Metastatic Melanoma
Conditions
Brief summary
Background: Adoptive T cell therapy with tumor infiltrating lymphocytes (TILs) has been reported to induce durable clinical responses in patients with metastatic melanoma. From patients own tumor material T cells are extracted, expanded and activated in vitro in a 4-6 weeks culture period. Before TIL infusion patients are preconditioned with a lymphodepleting chemotherapeutic regimen. After TIL infusion, patients are treated with IL-2 to support T cell activation and expansion in vivo. The BRAF inhibitor is an approved treatment of metastatic melanoma and functions by selectively inhibiting the BRAF mutated enzyme, consequently halting the proliferation of tumor cells. Furthermore, in vitro tests have shown that vemurafenib has immunomodulatory effects that are hypothesized to synergize with TIL therapy, which has been confirmed in animal studies. Objectives: * To evaluate safety and feasibility when combining vemurafenib and ACT with TILs. * To evaluate treatment related immune responses * To evaluate clinical efficacy Design: * Patients will be screened with a physical exam, medical history, blood samples and ECG. * Patients will start vemurafenib 960 mg BID and will continue during TIL preparation. * 7 days after start of vemurafenib, patients will undergo surgery to harvest tumor material for TIL production. * Patient stops vemurafenib and is admitted day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. * On day 0 patients receive TIL infusion and shortly after starts IL-2 infusion continually following the decrescendo regimen. * The patients will followed until progression or up to 5 years.
Interventions
DRUGVemurafenib
Vemurafenib is used to treat patients with BRAF mutated metastatic melanoma. Patients will start treatment in a dose of 960 BID 7 days before tumor harvest and ends at the day of admission (day -8).
First patients undergo lymphodepleting chemotherapy regimen consisting of cyclophosphamide 60 mg/kg for 2 days and fludarabine 25 mg/m2 for 5 days (constitutes day -7 to -1 of admission).
DRUGTIL infusion
7 days after start of vemurafenib treatment, patients undergo surgery to removal of a tumor in order to isolate, activate and expand tumor infiltrating lymphocytes (TIL) to high numbers. In vitro preparation usually takes 4-6 weeks using the young TIL method. On day 0 patients receive an infusion of TIL (1x10e9-2x10e11 cells).
DRUGInterleukin-2
After infusion of TILs, patients will receive interleukin-2 infusions according to the decrescendo regimen (18 MIU/m2 for 6 hours, 18 MIU/m2 for 12 hours, 18 MIU/m2 for 24 hours followed by 4,5 MIU/m2 for another 3 x 24 hours)
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 measureable disease after resection. * Pathologically verified BRAF mutation. * ECOG performance status 0-1. * Life expectancy ≥ 3 months. * No significant toxicity (CTC ≤ 1) 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 of 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 metastasis can participate if surgically removed or treated with stereotactic radiotherapy if stable \> 28 days after treatment measured by MRI. Patients with asymptomatic and untreated CNS metastasis can participate based on investigators evaluation. * Patients with ocular melanoma. * Previous treatment with a BRAF inhibitor. * Severe allergies, history of anaphylaxis or known allergies to drugs administered. * Serious medical or psychiatric comorbidity. * QTc ≥ 450 ms. * Clearance \< 70 ml/min. * Acute or chronic infection with e.g. HIV, hepatitis, tuberculosis * Active autoimmune disease. * Pregnant og nursing women. * Need for immunosuppressive treatment, e.g. corticosteroids or methotrexate. * Concomitant treatment with other experimental drugs. * Patients with uncontrolled hypercalcemia * More than four weeks must have elapsed since any prior systemic therapy at the time of treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Reported Adverse Events | 0-40 weeks | Determine the safety of the administration of vemurafenib in combination with TIL therapy including lymphodepleting chemotherapy and interleukin-2 treatment by collecting adverse events according to CTCAE v. 4.0. From start of treatment until 24 weeks after T cell infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 40 months | Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve. |
| Treatment Related Immune Responses | 0-24 weeks | Number of patients whose infusion product contained anti-tumor reactive T cells by in vitro testing. Anti-tumor reactive T cells is defined by positive staining for two of the three markers (interferon gamma, tumor necrosis factor alpha and CD107a) in an intracellular cytokine staining using flow cytometry. |
| Objective Response Rate | Up to 12 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
| Progression Free Survival | Up to 40 months | Progression-free survival (PFS), defined as the time from start of treatment to disease progression, relapse or death due to any cause, whichever is earlier, will be described with the Kaplan-Meier curve. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Countries
Denmark
Participant flow
Pre-assignment details
One patient was enrolled in the trial and started vemurafenib, but had rapid progression of a brain metastasis and it was deemed unsafe to continue with protocol treatment. Thus, the patient was excluded before receiving T cell infusion and did not complete treatment.
