A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab
A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab
Background:

 Cell therapy is an experimental cancer therapy. It takes young tumor infiltrating lymphocytes
 (Young TIL) cells from a person s tumors and grows them in a lab. Then they are returned to
 the person. Researchers think adding the drug pembrolizumab might make the therapy more
 effective.

 Objective:

 To test if adding pembrolizumab to cell therapy is safe and effective to shrink melanoma
 tumors.

 Eligibility:

 People ages 18 70 years with metastatic melanoma

 Design:

 Participants will be screened with:

 Physical exam

 CT, MRI, or PET scans

 X-rays

 Heart and lung function tests

 Blood and urine tests

 Before treatment, participants will have:

 A piece of tumor taken from a biopsy or during surgery in order to grow TIL cells

 Leukapheresis: Blood flows through a needle in one arm and into a machine that removes white
 blood cells.

 The rest of the blood returns through a needle in the other arm.

 An IV catheter placed in the chest for getting TIL cells, aldesleukin, and pembrolizumab (if
 assigned)

 Participants will stay in the hospital for treatment. This includes:

 Daily chemotherapy for 1 week

 For some participants, pembrolizumab infusion 1 day after chemotherapy

 TIL cell infusion 2 4 days after chemotherapy, then aldesleukin infusion every 8 hours for up
 to 12 doses

 Possible filgrastim injection

 Recovery for 1 2 weeks

 After treatment, participants will:

 Take an antibiotic and antiviral for at least 6 months

 If assigned, have pembrolizumab treatment every 3 weeks for 3 more doses. They may have
 another round.

 Have 2-day follow-up visits every 1 3 months for 1 year and then every 6 months
Background:

 - Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) can
 mediate the regression of bulky metastatic melanoma when administered along with highdose
 aldesleukin (IL-2) following a non-myeloablative lymphodepleting

 preparative regimen consisting of cyclophosphamide and fludarabine.

 - Pembrolizumab, a monoclonal antibody that binds to PD-1 and blocks the PD-1/PD-L1 axis,
 facilitates the activity of anti-tumor lymphocytes in the tumor micro environment.
 Pembrolizumab administration can result in objective tumor responses in patients with

 metastatic melanoma and is approved for use by the FDA for the treatment of these patients.

 -  Administered TIL express low levels of PD-1, though PD-1 can be re-expressed on TIL in
 vivo following TIL administration

 -  In pre-clinical models, the administration of an anti-PD1 antibody enhances the
 anti-tumor activity of transferred T-cells.

 Objectives:

 Primary Objectives:

 -  Determine in a prospective randomized trial whether the addition of pembrolizumab to the
 standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 can improve
 complete response rates in patients with metastatic melanoma who have received prior
 anti PD-1/PD-L1 therapy (Cohort 1)

 -  Determine the complete response rate to the standard non-myeloablative conditioning
 regimen, TIL, and high-dose IL-2 in combination with pembrolizumab in patients with
 metastatic melanoma who have not received prior anti-PD-1/PD-L1 therapy (Cohort 2)

 Eligibility:

 -  Age greater than or equal to 16 and less than or equal to 70 years

 -  Evaluable metastatic melanoma

 -  Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL

 -  No allergies or hypersensitivity to high-dose aldesleukin administration

 -  No concurrent major medical illnesses or any form of immunodeficiency

 Design:

 -  Patients with metastatic melanoma will have lesions resected for TIL

 -  Patients will be assigned one of 2 cohorts: (1)

 -  patients who are refractory to prior anti PD-1/PD-L1

 -  patients who have not received prior anti PD-1/PD-L1

 -  After TIL growth is established:

 -  Patients assigned to Cohort 1 will be randomized to either receive or not receive
 pembrolizumab in combination with the standard non-myeloablative conditioning
 regimen, TIL and high dose IL-2

 -  All patients assigned to Cohort 2 will receive the standard nonmyeloablative
 conditioning regimen, TIL, and high-dose IL-2ACT in combination with pembrolizumab.

