- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02354690
Vemurafenib and TIL Therapy for Metastatic Melanoma
T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated 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.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Herlev
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Copenhagen, Herlev, Denmark, 2730
- Center for Cancer Immune Therapy, Dept. of Haematology/Oncology
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: 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.
|
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:
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:
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:
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:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
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0-40 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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. |
0-24 weeks
|
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
|
Up to 12 months
|
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.
|
Up to 40 months
|
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. |
Up to 40 months
|
Collaborators and Investigators
Sponsor
Investigators
- 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
Publications and helpful links
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroendocrine Tumors
- Nevi and Melanomas
- Melanoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Analgesics, Non-Narcotic
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Protein Kinase Inhibitors
- Cyclophosphamide
- Fludarabine
- Interleukin-2
- Vemurafenib
Other Study ID Numbers
- MM1414
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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