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

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.

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.