A Phase I/II Study to Assess the Safety and Activity of Enhanced TCR Transduced Autologous T cells against Cancer-testis Antigens in Metastatic Melanoma
Trial Purpose and Description
This proof of concept (phase 1) clinical trial will test the hypothesis that enhanced TCRs are safe and can promote tumor regression after non-myeloablative chemotherapy in patients with metastatic melanoma. This trial incorporates several improvements in T cell manufacturing that should streamline the development of adoptive T cell therapy. In addition, extensive correlative laboratory studies are included for proof of concept.The primary efficacy endpoints are response by RECIST criteria and progression free survival. There will be 6 patients in each of 2 study groups (NY-ESO-1 positive and MAGE-3 positive), and the goal is to estimate the efficacy endpoints within each group, rather than comparing them with one another. In this case, the effective sample size for each test or confidence interval is 6 patients.
- 18 Years and older
- Patients must have histologically or cytologically confirmed melanoma stage III/IV, unresectable.
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with spiral CT scan.
- One prior cytotoxic therapy for the treatment of metastatic disease is allowed.
- Unlimited regimens using biological agents (vaccines), immunotherapy, or targeted agents is permitted. For example, BRAF inhibitors and ipilimumab are permitted.
- Patients must have fully recovered from the acute toxicities related to any prior therapy. Prior therapy must be completed >28 days before the first dose of cyclophosphamide.
- Age >18 years.
- Because no dosing or adverse event data are currently available on the use of TCR gene therapy with the A3A or the C259 receptor in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric phase 2 trials.
- Life expectancy of greater than 3 months.
- Tumor must express the cancer-testis antigen as determined by the study laboratory. The patient must express HLA class I allele HLA-A*0201 for NY-ESO-1/LAGE. Tumor antigen expression analysis will be provided to the PI by a qualified central laboratory (e.g. Cambridge Biomedical (CB).
- The effects of transduced T cells on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because cyclophosphamide is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control abstinence) prior to study entry, and for 18 months post treatment and the persistence of gene modified cells are not detected in the blood. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- Ability of the patient (or legally authorized representative if applicable) to understand and the willingness to sign a written informed consent document.
- Patients who have had 2 or more regimens containing cytotoxic chemotherapy for metastatic melanoma.
- Patients may not be receiving any other investigational agents.
- Patients with active brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide or other agents used in the study.
- Active infection.
- Prior malignancy (except non-melanoma skin cancer) within 3 years.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. All patients will undergo a cardiac stress test for evaluation of cardiac function. PI will use his/her discretion to choose the stress test best suited to evaluate the patient.
- Pregnant women are excluded from this study because cyclophosphamide has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cyclophosphamide, breastfeeding should be discontinued if the mother is treated with cyclophosphamide. These potential risks may also apply to other agents used in this study.
- Active infection with HIV, HBV or HCV, due to the immunosuppressive effects of cyclophosphamide used and the unknown risks associated with viral replication.
- Positive serology for HIV.
- Active Hepatitis B infection as determined by test for hepatitis B surface antigen.
- Active Hepatitis C. Patients will be screened for HCV antibody. If the HCV antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed at screening by a local laboratory with a CLIA certification or its equivalent. Eligibility will be determined based on a negative screening value. The test is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided.
- Adaptimmune LLC
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