Vemurafenib and TIL Therapy for Metastatic Melanoma
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|ClinicalTrials.gov Identifier: NCT02354690|
Recruitment Status : Completed
First Posted : February 3, 2015
Results First Posted : February 24, 2020
Last Update Posted : March 23, 2020
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.
- To evaluate safety and feasibility when combining vemurafenib and ACT with TILs.
- To evaluate treatment related immune responses
- To evaluate clinical efficacy
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Melanoma||Drug: Vemurafenib Drug: Lymphodepleting chemotherapy Drug: TIL infusion Drug: Interleukin-2||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||13 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma|
|Actual Study Start Date :||November 2014|
|Actual Primary Completion Date :||December 31, 2018|
|Actual Study Completion Date :||December 31, 2018|
7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine, followed by TIL infusion and interleukin-2.
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).
Drug: Lymphodepleting chemotherapy
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).
Drug: TIL 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).
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)
Other Name: IL-2
- Number of Reported Adverse Events [ Time Frame: 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.
- Treatment Related Immune Responses [ Time Frame: 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 [ Time Frame: 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
- Overall Survival [ Time Frame: 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.
- Progression Free Survival [ Time Frame: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02354690
|Center for Cancer Immune Therapy, Dept. of Haematology/Oncology|
|Copenhagen, Herlev, Denmark, 2730|
|Study Director:||Inge Marie Svane, Prof., MD||Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark|
|Principal Investigator:||Troels Holz Borch, MD||Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark|