Patient case: 74-year-old female with melanoma; genetic feature: no tumor infiltrating lymphocytes

Clinical trial: MK-3475 With Lymphodepletion, TIL and High or Low Dose Interleukin-2 (IL-2)

Summary: The goal of this clinical research study is to learn if pembrolizumab, an infusion of T-cells, chemotherapy (cyclophosphamide and fludarabine), and either high or low dose interleukin-2 (IL-2) can help to control metastatic melanoma. The safety of this drug combination will also be studied.
  T-cells are white blood cells in your body that are important to the immune system. The T-cells used in this study will be collected and grown in a separate study (MD Anderson Protocol 2004-0069)

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 treatment groups (treatment arms):
  -  If you are assigned to Arm A, you will receive high-dose IL-2.
  -  If you are assigned to Arm B, you will receive low-dose IL-2.
  Both you and the study staff will know to which dose of IL-2 you have been assigned.
  The dose level of cyclophosphamide, fludarabine, you receive will depend on your weight and what the study doctor thinks is in your best interest. The dose of T-cells that you receive will depend on the amount than can be made by the lab. You will receive a fixed dose of pembrolizumab.
  Study Drug Administration:
  The days leading up to Day 1 of the study are considered negative days. For example, the day before Day 0 is Day -1. Day 0 is when you will receive the T-cells (described below).
  You will stay in the hospital to receive the T-cells, chemotherapy, and IL-2 starting on Day -7. You may stay in the hospital up to 3 weeks.
  On Days -7 and -6, you will receive cyclophosphamide by vein over about 2 hours.
  On Days -5 to -1, you will receive fludarabine by vein over about 15-30 minutes.
  On Day 0, you will receive T-cells through a central venous catheter (CVC) over about 15-60 minutes. A CVC is a thin flexible tube that is inserted into the body. The catheter may be placed into a vein in your arm or in a large vein in your neck. If the cells need to be given through a large vein in your upper chest or in your neck, the area will be numbed with anesthetic before the catheter is put in. Tylenol (acetaminophen) will be given by mouth before the T-cell infusion to decrease the risk of these side effects.
  If you are assigned to Arm B, you will receive low dose IL-2 as an injection under the skin (like a shot) 1 time each day for 14 days. Other catheters may be needed in 1 or both of your arms to give you fluids, drugs, or extra nutrition. You will sign a separate consent form for the catheter, which will describe the procedure and its risks in more detail.
  On Day 1, if you are assigned to Arm A, you will receive a high dose of IL-2 by catheter over about 15 minutes every 8-16 hours for up to 5 days.
  On Day 21 (+/- 7 days) and then every 3 weeks after that, you will receive pembrolizumab by vein over 30 minutes.
  You will be given standard drugs by vein to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.
  Study Visits:
  Before the start of treatment:
  Within 28 days before your hospital stay:
  -  You will have a physical exam.
  -  Blood (about 3 teaspoons) will be drawn for routine tests.
  -  Blood (about 4 ½ tablespoons) will be drawn to check what type of T-cells you have in your body.
  Every 1-2 days during your hospital stay, blood (about 3 teaspoons) will be drawn for routine tests.
  If the blood tests performed at screening showed you had CMV in the past, on Days 0 and 3, blood (about 2 teaspoons) will be drawn to check for CMV.
  On Day 7, blood (about 4½ tablespoons) will be drawn to study different types of T-cells and how active they are in the body.
  On Days 21 and 42 and then every 3 weeks after that (Weeks 12, 15, 18, and so on):
  -  You will have a physical exam.
  -  Blood (about 3 tablespoons) will be drawn for routine tests.
  -  On Day 21 only, blood (about 2 teaspoons) will be drawn to test for CMV.
  -  On Days 21 and 42 only, you will also a tumor biopsy to check the status of the disease, if the doctor thinks it is safe. The type of biopsy you have will depend on the size and location of the tumor. Your doctor will discuss this with you.
  -  On Days 21 and 42 only, blood (about 4½ tablespoons) will be drawn to study different types of T-cells and how active they are in the body.
