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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

About this trial

This is an interventional treatment trial for Stage IV Skin Melanoma focused on measuring Melanoma, TCR

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Intervention Type

Biological

Intervention Name(s)

TCR transduced T-cells

Intervention Description

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

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

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

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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