Participants by arm
| Arm | Count |
|---|---|
| T Cell Therapy With Vemurafenib Pretreatment 7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2.
Vemurafenib: Patients will start treatment in a dose of 960 BID 7 days before tumor harvest and ends at the day of admission (day -8).
Lymphodepleting chemotherapy regimen consisting of cyclophosphamide 60 mg/kg for 2 days and fludarabine 25 mg/m2 for 5 days (constitutes day -7 to -1 of admission).
TIL infusion: A tumor is surgically removed in order to isolate, activate and expand tumor infiltrating lymphocytes (TIL) to high numbers. In vitro preparation usually takes 4-6 weeks using the young TIL method.
On day 0 patients receive an infusion of TIL (1x10e9-2x10e11 cells).
Interleukin-2 is administered according to the decrescendo regimen (18 MIU/m2 for 6 hours, 18 MIU/m2 for 12 hours, 18 MIU/m2 for 24 hours followed by 4,5 MIU/m2 for another 3 x 24 hours) | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | T Cell Therapy With Vemurafenib Pretreatment | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 2 Participants | — |
| Age, Categorical Between 18 and 65 years | 10 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 5 Participants | — |
| Sex: Female, Male Male | 7 Participants | — |
| Stage at inclusion M1a | 1 Participants | — |
| Stage at inclusion M1b | 1 Participants | — |
| Stage at inclusion M1c | 10 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 4 / 12 |
Outcome results
Primary
Number of Reported Adverse Events
Determine the safety of the administration of vemurafenib in combination with TIL therapy including lymphodepleting chemotherapy and interleukin-2 treatment by collecting adverse events according to CTCAE v. 4.0. From start of treatment until 24 weeks after T cell infusion.
Time frame: 0-40 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Therapy With Vemurafenib Pretreatment | Number of Reported Adverse Events | Total | 124 Treatment related adverse events |
| T Cell Therapy With Vemurafenib Pretreatment | Number of Reported Adverse Events | Grade 1-2 | 89 Treatment related adverse events |
| T Cell Therapy With Vemurafenib Pretreatment | Number of Reported Adverse Events | Grade 3-4 | 35 Treatment related adverse events |
Secondary
Objective Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: Up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T Cell Therapy With Vemurafenib Pretreatment | Objective Response Rate | 9 Participants |
Secondary
Overall Survival
Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve.
Time frame: Up to 40 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T Cell Therapy With Vemurafenib Pretreatment | Overall Survival | 28.8 Months |
Secondary
Progression Free Survival
Progression-free survival (PFS), defined as the time from start of treatment to disease progression, relapse or death due to any cause, whichever is earlier, will be described with the Kaplan-Meier curve. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Up to 40 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T Cell Therapy With Vemurafenib Pretreatment | Progression Free Survival | 4.8 Months |
Secondary
Treatment Related Immune Responses
Number of patients whose infusion product contained anti-tumor reactive T cells by in vitro testing. Anti-tumor reactive T cells is defined by positive staining for two of the three markers (interferon gamma, tumor necrosis factor alpha and CD107a) in an intracellular cytokine staining using flow cytometry.
Time frame: 0-24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T Cell Therapy With Vemurafenib Pretreatment | Treatment Related Immune Responses | 10 Participants |