Vemurafenib and TIL Therapy for Metastatic Melanoma

NCT ID: NCT02354690

Last Updated: 2020-03-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-11-30
• Study Completion Date: 2018-12-31

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.

Conditions

Metastatic Melanoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

A

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.

Group Type: EXPERIMENTAL

Vemurafenib

Intervention Type: 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).

Lymphodepleting chemotherapy

Intervention Type: 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).

TIL infusion

Intervention Type: 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).

Interleukin-2

Intervention Type: 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)

Interventions

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).

Intervention Type: 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).

Intervention Type: 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).

Intervention Type: 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)

Intervention Type: DRUG

Other Intervention Names

Zelboraf; BRAF inhibitor; cyclophosphamide; fludarabine; Adoptive cell transfer; T cell therapy; IL-2

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Inge Marie Svane

OTHER

Sponsor Role: lead

Responsible Party

Inge Marie Svane

Professor, MD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Inge Marie Svane, Prof., MD

Role: STUDY_DIRECTOR

Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark

Troels Holz Borch, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark

Locations

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

Copenhagen, Herlev, Denmark

Countries

Denmark

References

Borch TH, Andersen R, Ellebaek E, Met O, Donia M, Svane IM. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer. 2020 Jul;8(2):e000668. doi: 10.1136/jitc-2020-000668.

Reference Type: DERIVED

PMID: 32747469 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MM1414

Identifier Type: -

Identifier Source: org_study_id