Autologous Tumor Infiltrating Lymphocytes MDA-TIL in Treating Patients With Recurrent or Refractory Ovarian Cancer, Osteosarcoma, or Pancreatic Ductal Adenocarcinoma

PRIMARY OBJECTIVES:

I. To evaluate efficacy using objective response rate (ORR) using the Response Evaluation
Criteria in Solid Tumors (RECIST) version (v)1.1 in subjects with ovarian cancer, pancreatic
ductal adenocarcinoma (PDAC), and osteosarcoma.

SECONDARY OBJECTIVES:

I. Determine the disease control rate (DCR) within and across cohorts. II. Determine the
duration of response (DOR). III. Determine progression-free survival (PFS) and overall
survival (OS). IV. Further characterize the safety profile of adoptive cell therapy (ACT)
with tumor-infiltrating lymphocytes (TIL) across multiple tumor types.

EXPLORATORY OBJECTIVES:

I. Establish duration of TIL persistence. II. Compare the molecular and immunological
features of tumors before and after TIL therapy.

III. Prospectively evaluate the existing immunotherapy response criteria (irRECIST) as the
best response assessment tool for TIL therapy among a diverse group of solid tumors.

IV. Investigate TIL attributes (CD8 %, CD27 and CD28 expression) and correlation with
response to therapy.

V. Assess tumor marker (CA19-9; CA-125) response in patients who produce this tumor marker.

VI. Assess Health-Related Quality of Life (HRQOL).

OUTLINE:

LYMPHODEPLETION REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 2 hours on
days -7 and -6, and fludarabine IV over 30 minutes on days -5 to -1 in the absence of disease
progression or unacceptable toxicity.

T-CELL INFUSION: Patients receive autologous tumor infiltrating lymphocytes MDA-TIL IV over
45 minutes on day 0. Patients then receive IL-2 IV over 30 minutes on days 1-4 for up to 6
doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at week 18, at 6, 9, 12, 18,
and 24 months, and then every 3 months for up to 3 years.

Inclusion Criteria:

- Age between 18 and 70 (subjects aged 16 - 70 may be enrolled into the osteosarcoma
cohort)

- Subjects must be willing and able to provide informed consent. For patients < 18 years
of age, their parents or legal guardians must sign a written informed consent. Assent,
when appropriate, will be obtained according to institutional guidelines

- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1 at
enrollment and within 7 days of initiating lymphodepleting chemotherapy

- Subjects must have an area of tumor amenable to excisional biopsy for the generation
of TIL separate from, and in addition to, a target lesion to be used for response
assessment

- Any prior therapy directed at the malignant tumor, including radiation therapy,
chemotherapy, and biologic/targeted agents must be discontinued at least 28 days prior
to tumor resection for preparing TIL therapy

- Absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days of enrollment and with 24
hours of starting lymphodepleting chemotherapy)

- Hemoglobin >= 9.0 g/dL (transfusion allowed) (within 7 days of enrollment and with 24
hours of starting lymphodepleting chemotherapy)

- Platelet count >= 100,000/mm^3 (within 7 days of enrollment and with 24 hours of
starting lymphodepleting chemotherapy)

- Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) and
aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) < 2.5
x the upper limit of normal (ULN) (patients with liver metastases may have liver
function test [LFT] =< 5.0 x ULN) (within 7 days of enrollment and with 24 hours of
starting lymphodepleting chemotherapy)

- Calculated creatinine clearance (Cockcroft-Gault) >= 50.0 mL/min (within 7 days of
enrollment and with 24 hours of starting lymphodepleting chemotherapy)

- Total bilirubin =< 1.5 x ULN (within 7 days of enrollment and with 24 hours of
starting lymphodepleting chemotherapy)

- Prothrombin time (PT) & activated partial thromboplastin time (aPTT) =< 1.5 x ULN
(correction with vitamin K allowed) unless subject is receiving anticoagulant therapy
(which should be managed according to institutional norms prior to and after
excisional biopsy) (within 7 days of enrollment and with 24 hours of starting
lymphodepleting chemotherapy)

- Negative serum pregnancy test (female subjects of childbearing potential) (within 7
days of enrollment and with 24 hours of starting lymphodepleting chemotherapy)

- Subjects must not have a confirmed human immunodeficiency virus (HIV) infection

