Phase I clinical trial to determine the Phase II dose of autologous TIL 1383I TCR gene
modified T Cells using a retrovirus. This is a novel National Cancer Institute (NCI) funded
investigator initiated therapy for patients with advanced melanoma.
This is a Phase 1 dose escalation study designed to find the highest dose of TIL 1383I TCR
transduced T cells that can safely be given. Three cohorts of 3 patients will be treated with
increasing doses of TIL 1383I TCR transduced T cells. Patients will be monitored clinically
and immunologically for a year after infusion. Subjects in Cohort 1 will receive 7.5 X
10^6/kg TIL 1383I TCR transduced T cells. Subjects in Cohort 2 will receive 2.5 x 10^7/kg TIL
1383I TCR transduced T cells. Subjects in Cohort 3 will receive 7.5 x 10^7/kg TIL 1383I TCR
transduced T cells.
Inclusion Criteria:
- Patients must have a diagnosis of metastatic melanoma which is evaluable either
clinically or radiologically.
- Patients must be 18 years of age or older.
- Patients must consent to be in the study and must have signed and dated an approved
consent form, which conforms to federal and institutional guidelines.
- Patients must have a performance status (PS) of 0 or 1 ECOG PS scale.
- Patients must have the ability to provide written informed consent prior to study
specific screening procedures, with the understanding that the patient has the right
to withdraw from the study at any time.
- Patients melanoma must be positive for both tyrosinase and HLA-A2 pathologic review
from FNA, core or excisional biopsy of lesion.
- Cardiac ejection fraction greater than 50 percent as determined by screening
echocardiogram.
- Patients that have undergone treatment with anti-CTLA-4, Cytotoxic T-Lymphocyte
Antigen 4, antibody must have at least 6 weeks from last dose of CTLA-4 antibody and
evidence of tumor progression before they can be enrolled into this study.
- Patients that have undergone treatment with anti-PD-1, Programmed Death Receptor 1,
Blockade or anti-PD-L1 antibody must have at least 4 weeks from last dose of antibody
and evidence of tumor progression before they can be treated in this study.
- Patients with V600E mutations are eligible if they have failed an approved BRAF
inhibitor or MEK inhibitor therapy or have refused treatment with an approved BRAF
inhibitor or MEK inhibitor.
- Patients treated with prior Interleukin-2 (IL-2) are eligible.
- Sufficient cardiopulmonary reserve for IL-2 per institutional guidelines.
Exclusion Criteria:
- Special classes of subjects such as fetuses, pregnant women, children, prisoners,
institutionalized individuals, or others who are likely to be vulnerable.
- ECOG performance status of 2 or greater.
- Patients with a history metastatic melanoma involving the brain will be excluded if
they have active disease or have had active disease within the prior three months that
was not controlled with surgery or radiotherapy.
- Patients taking steroids for disease control or pain management
- Patients must not be pregnant or nursing because of the potentially harmful effects of
these agents on a developing fetus. Women or men of reproductive potential must have
agreed to use an effective contraceptive method.
- Patients whose BRAF V600 mutation status is unknown should undergo an attempt to
determine this information, patients who have a BRAF V600 mutation and are responding
to BRAF with or without MEK inhibitor therapy, or have a BRAF V600 mutation and have
not been offered the option of receiving BRAF with or without MEK inhibitor therapy
for the treatment of their melanoma are excluded.
- No prior malignancy is allowed except for the following- adequately treated basal cell
or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or
II cancer from which the patient is currently in complete remission, or any other
cancer from which the patient has been disease-free for two years.
- Patients that have undergone immunotherapy targeting tyrosinase.
- Patients that have undergone immunotherapy in combination with non-myeloablative
chemotherapy.
- Any of the following abnormal laboratory values Absolute neutrophil count less than
1.5 x 10^9/L Platelet count less than 100 x 10^9/L Serum bilirubin greater than 1.5 x
upper limit of normal ULN Serum ALT, AST greater than 2.5 x ULN Serum ALP greater than
2 x ULN Serum Albumin less than 2.5 g dL International Normalized Ratio, INR greater
than 1.5 Serum creatinine calculated creatinine clearance by the method of Cockcroft
and Gault, less than 50mL min.
- Patients should not have any evidence of active or uncontrolled infection requiring
treatment with antibiotics.
- Any severe or poorly controlled systemic disease, for example hypertension, clinically
significant cardiovascular, pulmonary, or metabolic disease, disorders of
wound-healing, ulcer or bone fracture.
- Patients who have received any chemotherapy or investigational treatment within 4
weeks of study start.
- Known infection with HIV, HBV, or HCV.
- Known hypersensitivity to any of the components of the study drugs.
- Patients assessed by the investigator to be unable or unwilling to comply with the
requirements of the protocol.