  On Day 63 and then every 12 weeks after that (Weeks 21, 33, 45, and so on):
  -  You will have a physical exam.
  -  Blood (about 4½ tablespoons) will be drawn to study different types of T-cells and how active they are in the body.
  -  You will have a CT, MRI, and/or PET/CT scan.
  -  Blood (about 2 teaspoons) and urine will be collected for routine tests. This routine blood and urine collection will also include a pregnancy test, if you can become pregnant.
  -  On Day 63 only, you will have an EKG.
  -  You will fill out the 2 questionnaires about your quality of life. If the doctor thinks it is needed and safe, you will have a tumor biopsy to check the status of the disease.
  -  If the doctor thinks it is needed, you will have photographs taken of any skin lesions.
  You may have any of the above tests/procedures repeated at any time during the study, if the doctor thinks it is needed.
  Length of Study Drug Dosing:
  You may receive up to 2 years of pembrolizumab. You will only receive T-cells, chemotherapy, and IL-2 one time (while you are hospitalized). You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Your participation on the study will be over after you have completed the follow-up visits.
  End-of-Treatment Visit:
  As soon as you stop taking pembrolizumab:
  -  You will have a physical exam.
  -  Blood (about 3 tablespoons) will be drawn for routine tests.
  -  Blood (about 2 teaspoons) will be drawn to study different types of T-cells and how active they are in the body.
  -  You will have a CT, MRI, and/or PET/CT scan.
  -  If the doctor thinks it is needed, you will have photographs taken of any skin lesions.
  Follow-Up:
  After you have completed up to 2 years of pembrolizumab, you will be called every 3 months by a member of the study staff to ask how you are doing and if you are having any side effects. The call will last about 15 minutes.
  This is an investigational study. Cyclophosphamide is FDA approved and commercially available for the treatment of several types of cancer such as leukemia, lymphoma, and breast cancer. Fludarabine is FDA approved and commercially available for the treatment of B-cell chronic lymphocytic leukemia. It is considered investigational to give cyclophosphamide and fludarabine to treat melanoma.
  High dose IL-2 is FDA approved and commercially available for the treatment of metastatic melanoma and a type of kidney cancer. If you are assigned to receive low-dose IL-2, the drug will be provided by the supporting company Prometheus at no cost to you.
  Pembrolizumab is FDA approved and commercially available for the treatment of melanoma.
  T-cells are not FDA approved or commercially available. This therapy is currently being used for research purposes only.
  The study doctor can explain how the study drugs are designed to work.
  Up to 36 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Turnstile I - Screening: Patients must have metastatic melanoma or stage III in-transit, subcutaneous, or regional nodal disease.
  2. Patients must have a lesion amenable to resection for the generation of TIL on MD Anderson Protocol 2004-0069.
  3. Patients must receive an MRI/CT/PET of the brain within 6 months of signing informed consent. If new CNS lesions are present, patient must have definitive treatment (including surgery or radiation). PI or his designee should make final determination regarding enrollment.
  4. Age greater than or equal to 18 years.
  5. Clinical performance status of ECOG 0 - 1 within 30 days of signing informed consent.
  6. Patients previously treated with immunotherapy, targeted therapy, or no therapy (treatment naïve) will be eligible.
  7. Patients receiving cytotoxic agents will be evaluated by the PI or his designee for eligibility suitability.
  8. Patients with a negative pregnancy test (urine or serum) must be documented within 14 days of screening for women of childbearing potential (WOCBP). A WOCBP has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who has not had menses at any time in the preceding 12 consecutive months).
  9. Turnstile II - Treatment: Patients must sign the treatment consent document before Turnstile II screening procedures. Before the treatment starts and at each visit, the patient will be asked to complete two quality of life questionnaires. It should take about 15 minutes to complete the questionnaires (FACT-G, FACT-Melanoma). Patients must fulfill all of the following criteria to be eligible for Turnstile II of the study.
