Study With T-cel Receptor Gene Therapy in Metastatic Melanoma (TCR)
Primary Purpose
Stage IV Skin Melanoma, Eye; Melanoma
Status
Unknown status
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
TCR transduced T-cells
Biopsy
Blood taking
Sponsored by
About this trial
This is an interventional treatment trial for Stage IV Skin Melanoma focused on measuring Melanoma, TCR
Eligibility Criteria
Inclusion Criteria:
- Patients must be ≥ 18 years of age.
- Patients must have inoperable stage IIIc or stage IV melanoma (AJCC), including ocular or mucosal melanoma, progressing after standard of care therapy, if available.
- Patients must be HLA-A*0201 positive.
- The primary tumor and/or metastasis have to be positive for MART-1 (>10% of tumor cells).
- Patients with measurable disease (RECIST 1.1)
- Patients must have a clinical performance status of ECOG 0 or 1.
- Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen.
- Patients must be able to understand and sign the Informed Consent document. Specific lab values
Exclusion Criteria:
- Life expectancy of less than three months.
- Requirement for systemic steroid therapy.
- Patients who have a history of CNS metastases.
- Patients with malignant pleural effusion or ascites.
- Any immunosuppressive chemotherapy or systemic steroid therapy within the last 3 weeks.
- Patients who have: history of coronary revascularization, documented LVEF of less than 45%, clinically significant atrial and/or ventricular arrhythmias including but not limited to atrial fibrillation, ventricular tachycardia, 2° or 3° heart block, documented FEV1 less than or equal to 60% predicted for patients with a history of cigarette smoking (greater than 20 pack/year within the past 2 years) and with symptoms of respiratory distress
- All patients' toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less.
- Women who are pregnant or breastfeeding, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. A negative pregnancy test before inclusion in the trial is required for all women of child bearing potential.
- Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune disease requiring anti-TNF treatment.
Sites / Locations
- Antoni van Leeuwenhoek ziekenhuis
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
TCR treatment
Arm Description
Eligible patients will undergo leukapheresis to isolate autologous T cells. These T cells will be transduced with a retroviral vector encoding the 1D3 HM CysTCR, and subsequently expanded during short-term ex vivo culture. Following pre-treatment with nonmyeloablative chemotherapy, patients will receive the adoptive transfer of autologous, TCR transduced T cells.
Outcomes
Primary Outcome Measures
Safety of the TCR treatment (according to CTCAE 4.0)
Safety of the TCR treatment will be measured by noting the toxicity (according to CTCAE 4.0) that the patient experiences while on treatment.
Objective response rate according to RECIST 1.1.
The objective response rate will be measured by RECIST 1.1.
Secondary Outcome Measures
1-year progression free survival (PFS)
1-year PFS will we measured by the number of patients still free of disease after 1 year, using RECIST 1.1 to measure progressive disease
Efficacy of induction of tumor specific T cell responses as measured by the persistence of Melan-A/MART1 specific T cells in peripheral blood samples
Efficacy of induction of tumor specific T cell responses as measured by the persistence of Melan-A/MART1 specific T cells in peripheral blood samples at several time points following adoptive transfer and in tumor biopsies when possible.
Overall survival
Systemic release of inflammatory cytokines after administration of transduced T cells compared to baseline
To study whether the infusion of MART-1 specific TCR (1D3 HMCys) transduced T cells will lead to systemic release of inflammatory cytokines.
Full Information
NCT ID
NCT02654821
First Posted
January 8, 2016
Last Updated
October 31, 2018
Sponsor
The Netherlands Cancer Institute
1. Study Identification
Unique Protocol Identification Number
NCT02654821
Brief Title
Study With T-cel Receptor Gene Therapy in Metastatic Melanoma
Acronym
TCR
Official Title
Multicenter Phase I/IIa Study Using T-cell Receptor Gene Therapy in Metastatic Melanoma
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Unknown status
Study Start Date
March 2012 (Actual)
Primary Completion Date
October 2019 (Anticipated)
Study Completion Date
January 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Netherlands Cancer Institute
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Patients with stage IV melanoma (also eye melanoma) will be treated with TCR transduced cells.
Detailed Description
In this multicenter phase I/IIa trial 25 patients will be treated with non-myeloablative chemotherapy followed by adoptive transfer of autologous TCR transduced T cells, to study the feasibility, safety and efficacy of this treatment.
Patients will receive a non-myeloablative lymphocyte-depleting preparative regimen consisting of cyclophosphamide (60 or 30 mg/kg/day x 2 days i.v.) and fludarabine (25 mg/m2/day i.v. x 5 days). Following this regimen, patients will receive one single intravenous adoptive transfer of transduced T cells starting with the first dose level.
