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Completed

NCT Number: NCT02354690

Vemurafenib and TIL Therapy for Metastatic Melanoma

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.

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Key information

Conditions

Metastatic Melanoma Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Center for Cancer Immune Therapy, Dept. of Haematology/Oncology

Copenhagen, Herlev, 2730, Denmark

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Vemurafenib

Drug

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).

Other names: Zelboraf, BRAF inhibitor

Lymphodepleting chemotherapy

Drug

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).

Other names: cyclophosphamide, fludarabine

TIL infusion

Drug

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).

Other names: Adoptive cell transfer, T cell therapy

Interleukin-2

Drug

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 names: IL-2

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. 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

  3. 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.

  4. 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.

Sponsors and collaborators

Lead sponsor

Inge Marie Svane

Other

Registry information

Official study title

T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma

Important dates

Study start
2014
Primary completion
2018
Study completion
2018
First posted
Feb 3, 2015
Registry last updated
Mar 23, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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