Back to resultsVemurafenib and TIL Therapy for Metastatic Melanoma
Primary Purpose
Metastatic Melanoma
Status
Completed
Phase
Phase 1
Locations
Denmark
Study Type
Interventional
Intervention
Vemurafenib
Lymphodepleting chemotherapy
TIL infusion
Interleukin-2
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Melanoma
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
Sites / Locations
- Center for Cancer Immune Therapy, Dept. of Haematology/Oncology
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
A
Arm Description
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.
Outcomes
Primary Outcome Measures
Number of Reported Adverse Events
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 Outcome Measures
Treatment Related Immune Responses
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
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
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
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02354690
Brief Title
Vemurafenib and TIL Therapy for Metastatic Melanoma
Official Title
T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
November 2014 (Actual)
Primary Completion Date
December 31, 2018 (Actual)
Study Completion Date
December 31, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Inge Marie Svane
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Vemurafenib
Other Intervention Name(s)
Zelboraf, BRAF inhibitor
Intervention Description
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
Intervention Name(s)
Lymphodepleting chemotherapy
Other Intervention Name(s)
cyclophosphamide, fludarabine
Intervention Description
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
Intervention Name(s)
TIL infusion
Other Intervention Name(s)
Adoptive cell transfer, T cell therapy
Intervention Description
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
Intervention Name(s)
Interleukin-2
Other Intervention Name(s)
IL-2
Intervention Description
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)
Primary Outcome Measure Information:
Title
Number of Reported Adverse Events
Description
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.
Time Frame
0-40 weeks
Secondary Outcome Measure Information:
Title
Treatment Related Immune Responses
Description
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.
Time Frame
0-24 weeks
Title
Objective Response Rate
Description
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
Time Frame
Up to 12 months
Title
Overall Survival
Description
Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve.
Time Frame
Up to 40 months
Title
Progression Free Survival
Description
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.
Time Frame
Up to 40 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Inge Marie Svane, Prof., MD
Organizational Affiliation
Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Troels Holz Borch, MD
Organizational Affiliation
Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark
Official's Role
Principal Investigator
Facility Information:
Facility Name
Center for Cancer Immune Therapy, Dept. of Haematology/Oncology
City
Copenhagen
State/Province
Herlev
ZIP/Postal Code
2730
Country
Denmark
12. IPD Sharing Statement
Citations:
PubMed Identifier
32747469
Citation
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.
Results Reference
derived
Learn more about this trial
Vemurafenib and TIL Therapy for Metastatic Melanoma
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