Dose level 1: 5x10^7 transduced T cells, cyclophosphamide 60 mg/kg/day
Dose level 1a: 1,0x10^8 transduced T cells, cyclophosphamide 30 mg/kg/day
Dose level 2: 2,5x10^8 transduced T cells, cyclophosphamide 60 mg/kg/day
Dose level 3: maximum 1x10^9 transduced T cells (depending on production yield). At time points 4, 8, and 12 weeks and every 3 months thereafter patients will be evaluated for response to treatment. After 3 patients have been treated in each dose level, but not before 8 weeks after the last patient has been infused with transduced T cells, the DSMB will be informed about the observed toxicity and efficacy within this cohort and decide, based on this information, whether the trial will be continued to the next dose level or will continue in the current dose level. The study will continue as the first stage (2-stage Simon), until a total of 16 patients have been enrolled and treated: if less than 2 responses are observed, the trial will be stopped and the conclusion will be that TCR lacks efficacy. Otherwise, the trial will continue its second stage. In addition, safety data after these first 16 patients will be evaluated by the DSMB. Any unexpected or serious (grade 3/4 or higher) toxicities during the trial, will be reported immediately to the DSMB and CCMO. Second stage: overall 25 patients will be enrolled (including the first stage): if the total number of responses for the two stages combined is less than 5, the trial will be stopped as soon as this is evident and the conclusion will be that TCR lacks efficacy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stage IV Skin Melanoma, Eye; Melanoma
Keywords
Melanoma, TCR
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
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TCR treatment
Arm Type
Experimental
Arm Description
Eligible patients will undergo leukapheresis to isolate autologous T cells. These T cells will be transduced with a retroviral vector encoding the 1D3 HM CysTCR, and subsequently expanded during short-term ex vivo culture. Following pre-treatment with nonmyeloablative chemotherapy, patients will receive the adoptive transfer of autologous, TCR transduced T cells.
Intervention Type
Biological
Intervention Name(s)
TCR transduced T-cells
Intervention Description
Eligible patients will undergo leukapheresis to isolate autologous T cells. These T cells will be transduced with a retroviral vector encoding the 1D3 HM CysTCR, and subsequently expanded during short-term ex vivo culture. Following pre-treatment with nonmyeloablative chemotherapy, patients will receive the adoptive transfer of autologous, TCR transduced T cells.
Intervention Type
Procedure
Intervention Name(s)
Biopsy
Intervention Description
During screening, after treatment and at time of regression/progression a biopsy will be taken for translational research.
Intervention Type
Procedure
Intervention Name(s)
Blood taking
Intervention Description
During screening, after the infusion with T-cells, after treatment and at time of regression/progression blood will be taken for translational research.
Primary Outcome Measure Information:
Title
Safety of the TCR treatment (according to CTCAE 4.0)
Description
Safety of the TCR treatment will be measured by noting the toxicity (according to CTCAE 4.0) that the patient experiences while on treatment.
Time Frame
Baseline until release from the hospital, about 4 weeks.
Title
Objective response rate according to RECIST 1.1.
Description
The objective response rate will be measured by RECIST 1.1.
Time Frame
Baseline until progressive disease, median 6 months.
Secondary Outcome Measure Information:
Title
1-year progression free survival (PFS)
Description
1-year PFS will we measured by the number of patients still free of disease after 1 year, using RECIST 1.1 to measure progressive disease
Time Frame
Baseline until 1 year after treatment.
Title
Efficacy of induction of tumor specific T cell responses as measured by the persistence of Melan-A/MART1 specific T cells in peripheral blood samples
Description
Efficacy of induction of tumor specific T cell responses as measured by the persistence of Melan-A/MART1 specific T cells in peripheral blood samples at several time points following adoptive transfer and in tumor biopsies when possible.
Time Frame
Baseline until progressive disease, median 6 months.
Title
Overall survival
Time Frame
Assessed up to 12 months
Title
Systemic release of inflammatory cytokines after administration of transduced T cells compared to baseline
Description
To study whether the infusion of MART-1 specific TCR (1D3 HMCys) transduced T cells will lead to systemic release of inflammatory cytokines.
Time Frame
Baseline until progressive disease, median 6 months.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients must be ≥ 18 years of age.
Patients must have inoperable stage IIIc or stage IV melanoma (AJCC), including ocular or mucosal melanoma, progressing after standard of care therapy, if available.
Patients must be HLA-A*0201 positive.
The primary tumor and/or metastasis have to be positive for MART-1 (>10% of tumor cells).
Patients with measurable disease (RECIST 1.1)
Patients must have a clinical performance status of ECOG 0 or 1.
Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen.
Patients must be able to understand and sign the Informed Consent document. Specific lab values
Exclusion Criteria:
Life expectancy of less than three months.
Requirement for systemic steroid therapy.
Patients who have a history of CNS metastases.
Patients with malignant pleural effusion or ascites.
Any immunosuppressive chemotherapy or systemic steroid therapy within the last 3 weeks.
Patients who have: history of coronary revascularization, documented LVEF of less than 45%, clinically significant atrial and/or ventricular arrhythmias including but not limited to atrial fibrillation, ventricular tachycardia, 2° or 3° heart block, documented FEV1 less than or equal to 60% predicted for patients with a history of cigarette smoking (greater than 20 pack/year within the past 2 years) and with symptoms of respiratory distress
All patients' toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less.
Women who are pregnant or breastfeeding, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. A negative pregnancy test before inclusion in the trial is required for all women of child bearing potential.
Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune disease requiring anti-TNF treatment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John B.A.G. Haanen, Prof.
Organizational Affiliation
Antoni van Leeuwenhoek Ziekenhuis
Official's Role
Principal Investigator
Facility Information:
Facility Name
Antoni van Leeuwenhoek ziekenhuis
City
Amsterdam
State/Province
NH
ZIP/Postal Code
1066CX
Country
Netherlands
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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Study With T-cel Receptor Gene Therapy in Metastatic Melanoma
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