A Pilot Study of NY-ESO-1ᶜ²⁵⁹T Cells in Subjects With Advanced Myxoid/ Round Cell Liposarcoma

Study Description

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Brief Summary:

This study is for men and women who have a type of sarcoma that has returned after being treated, or that cannot be surgically removed. The specific type of sarcoma is Myxoid / Round Cell Liposarcoma, also known as High Grade Myxoid Liposarcoma.

In addition to this disease patients must also have the tissue type HLA-A*02:01, HLA-A*02:05 or HLA-A*02:06, and a sample of tumor tissue must test positive for the NY-ESO-1 protein.

The study treatment is made from some of the patient's own white blood cells called T cells. T cells are collected from the patient and sent to a laboratory to be genetically modified, with the aim that they will be able to destroy the cancer cells.

Manufacturing the T cells takes about 1 month to complete. The T cells will be given back to the patient by an intravenous infusion. The purpose of this study is to test whether the T cells have an effect on the cancer and to test whether the treatment can be given safely to patients with this disease.

Condition or disease	Intervention/treatment	Phase
Neoplasms	Genetic: Autologous genetically modified T Cells, NY-ESO-1ᶜ²⁵⁹T	Phase 2

Detailed Description:

This is an open label pilot study of gene modified autologous T cells for the treatment of advanced myxoid/ round cell liposarcoma or high-grade myxoid liposarcoma.

Subjects with the HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 allele, whose tumor expresses the NY-ESO-1 antigen and who meet study entry criteria will be eligible for enrollment. Following enrollment, subjects will undergo leukapheresis for collection of autologous cells for processing and manufacture into the NY-ESO-1ᶜ²⁵⁹T cell investigational product.

Leukapheresis is performed to obtain cells for the manufacture of autologous NY-ESO-1ᶜ²⁵⁹T cells. When the manufactured NY-ESO-1ᶜ²⁵⁹T cells are available, subjects will undergo lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by a single infusion of NY-ESO-1ᶜ²⁵⁹T (transduced cell range: 1 to 8 billion cells) that will be administered on Day 1.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	10 participants
Intervention Model:	Single Group Assignment
Primary Purpose:	Treatment
Official Title:	A Pilot Study of NY-ESO-1ᶜ²⁵⁹T Cells in Subjects With Advanced Myxoid/ Round Cell Liposarcoma
Actual Study Start Date :	December 6, 2016
Estimated Primary Completion Date :	June 26, 2020
Estimated Study Completion Date :	June 26, 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Autologous genetically modified T Cells, NY-ESO-1ᶜ²⁵⁹T; Genetic: Autologous genetically modified T Cells, NY-ESO-1ᶜ²⁵⁹T Cytoreductive chemotherapy followed by infusion with NY-ESO-1(c259) transduced autologous T cells. Subjects will receive one infusion of NY-ESO-1 genetically engineered T cells on Day 1.	Genetic: Autologous genetically modified T Cells, NY-ESO-1ᶜ²⁵⁹T; Cytoreductive chemotherapy followed by infusion with NY-ESO-1(c259) transduced autologous T cells. Subjects will receive one infusion of NY-ESO-1 genetically engineered T cells on Day 1.

Outcome Measures

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Primary Outcome Measures :

1. Proportion of subjects with a confirmed Complete Response (CR) or Partial Response (PR). [ Time Frame: 1 Year ]
   Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to RECIST v1.1.

Secondary Outcome Measures :

1. Interval between the date of first T cell infusion dose and first documented evidence of CR or PR. [ Time Frame: 1 Year ]
   Evaluation of the efficacy of the treatment by assessment of time to first response.
2. Interval between the date of first documented evidence of CR or PR until first documented disease progression or death due to any cause. [ Time Frame: 1 Year ]
   Evaluation of the efficacy of the treatment by assessment of duration of response.
3. Interval between the date of first documented evidence of SD until first documented disease progression or death due to any cause. [ Time Frame: 1 Year ]
   Evaluation of the efficacy of the treatment by assessment of duration of stable disease.
4. Interval between the date of first T cell infusion and the earliest date of disease progression or death due to any cause. [ Time Frame: 1 Year ]
   Evaluation of the efficacy of the treatment by assessment of progression-free survival.
5. Interval between the date of first T cell infusion and date of death due to any cause. [ Time Frame: 1 Year ]
   Evaluation of the efficacy of the treatment by assessment of overall survival.
6. Number of subjects with adverse events (AE), including serious adverse events (SAE). [ Time Frame: 1 Year ]
   Determine if treatment with autologous genetically modified T cells (NY-ESO-1ᶜ²⁵⁹T) is safe and tolerable through laboratory assessments, including chemistry and hematology, and anti-NY-ESO-1 antibodies; and cardiac assessments, including ECG.

