Vemurafenib and TIL Therapy for Metastatic Melanoma

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.

Conditions

• Metastatic Melanoma

Interventions

DRUG

Vemurafenib

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).

DRUG

Interleukin-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 & Collaborators

• Inge Marie Svane

  lead OTHER

Principal Investigators

• Inge Marie Svane, Prof., MD · Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark

• Troels Holz Borch, MD · Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-11-30

Primary Completion

2018-12-31

Completion

2018-12-31

Countries

• Denmark

Study Locations