a pilot study of genetically engineered ny-eso-1 specific ny-eso-1ᶜ²⁵⁹t in hla-a2+ patients with synovial sarcoma

Conditions: Neoplasms

Summary: the purpose of this early (pilot) clinical trial is to test the effects (both good and bad) of chemotherapy and adoptive immunotherapy with t cells engineered to recognize ny-eso-1 peptide in patients with unresectable, metastatic or recurrent synovial sarcoma.

design * patients will undergo apheresis at the enrolling institution. pbmc will be shipped to a central manufacturer for gene transduction, activation and expansion, then cryopreserved and shipped back to the enrolling institution. * the trial seeks to enroll up to 65 patients, that is, up to 20 patients in cohort 1 and up to 15 patients in cohorts 2-4. depending on the cohort patients are enrolled in, patients will undergo lymphodepletion with cyclophosphamide with or without fludarabine. * cohort 1: complete * cohort 2: up to 15 patients may be enrolled to achieve at least 10 evaluable patients treated with ny-eso-1ᶜ²⁵⁹t. patients will undergo lymphodepletion with cyclophosphamide plus fludarabine on days -3 and -2, and without fludarabine on days -5 and -4. * cohort 3: up to 15 patients may be enrolled to achieve at least 10 evaluable patients treated with ny-eso-1ᶜ²⁵⁹t. patients will undergo lymphodepletion with cyclophosphamide only on days -3 and -2. (cohort complete) * cohort 4: up to 15 patients may be enrolled to achieve at least 5 evaluable patients treated with ny-eso-1ᶜ²⁵⁹t. patients will undergo lymphodepletion with cyclophosphamide plus fludarabine on days -7 to -5. on day 0, patients ≥40 kg will receive the minimum cell dose of at least 1x10⁹ transduced ny-eso-1ᶜ²⁵⁹t cells with a maximum of 6x10⁹ transduced cells. the target dose for this protocol is 5x10⁹ transduced ny-eso-1ᶜ²⁵⁹t cells. patients \<40 kg will be dosed per body weight with a minimum 0.025x10⁹ transduced cells/kg, with a target dose of 0.125 x10⁹ transduced cells/kg. * patients will be monitored for toxicity, antitumor effects and immune endpoints. * patients who have a confirmed response, or have stable disease for \>3 months then progress may receive a 2nd t cell infusion, provided eligibility criteria are met. the 2nd treatment cell infusion will be administered in the same manner as the first. patients who meet the eligibility criteria may receive a 2nd infusion of ny-eso-1ᶜ²⁵⁹t no sooner than 60 days and no later than 2 years following completion of the first treatment.

Eligibility criteria:
inclusion criteria: * synovial sarcoma that has been treated with standard chemotherapy containing ifosfamide and/or doxorubicin and remains: unresectable or metastatic or progressive/persistent or recurrent disease * measurable disease * patients must have proven positive tumor sample for ny-eso-1 as follows: * cohort 1 -positive expression is defined as 2+ and/or 3+ by immunohistochemistry in ≥ 50% of cells. * cohort 2 -positive expression is defined as ≥1+ by immunohistochemistry in ≥1% cells, but not to exceed 2+ and/or 3+ in ≥ 50% of cells. * cohort 3 -positive expression is defined as 2+ and/or 3+ by immunohistochemistry in ≥ 50% of cells. * cohort 4 -positive expression is defined as 2+ and/or 3+ by immunohistochemistry in ≥ 50% of cells. * hla-a\*02:01, hla-a\*02:05, and/or hla-a\*02:06 by high resolution testing at a local or central laboratory * weigh more than 18 kg * all previous cytotoxic chemotherapy, monoclonal antibody therapy, or immune therapy must be washed out 3 weeks before apheresis and must be completed at least 3 weeks prior to pre-infusion lymphodepletive chemotherapy. * systemic corticosteroid or other immunosuppressive therapy should be washed out 2 weeks before apheresis and must be completed at least 2 weeks prior to pre-infusion lymphodepletive chemotherapy. * biologic or other approved molecular targeted small molecule inhibitors should be washed out 1 week or 5 half-lives (whichever is longer) before apheresis and must be completed at least 1 week or 5 half-lives (whichever is longer) prior to pre-infusion lymphodepletive chemotherapy. * any grade 3 or 4 hematologic toxicity of any previous therapy must have resolved to grade 2 or less prior to apheresis and any grade 3 or 4 toxicity must have resolved to grade 2 or less prior to pre-infusion lymphodepletive chemotherapy. * ecog 0-1, or for children ≤10 years of age, lansky \> 60 * life expectancy \> 3 months * left ventricular ejection fraction ≥ 40% or fractional shortening ≥ 28% * t. bilirubin \< 2 mg/dl (patients with gilbert syndrome total bilirubin \<3xuln and direct bilirubin ≤ 35%) * ast, alt ≤ 2.5 x upper limit of normal * anc ≥ 1.0 x 10⁹/l * platelets ≥ 75 x 10⁹/l * age-adjusted normal serum creatinine or a creatinine clearance ≥ 40 ml/min * ability to give informed consent for patients greater than 18 years of age. for patients less than 18 years of age the legal guardian must give informed consent. * male patients must be willing to practice birth control (including abstinence) during and for 4 months after treatment. female patients must be willing to practice birth control (including abstinence) during treatment and for 4 months after gene modified cells are no longer detected in body. exclusion criteria: * active hiv, hbv, hcv or htlv 1/2 infection (due to increased risk of complications during lymphodepleting regimen and confounding effects on the immune system). active hepatitis b or c infection is defined by seropositive for hepatitis b surface antigen (hbsag) or hepatitis c antibody.

Keywords: t cell receptor sarcoma cell therapy t cell therapy previously treated ny-eso-1 metastatic immuno-oncology