Other Outcome Measures:

1. Evaluation of the persistence of genetically modified T cells. [ Time Frame: 1 Year ]
   Evaluation of the persistence of the infused T cells in the periphery.
2. Measurement of RCL in genetically modified T cells. [ Time Frame: 1 Year ]
   Evaluation of RCL in Subject PBMCs using PCR-based assay.
3. Mean fluorescence intensity (expression) of specific surface markers on gene-modified T cells [ Time Frame: 1 Year ]
   Killing profile and cytokine profile of genetically modified T cells will be evaluated using flow cytometry.
4. Percentage of total gene modified T cells with memory subtype [ Time Frame: 1 Year ]
   Memory phenotype of genetically modified T cells will be evaluated using flow cytometry.
5. Percentage of total gene modified T cells with exhaustion marker expression [ Time Frame: 1 Year ]
   Exhaustion profile of genetically modified T cells will be evaluated using flow cytometry
6. Evaluation of NY-ESO-1 expression pre and post infusion using IHC [ Time Frame: 1 Year ]
   NY-ESO-1 will be assessed in tumor biopsies taken at baseline, Week 8 and at the time of disease progression by measuring frequency (percentage of positive cells) and intensity of expression (e.g. 1+, 2+, 3+). The results will be correlated to clinical outcome.
7. Correlation of candidate biomarkers with clinical response to treatment [ Time Frame: 1 Year ]
   Biomarkers will be assessed in tumor biopsies taken at baseline, Week 8 and at the time of disease progression, and in peripheral blood by protein or gene expression analysis. Leukocyte infiltration (percentage); tumor microenvironment markers (expression level); epitope spreading (length and number of unique T cell CDR3 sequences); function and phenotype of TILs and gene-modified T cells will be assessed. The results will be correlated to clinical outcome.
8. Evaluation of cytokine levels [ Time Frame: 1 Year ]
   Analysis of serum cytokine levels taken before and after T cell infusion
9. Evaluation of germline polymorphisms in IL-6, TNF-α, IL-10, INF-γ and TGF-β and their association with cytokine release syndrome [ Time Frame: 1 Year ]
   Assessment of germline polymorphisms in the listed cytokines though analysis of peripheral blood sample

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Subject (or legally authorized representative) has voluntarily agreed to participate by giving written informed consent in accordance with ICH GCP guidelines and applicable local regulations.
• Subject has agreed to abide by all protocol required procedures including study related assessments, and management by the treating institution for the duration of the study and long term follow-up.
• Subject is ≥18 years of age at the time of signing the study informed consent.
• Subject has a diagnosis of high grade myxoid liposarcoma / myxoid round cell liposarcoma confirmed histologically and by the presence of the reciprocal chromosomal translocation t(12;16)(q13;p11) or t(12; 22) (q13;q12)
• Subject has advanced (metastatic or inoperable) high grade myxoid liposarcoma / myxoid round cell liposarcoma. Inoperable refers to a tumor lesion in which clear margins cannot be obtained without leading to significant functional compromise
• Subject has measurable disease according to RECIST v1.1 criteria.
• Subject must be HLA A*02:01, HLA A*02:05 and/or HLA-A*02:06 positive.
• Subject's tumor (either the most recent archival specimen or a fresh biopsy) shows positive NY-ESO-1 expression defined as ≥30% of cells that are 2+ or 3+ by immunohistochemistry. All samples must have been pathologically reviewed by an Adaptimmune designated central laboratory.
• Subject must have previously received or be intolerant to anthracycline based therapy for advanced (metastatic or inoperable) disease. Subjects who received neoadjuvant/adjuvant anthracycline based therapy and progressed within 6 months of completion of therapy will be eligible
• Subject has an ECOG Performance Status 0-1.
• Subject has a left ventricular ejection fraction ≥45%.
• Subject is fit for apheresis and has adequate venous access for the cell collection.
• Female subjects of childbearing potential (FCBP) must have a negative urine or serum pregnancy test AND must agree to use effective contraception throughout the study, starting at the first dose of chemotherapy for at least 12 months thereafter and 4 months after the gene modified cells are no longer detected in the blood, whichever is longer.

Or

• Male subjects must be surgically sterile or agree to use effective contraception starting at the first dose of chemotherapy and for 4 months thereafter (if indicated in the country specific monograph/label for cyclophosphamide).
• Subject must have adequate organ function as indicated by the laboratory values below:

Absolute Neutrophil count (ANC) ≥ 1.5 x 10⁹/L (without G-CSF support) Platelets ≥ 100 x 10⁹/L Hemoglobin ≥ 80 g/L (without transfusion support within 7 days prior to leukapheresis) Prothrombin Time or INR ≤ 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation.