 -  For those patients receiving pembrolizumab- Pembrolizumab will be administered
 immediately prior to TIL administration and continue for an additional three cycles
 following the cell infusion.

 -  Up to 170 patients may be enrolled over 3-4 years.
-INCLUSION CRITERIA:

 1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL
 generation.

 2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of
 NCI.

 3. Patients must have received at least one prior therapy for metastatic melanoma.

 4. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
 asymptomatic are eligible. Lesions that have been treated with stereotactic
 radiosurgery must be clinically stable for 1 month after treatment for the patient to
 be eligible. Patients with surgically resected brain metastases are eligible.

 5. Greater than or equal to 16 years of age and less than or equal to 70 years of age.

 6. All participants and/or their parents or legally authorized representatives must sign
 a written informed consent. Assent will be obtained for all participants under the age
 of 18 years.

 7. All participants greater than or equal to 18 years of age or older must be willing to
 sign a durable power of attorney

 8. Clinical performance status of ECOG 0 or 1.

 9. Patients of both genders must be willing to practice birth control from the time of
 enrollment on this study and for up to four months after treatment.

 10. Serology:

 -  Seronegative for HIV antibody. (The experimental treatment being evaluated in
 this protocol depends on an intact immune system. Patients who are HIV
 seropositive can have decreased immune-competence and thus are less responsive to
 the experimental treatment and more susceptible to its toxicities.)

 -  Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.
 If hepatitis C antibody test is positive, then patient must be tested for the
 presence of antigen by RT-PCR and be HCV RNA negative.

 11. Women of child-bearing potential must have a negative pregnancy test because of the
 potentially dangerous effects of the treatment on the fetus.

 12. Hematology

 -  Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim

 -  WBC greater than or equal to 3000/mm3

 -  Platelet count greater than or equal to 100,000/mm3

 -  Hemoglobin > 8.0 g/dl

 13. Chemistry:

 -  Serum ALT/AST less than or equal to 2.5 times the upper limit of normal

 -  Serum Creatinine less than or equal to 1.6 mg/dl

 -  Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert
 s Syndrome who musthave a total bilirubin less than 3.0 mg/dl.

 14. More than four weeks must have elapsed since any prior systemic therapy at the time
 the patient receives the preparative regimen, and patients toxicities must have
 recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
 (Note: Patients may

 have undergone minor surgical procedures within the past 3 weeks, as long as all
 toxicities have recovered to grade 1 or less)

 15. Patients must demonstrate progressive disease at the time of treatment. (Note:
 Patients who have received tyrosine kinase inhibitors (e.g. vemurafinib) may be
 treated if they present with stable disease at the time of treatment).

 16. Subjects must be co-enrolled in protocol 03-C-0277.

 EXCLUSION CRITERIA:

 1. Women of child-bearing potential who are pregnant or breastfeeding because of the
 potentially dangerous effects of the treatment on the fetus or infant.

 2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
 Disease).

 3. Concurrent opportunistic infections (The experimental treatment being evaluated in
 this protocol depends on an intact immune system. Patients who have decreased immune
 competence may be less responsive to the experimental treatment and more susceptible
 to its toxicities).

 4. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation
 disorders or any other active major medical illnesses.

 5. History of major organ autoimmune disease

 6. Concurrent systemic steroid therapy.

 7. History of severe immediate hypersensitivity reaction to any of the agents used in
 this study.

 8. Grade 3 or 4 Major organ Immune-related Adverse Events (IRAEs) following treatment
 with anti PD-1/PD-L1.

 9. History of coronary revascularization or ischemic symptoms.

 10. Documented LVEF of less than or equal to 45%; note: testing is required in patients
 with:

 -  Age greater than or equal to 65 years old

 -  Clinically significant atrial and or ventricular arrhythmias including but not
 limited to: atrial fibrillation, ventricular tachycardia, second or third degree
 heart block or have a history of ischemic heart disease, chest pain.

 11. Documented FEV1 less than or equal to 60% predicted tested in patients with:

 -  A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2
 years).

 -  Symptoms of respiratory dysfunction

 12. Patients who are receiving any other investigational agents.