Patient case: 38-year-old male with Liposarcoma. Genetic variant: CDK4 Amplification. Other conditions: GERD.

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

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.

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.
  Once the NY-ESO-1ᶜ²⁵⁹T cells have been manufactured subjects will receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide on Days -7 to -5 and NY-ESO-1ᶜ²⁵⁹T cells by a single intravenous infusion on Day 1. Dose range is 1 x 10⁹ - 8 x 10⁹ transduced cells. Subjects will complete the interventional phase of the study upon confirmation of disease progression.

Eligibility: 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.

Relevance to patient case: not relevant