Partial Thromboplastin Time (PTT) ≤ 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation.

Calculated or measured creatinine clearance ≥ 40 mL/min Serum total bilirubin ≤ 1.5 x ULN (unless subject has documented Gilbert's Syndrome with direct bilirubin <35% of total bilirubin) Alanine aminotransferase (ALT)/Serum Glutamic Pyruvic Transaminase (SGPT) ≤ 2.5x ULN

Exclusion Criteria:

1. Subject has received or plans to receive the following therapy/treatment within the following periods prior to leukapheresis or lymphodepleting chemotherapy:

   • Cytotoxic chemotherapy within 4 weeks.
   • Immune therapy (monoclonal antibody therapy, checkpoint inhibitors) within 4 weeks.
   • Use of an anti-cancer vaccine within 2 months in the absence of tumor response, or the subject should be excluded if their disease is responding to an experimental vaccine given within 6 months.
   • Any previous gene therapy using an integrating vector.
   • Corticosteroids or any other immunosuppressive therapy within 2 weeks. Use of inhaled or topical cutaneous steroids is permitted.
   • Any previous allogeneic hematopoietic stem cell transplant.
   • Investigational treatment or clinical trial within 4 weeks.
2. Radiotherapy to the target lesions within 3 months prior lymphodepleting chemotherapy. A lesion with unequivocal progression may be considered a target lesion. There is no washout period for palliative radiation to non-target lesions.
3. Subject that has toxicity from previous anti-cancer therapy must have recovered to ≤ Grade 1 (except for non-clinically significant toxicities, e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral neuropathy) can be enrolled.
4. Subject has history of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study.
5. Subject has history of chronic or recurrent (within the last year prior to screening) severe autoimmune or immune mediated disease requiring steroids or other immunosuppressive treatments.
6. Subject has known active brain or leptomeningeal metastases. Subjects with prior history of brain metastasis who have undergone local therapy (i.e. metastatectomy and/or radiation) and show no evidence of local recurrence or progression over the past 3 months prior to screening are eligible.
7. Subject has other prior malignancy that is not in complete remission.
8. Subject has electrocardiogram (ECG) showing clinically significant abnormality at screening or an average QTc interval (Fridercia's or Bazett's formula) >450 msec in males and >470 msec in females (>480 msec for subjects with Bundle Branch Block (BBB)).

9. Subject has uncontrolled intercurrent illness including, but not limited to:

   • Ongoing or active infection.
   • Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 or Class 4.
   • Uncontrolled clinically significant arrhythmia in last 6 months.
   • Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months.
   • Interstitial lung disease (subjects with existing pneumonitis as a result of radiation are not excluded, however, subjects must not be oxygen dependent).
10. Subjects who in the opinion of the Investigator will be unlikely to fully comply with protocol requirements.

11. Subject has active infection with HIV, HBV, HCV or HTLV as defined below:

    • Positive serology for HIV
    • Active hepatitis B infection as demonstrated by test for hepatitis B surface antigen. Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B DNA and receive prophylaxis against viral reactivation.
    • Active hepatitis C infection as demonstrated by test for hepatitis C RNA. Subjects who are HCV antibody positive will be screened for HCV RNA by any RT PCR or bDNA assay. If HCV antibody is positive, eligibility will be determined based on a negative screening RNA value.
    • Positive serology for HTLV 1 or 2.
12. Subject is pregnant or breastfeeding.

Contacts and Locations

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Contacts

Contact: US GSK Clinical Trials Call Center	877-379-3718	GSKClinicalSupportHD@gsk.com

Locations

United States, Florida
GSK Investigational Site	Recruiting
Tampa, Florida, United States, 33612
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
United States, Michigan
GSK Investigational Site	Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
United States, Missouri
GSK Investigational Site	Recruiting
Saint Louis, Missouri, United States, 63110
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
United States, New York
GSK Investigational Site	Recruiting
New York, New York, United States, 10065
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
United States, Ohio
GSK Investigational Site	Recruiting
Columbus, Ohio, United States, 43210
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director:	GSK Clinical Trials	GlaxoSmithKline

More Information

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Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT02992743 History of Changes
Other Study ID Numbers:	208469; ADP-0011-007 ( Other Identifier: Adaptimmune Therapeutics )
First Posted:	December 14, 2016
Last Update Posted:	October 16, 2018
Last Verified:	October 2018

Keywords provided by GlaxoSmithKline:

Previously treated; Metastatic; Cell Therapy; T Cell Therapy	Sarcoma; NY-ESO-1; Immuno-oncology; T Cell Receptor

Additional relevant MeSH terms:

Liposarcoma; Neoplasms, Adipose Tissue; Neoplasms, Connective and Soft Tissue	Neoplasms by Histologic Type; Neoplasms; Sarcoma