Clinical trial NCT01343043: A Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO-1ᶜ²⁵⁹T in HLA-A2+ Patients With Synovial Sarcoma
Official title: A Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO-1ᶜ²⁵⁹T in HLA-A2+ Patients With Synovial Sarcoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Keywords: T Cell Receptor
Sarcoma
Cell Therapy
T Cell Therapy
Previously treated
NY-ESO-1
Metastatic
Immuno-oncology
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-04-27
Enrollment: 50
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to 4.5 years
Secondary outcomes:
measure: Duration of Overall Response
timeFrame: Up to 4.5 years
measure: Progression Free Survival
timeFrame: Up to 4.5 years
measure: Best Overall Response
timeFrame: Up to 4.5 years
measure: Overall Survival
timeFrame: Up to 4.5 years
measure: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 5 years
measure: Number of Participants With Worst Post-Baseline Grade Results for Hematology Parameters
timeFrame: Up to 4.5 years
measure: Number of Participants With Worst Post-Baseline Grade Results for Clinical Chemistry Parameters
timeFrame: Up to 4.5 years
measure: Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-infused (NY-ESO-1 Genetically Engineered T) Cell Antibody Result
timeFrame: Up to 4.5 years
measure: Concentration of Cytokines in Cytokine Release Syndrome (CRS) by CRS Status: Cohort 1: High NY-ESO-1 Expression Treated With Regimen A
timeFrame: Up to Week 4
measure: Concentration of Cytokines in CRS by CRS Status: Cohort 2: Low NY-ESO-1 Expression Treated With Regimen A
timeFrame: Up to Week 4
measure: Concentration of Cytokines in CRS by CRS Status: Cohort 3: High NY-ESO-1 Expression Treated With Regimen B
timeFrame: Up to Week 4
measure: Concentration of Cytokines in CRS by CRS Status: Cohort 4: High NY-ESO-1 Expression Treated With Regimen C
timeFrame: Up to Week 4
measure: Time to Maximum Persistence of NY-ESO-1 Genetically Engineered T Cells
timeFrame: Up to 4.5 years
Other outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Up to Day 21 (from first dose)
measure: Number of Participants With Clinically Significant Abnormal Electrocardiogram, Echocardiogram and Multigated Acquisition Scan Findings
timeFrame: Up to 4.5 years
measure: Percentage of Participants With Confirmed CR
timeFrame: Up to 4.5 years
Locations:
city: Duarte
country: United States
facility: GSK Investigational Site
state: California
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Bethesda
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Gyurdieva A, Zajic S, Chang YF, Houseman EA, Zhong S, Kim J, Nathenson M, Faitg T, Woessner M, Turner DC, Hasan AN, Glod J, Kaplan RN, D'Angelo SP, Araujo DM, Chow WA, Druta M, Demetri GD, Van Tine BA, Grupp SA, Fine GD, Eleftheriadou I. Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma. Nat Commun. 2022 Sep 8;13(1):5296. doi: 10.1038/s41467-022-32491-x.
citation: Ramachandran I, Lowther DE, Dryer-Minnerly R, Wang R, Fayngerts S, Nunez D, Betts G, Bath N, Tipping AJ, Melchiori L, Navenot JM, Glod J, Mackall CL, D'Angelo SP, Araujo DM, Chow WA, Demetri GD, Druta M, Van Tine BA, Grupp SA, Abdul Razak AR, Wilky B, Iyengar M, Trivedi T, Winkle EV, Chagin K, Amado R, Binder GK, Basu S. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. J Immunother Cancer. 2019 Oct 24;7(1):276. doi: 10.1186/s40425-019-0762-2.
citation: D'Angelo SP, Melchiori L, Merchant MS, Bernstein D, Glod J, Kaplan R, Grupp S, Tap WD, Chagin K, Binder GK, Basu S, Lowther DE, Wang R, Bath N, Tipping A, Betts G, Ramachandran I, Navenot JM, Zhang H, Wells DK, Van Winkle E, Kari G, Trivedi T, Holdich T, Pandite L, Amado R, Mackall CL. Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma. Cancer Discov. 2018 Aug;8(8):944-957. doi: 10.1158/2159-8290.CD-17-1417. Epub 2018 Jun 11.