection with HIV, HBV or HCV as defined below, due to the immunosuppressive effects of cyclophosphamide used and the unknown risks associated with viral replication. * Positive serology for HIV * Active Hepatitis B infection as determined by test for hepatitis B surface antigen. * Active Hepatitis C. Patients will be screened for HCV antibody. If the HCV antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed at screening by a local laboratory with a CLIA certification or its equivalent. Eligibility will be determined based on a negative screening value. The test is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events Related to Study Treatment | Up to 12 months | Number of Participants with NCI CTC V.4 Adverse Events related to study treatment greater than or equal to Grade 3 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response | Change from Baseline, every 4 weeks until Month 5 and then every other month through Month 11 | Number of participants with response as assessed by RECIST (version 1.1) criteria. |
| Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | 8 Weeks post T-cell infusion | Measurement of functionality of NY-ESO-1ᶜ²⁵⁹T cells in the blood and tumor sites. |
| Peak Persistence of Modified T-cells in the Peripheral Blood | Days 1, 5-9, 12-16, weekly thereafter through Week 12, monthly thereafter through Month 12, and during LTFU | Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood (copies of WPRE per µg of genomic PBMC DNA) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days Participants who received cytoreductive chemotherapy followed by infusion of lentivirus-mediated genetically engineered NY-ESO-1ᶜ²⁵⁹T (Target dose: 5-10 billion cells) | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 49 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 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 | 4 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 4 / 4 |
Outcome results
Primary
Adverse Events Related to Study Treatment
Number of Participants with NCI CTC V.4 Adverse Events related to study treatment greater than or equal to Grade 3
Time frame: Up to 12 months
Population: Participants who received cytoreductive chemotherapy followed by IV infusion of NY-ESO-1ᶜ²⁵⁹T
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Adverse Events Related to Study Treatment | 3 Participants |
Secondary
Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites.
Measurement of functionality of NY-ESO-1ᶜ²⁵⁹T cells in the blood and tumor sites.
Time frame: 8 Weeks post T-cell infusion
Population: Participants who received cytoreductive chemotherapy followed by infusion of NY-ESO-1ᶜ²⁵⁹T with functionality data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %PD-1+ | 1.24694 percentage of T cell sub population |
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %TIM-3+ | 97.74411 percentage of T cell sub population |
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory RA | 36.329 percentage of T cell sub population |
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Central Memory | 14.62221 percentage of T cell sub population |
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Stem Cell Memory | 31.1354 percentage of T cell sub population |
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %LAG-3+ | 0.40391 percentage of T cell sub population |
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory | 17.8215 percentage of T cell sub population |
| Subject 1 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Stem Cell Memory | 61.545 percentage of T cell sub population |
| Subject 1 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %TIM-3+ | 5.985 percentage of T cell sub population |
| Subject 1 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %LAG-3+ | 0 percentage of T cell sub population |
| Subject 1 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Central Memory | 3.42 percentage of T cell sub population |
| Subject 1 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory | 2.56 percentage of T cell sub population |
| Subject 1 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory RA | 32.475 percentage of T cell sub population |
| Subject 1 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %PD-1+ | 0.855 percentage of T cell sub population |
| Subject 2 - Manufactured Product | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %PD-1+ | 4.11214 percentage of T cell sub population |
| Subject 2 - Manufactured Product | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Stem Cell Memory | 18.65934 percentage of T cell sub population |
| Subject 2 - Manufactured Product | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Central Memory | 6.85214 percentage of T cell sub population |
| Subject 2 - Manufactured Product | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory RA | 34.50644 percentage of T cell sub population |
| Subject 2 - Manufactured Product | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory | 39.99068 percentage of T cell sub population |
| Subject 2 - Manufactured Product | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %LAG-3+ | 1.23488 percentage of T cell sub population |
| Subject 2 - Manufactured Product | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %TIM-3+ | 95.2126 percentage of T cell sub population |
| Subject 2 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory | 3.45 percentage of T cell sub population |
| Subject 2 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Effector Memory RA | 82.7 percentage of T cell sub population |
| Subject 2 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %PD-1+ | 0 percentage of T cell sub population |
| Subject 2 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Central Memory | 6.9 percentage of T cell sub population |
| Subject 2 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %Stem Cell Memory | 6.9 percentage of T cell sub population |
| Subject 2 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %TIM-3+ | 10.35 percentage of T cell sub population |
| Subject 2 - Day 60 | Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | %LAG-3+ | 0 percentage of T cell sub population |
Secondary
Peak Persistence of Modified T-cells in the Peripheral Blood
Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood (copies of WPRE per µg of genomic PBMC DNA)
Time frame: Days 1, 5-9, 12-16, weekly thereafter through Week 12, monthly thereafter through Month 12, and during LTFU
Population: Participants who received cytoreductive chemotherapy followed by infusion of NY-ESO-1ᶜ²⁵⁹T with persistence data
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Peak Persistence of Modified T-cells in the Peripheral Blood | 56561.22 copies per μg of DNA |
Secondary
Tumor Response
Number of participants with response as assessed by RECIST (version 1.1) criteria.
Time frame: Change from Baseline, every 4 weeks until Month 5 and then every other month through Month 11
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells Administered IV as a Split Dose Over 2 Days | Tumor Response | 0 Participants |