Metastatic Melanoma
Conditions
Brief summary
Adoptive T cell therapy with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. The TILs are isolated from the patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 are administered to support T cell activation and proliferation in vivo. In this trial the therapy is combined with peginterferon (the pegylated form of interferon alpha 2b). Interferon alpha has immunomodulatory effects and is known to upregulate HLA expression on melanoma cells and are hypothesized to synergize with TIL therapy.
Interventions
DRUGCyclophosphamide
Cyclophosphamide 60 mg/kg are administered i.v on day -7 and -6
DRUGFludarabine
Fludarabine 25 mg/m2 are administered i.v on day -5 to -1
BIOLOGICALTIL infusion
The maximum number of expanded TILs are infused over 30-45 min on day 0
DRUGInterleukin-2
Interleukin-2 are administered as a continuous i.v. infusion in a decrescendo regimen (18 MIU/m2 IL-2 over 6 hours, 18 MIU/m2 IL-2 over 12 hours, 18 MIU IL-2 over 24 hours followed by 4.5 MIU/m2 IL-2 over another 24 hours for three days)
DRUGPeginterferon alfa-2b
Peginterferon alpha-2b, 3 microgram/kg are administered as subcutaneous injection on day -2, day 7 and day 14.
Sponsors
Inge Marie Svane
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Histologically confirmed unresectable stage III or stage IV metastatic melanoma Metastasis available for surgical resection (about 2 cm3) and residual measurable disease after resection ECOG performance status 0-1 Life expectancy ≥ 3 months No significant toxicity from prior treatments Adequate renal, hepatic and hematologic function Women of childbearing potential (WOCBP) and men in a sexual relationship with a WOCBP must be using an effective method of contraception during treatment and for at least 6 months after completion af treatment. Able to comprehend the information given and willing to sign informed consent \-
Exclusion criteria
Other Malignancies, unless followed for ≥ 5 years with no sign of disease, except squamous cell carcinoma or adequately treated carcinoma in situ colli uteri. Cerebral metastasis. Patients with previously treated CNS metastases can participate if CNS metastases are surgically removed or treated with stereotactic radiosurgery and stable ≥ 28 days after treatment measured by MRI. Patients with asymptomatic, stable and untreated CNS metastasis can in be included according to investigators and sponsors decision. Patients with ocular melanoma Severe allergies, history of anaphylaxis or known allergies to the administered drugs. Serious medical or psychiatric comorbidity Creatinine clearance \< 70 ml/min Acute or chronic infection with e.g. HIV, hepatitis, tuberculosis Severe and active autoimmune disease Pregnant and nursing women Need for immunosuppressive treatment, e.g. corticosteroids or methotrexate Concomitant treatment with other experimental drugs Patients with uncontrolled hypercalcemia Less than four weeks since prior systemic antineoplastic treatment at the time of treatment. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events/Serious Adverse Events | 0-24 weeks | Determine the safety of the administration of peginterferon in combination with TIL therapy including lymphodepleting chemotherapy and Interleukin-2 by reporting adverse events according to CTCAE v. 4.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Related Immune Responses | Up to 12 months | Number of participants with detectable in vitro immune responses in the TIL infusion product using intracellular flow cytometry. |
| Objective Response Rate | Up to 36 months | Clinical responses will be evaluated by RECIST 1.1 (Response Criteria In Solid Tumors Criteria version 1.1) and assessed by CT scan. Complete response (CR), disapperance of all lesions; Partial response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective response (OR) = CR + PR |
| Overall Survival | Up to 36 months | Overall survival (OS), defined as time from treatment initiation to death, described using the Kaplan Meier method |
| Progression Free Survival | Up to 36 months | Progression free survival (PFS), defined as the time from treatment initiation to disease progression, relapse or death due to any cause, which ever comes first, will be described with the Kaplan Meier method. |
Countries
Denmark
Participant flow
Recruitment details
All patients were recruited from Danish melanoma centers.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: TIL + IFNalpha The patients are admitted to hospital day -8 and receive lymphodepleting chemotherapy with cyclophosphamide 60 mg/kg on day -7 and -6 and fludarabine 25 mg/m2 on day -5 to day -1.
TIL infusion: The maximum number of expanded TILs are infused over 30-45 min on day 0
Interleukin-2: Interleukin-2 are administered as a continuous i.v. infusion in a decrescendo regimen (18 MIU/m2 IL-2 over 6 hours, 18 MIU/m2 IL-2 over 12 hours, 18 MIU IL-2 over 24 hours followed by 4.5 MIU/m2 IL-2 over another 24 hours for three days)
Peginterferon alfa-2b: Peginterferon alpha-2b, 3 microgram/kg are administered as subcutaneous injection on day -2, day 7 and day 14. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Arm A: TIL + IFNalpha | — |
|---|---|---|
| Age, Continuous | 57 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Denmark | 12 participants | — |
| Sex: Female, Male Female | 6 Participants | — |
| Sex: Female, Male Male | 6 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 4 / 12 |
Outcome results
Primary
Number of Participants With Adverse Events/Serious Adverse Events
Determine the safety of the administration of peginterferon in combination with TIL therapy including lymphodepleting chemotherapy and Interleukin-2 by reporting adverse events according to CTCAE v. 4.0
Time frame: 0-24 weeks
Population: 12 patients were treated with TIL.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: TIL + IFNalpha | Number of Participants With Adverse Events/Serious Adverse Events | Adverse events | 12 Participants |
| Arm A: TIL + IFNalpha | Number of Participants With Adverse Events/Serious Adverse Events | Treatment-related adverse events | 12 Participants |
| Arm A: TIL + IFNalpha | Number of Participants With Adverse Events/Serious Adverse Events | Serious adverse events | 4 Participants |
Secondary
Objective Response Rate
Clinical responses will be evaluated by RECIST 1.1 (Response Criteria In Solid Tumors Criteria version 1.1) and assessed by CT scan. Complete response (CR), disapperance of all lesions; Partial response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective response (OR) = CR + PR
Time frame: Up to 36 months
Population: 12 patients were treated with TIL. 1 patient was not evaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: TIL + IFNalpha | Objective Response Rate | 2 Participants |
Secondary
Overall Survival
Overall survival (OS), defined as time from treatment initiation to death, described using the Kaplan Meier method
Time frame: Up to 36 months
Population: 12 patients were treated with TIL. 1 patient was not evaluable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: TIL + IFNalpha | Overall Survival | 11.75 months |
Secondary
Progression Free Survival
Progression free survival (PFS), defined as the time from treatment initiation to disease progression, relapse or death due to any cause, which ever comes first, will be described with the Kaplan Meier method.
Time frame: Up to 36 months
Population: 12 patients were treated with TIL. 1 patient was not evaluable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: TIL + IFNalpha | Progression Free Survival | 2.8 months |
Secondary
Treatment Related Immune Responses
Number of participants with detectable in vitro immune responses in the TIL infusion product using intracellular flow cytometry.
Time frame: Up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: TIL + IFNalpha | Treatment Related Immune Responses | 6 Participants |