- Subjects must have a 12-lead electrocardiogram (EKG) showing no active ischemia and
Fridericia's corrected QT interval (QTcF) less than 480 ms

- Subjects 40 years of age and older must also have a negative stress cardiac test (i.e.
EKG stress test, stress thallium, dobutamine echocardiogram or other stress test that
will rule out cardiac ischemia). Stress test may be required of subjects less than 40
years of age if warranted by family history or risk factors by the treating
investigator

- Subjects of childbearing potential must be willing to practice an approved highly
effective method of birth control starting at the time of informed consent and for 1
year after the completion of the lymphodepletion regimen. Approved methods of birth
control are as follows: hormonal contraception (i.e. birth control pills, injection,
implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation
or hysterectomy; subject/partner status post vasectomy; implantable or injectable
contraceptives; and condoms plus spermicide

- Able to adhere to the study visit schedule and other protocol requirements

- Pulmonary function tests (spirometry) demonstrating forced expiratory value (FEV) 1
greater than 65% predicted or forced vital capacity (FVC) greater than 65% of
predicted

- Ovarian cancer cohort only: Subjects must have high grade non-mucinous histology
(carcinosarcomas are allowed)

- Ovarian cancer cohort only: Subjects must have failed at least two prior lines of
chemotherapy (i.e. frontline adjuvant chemotherapy plus one additional line for
recurrent/progressive disease)

- Osteosarcoma cohort only: Subjects with osteosarcomas must have relapsed or become
refractory to conventional therapy and have received a regimen including some
combination of high-dose methotrexate, doxorubicin, cisplatin, and/or ifosfamide

- Pancreatic adenocarcinoma cohort only: Subjects must have histologically or
cytologically documented diagnosis of PDAC with oligo-metastatic disease

- Pancreatic adenocarcinoma cohort only: Subjects must have progressed on, or received
maximal benefit from, front-line therapy

- Pancreatic adenocarcinoma cohort only: Patients may have received unlimited lines of
prior standard of care therapy

- Pancreatic adenocarcinoma cohort only: Patients with ascites or carcinomatosis are not
eligible for the study

- Pancreatic adenocarcinoma cohort only: Patients will need an albumin of >= 3.0 mg/dL
within 7 days of enrollment

Exclusion Criteria:

- Active systemic infections requiring intravenous antibiotics, coagulation disorders or
other major medical illnesses of the cardiovascular, respiratory or immune system.
Principal investigator (PI) or his/her designee shall make the final determination
regarding appropriateness of enrollment

- Patients with active viral hepatitis

- Patients who have a left ventricular ejection fraction (LVEF) < 45% at screening

- Patients with a history of prior adoptive cell therapies

- Persistent prior therapy-related toxicities greater than grade 2 according to Common
Toxicity Criteria for Adverse Events (CTCAE) v. 4.03, except for peripheral
neuropathy, alopecia, or vitiligo prior to enrollment

- Primary immunodeficiency

- History of organ or hematopoietic stem cell transplant

- Chronic steroid therapy, however prednisone or its equivalent is allowed at < 10
mg/day

- Patients who are pregnant or nursing

- Presence of a significant psychiatric disease, which in the opinion of the principal
investigator or his/her designee, would prevent adequate informed consent

- History of clinically significant autoimmune disease including active, known, or
suspected autoimmune disease. Subjects with resolved side effects from prior
checkpoint inhibitor therapy, vitiligo, psoriasis, type 1 diabetes or resolved
childhood asthma/atopy would be an exception to this rule. Subjects that require
intermittent use of bronchodilators or local steroid injections would not be excluded.
Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will
not be excluded

- History of clinically significant chronic obstructive pulmonary disease (COPD),
asthma, or other chronic lung disease

- History of a second malignancy (diagnosed in the last 5 years). Exceptions include
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ
cervical cancer that has undergone potentially curative therapy

- History of known active central nervous system metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to initiation of lymphodepletion

- Has received a live vaccine within 30 days prior to the initiation of lymphodepletion

- Patients who have a contraindication to or history of hypersensitivity reaction to any
components or excipients of the TIL therapy or the other study drugs: NMA-LD
(cyclophosphamide, mesna, and fludarabine); IL-2; any component of the TIL infusion
product formulation including human serum albumin (HSA), IL-2, and dextran-40

- Any other condition that in the investigator's judgement would significantly increase
the risks of participation