Patient case: 69-year-old female with melanoma; genetic feature: high serum LDH levels

Clinical trial: 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

Summary: 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

Detailed description: Background:
  -  Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy 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:
  -  To 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)
  -  To determine the complete response rate to the standard non-myeloablative conditioning regimen, TIL, high dose IL-2 in combination with pembrolizumab in patients with metastatic melanoma who have not received prior therapy with anti PD-1/PD-L1 (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 contraindications 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 to 2 cohorts:
  -  Cohort 1 patients who are refractory to treatment with anti PD-1/PD-L1
  -  Cohort 2 patients who have not received treatment with PD-1/PD-L1
  -  After TIL growth is established:
  -  Patients who are assigned to Cohort 1 will be randomized to either receive or not receive pembrolizumab in combination with the standard Adoptive Cell Therapy (ACT) with TIL (non-myeloablative conditioning regimen, TIL and high dose IL-2)
  -  Patients who are assigned to Cohort 2 will all receive the standard ACT with TIL in combination with pembrolizumab
  -  Pembrolizumab will be administered immediately prior to TIL administration and continue for
  3 additional cycles.
  -  Up to 170 patients may be enrolled over 3-4 years.

Eligibility: -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 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. Four weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, at the time the patient receives the preparative regimen to allow antibody levels to decline.
  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, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  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 > 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.

Relevance to patient case: not relevant