  10. Patients must have adequate TIL that were previously harvested and then cryopreserved on MDACC protocol 2004-0069.
  11. Patients who have had prior therapy (BRAF inhibitors, ipilimumab, anti PD-1 antibody or anti PD-L1 antibody) or treatment naïve patients are eligible as long as toxicity from therapy is grade </= 1 or at baseline.
  12. Patients must have at least one biopsiable measurable metastatic melanoma, lesion > 1cm and must be amenable to undergoing serial biopsies through the course of therapy. This lesion must not be documented as one of the target lesions
  13. Patients may have CNS metastases which have been treated and are radiographically stable for at least 4 weeks
  14. Patients of both genders must practice birth control for four months after receiving the preparative regimen (lymphodepletion) and continue to practice birth control throughout the study. Patients must have a documented negative pregnancy test (urine or serum) for women who have menstruated in the past 12 months and without sterilization surgery.
  15. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), or if the patient is post-menopausal, the patient agrees to continue to use a barrier method of contraception throughout the study such as: condom, diaphragm, hormonal, IUD, or sponge plus spermicide. Abstinence is an acceptable form of birth control.
  16. Pregnancy testing will be performed within 14 days of screening for women of childbearing potential (WOCBP). A WOCBP has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who has not had menses at any time in the preceding 12 consecutive months).
  17. Clinical performance status of ECOG 0-1 within 30 days of signing consent
  18. A stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) within 1 month of lymphodepletion.
  19. 12-lead EKG showing no active ischemia and QTc interval less than 480 msec
  20. Pulmonary function tests (FEV1>65% or FVC>65% of predicted) within 1 month of lymphodepletion.
  21. Have measurable disease based on RECIST 1.1 and irRC criteria
  22. Demonstrate adequate organ function as defined below, all screening labs should be performed within 10 days of treatment initiation.
  23. System Hematological Absolute neutrophil count (ANC) >/= 1,500 /mcL; Platelets >/= 100,000 / mcL; Hemoglobin >/= 9 g/dL or >/= 5.6 mmol/L Renal Serum creatinine OR Measured or calculated a creatinine clearance (GFR can also be used in place of creatinine or CrCl) </= 1.5 X upper limit of normal (ULN) OR >/= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin </= 1.5 X ULN OR Direct bilirubin </= ULN for subjects with total bilirubin levels > 1.5 ULN; AST (SGOT) and ALT (SGPT) </= 2.5 X ULN OR </= 5 X ULN for subjects with liver metastases.
  24. Contd #23: Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) </= 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants </= 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
  Exclusion Criteria:
  1. Turnstile I - Screening: Active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system. PI or his designee shall make the final determination regarding appropriateness of enrollment
  2. Primary immunodeficiency and need for chronic steroid therapy, Exception: Patients on chronic physiologic dose of steroid equivalent to prednisone < 10 mg/day is allowed.
  3. Patients who are pregnant or nursing.
  4. Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent.
  5. Turnstile II - Treatment: Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
  6. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiation of lymphodepletion. Exception: Patients on chronic physiologic dose of steroid equivalent to prednisone < 10 mg/day is allowed.
  7. Has not recovered (i.e., </= Grade 1 or at baseline) from adverse events due to investigational or standard agents administered more than 4 weeks earlier.
  8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to lymphodepletion or who has not recovered (i.e., </= Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Subjects with </= Grade 2 neuropathy, alopecia, hypophysitis stable on physiologic dose of steroid equivalent to prednisone < 10 mg/day, hypothyroidism stable on hormone replacement are an exception to this criterion and may qualify for the study. - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  9. Has a known additional malignancy that is progressing or requires active treatment. 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.
  10. Has known active central nervous system (CNS) 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.
  11. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease. Subjects with vitiligo 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 from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. Subjects with hypophysitis stable on physiologic dose of steroid will not be excluded from the study.
  12. Has evidence of interstitial lung disease or has a history of non-infectious pneumonitis that required steroids or current pneumonitis.
  13. Has an active infection requiring systemic therapy.
  14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  18. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
  19. Any active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, such as abnormal stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. PI or his designee shall make the final determination regarding appropriateness of enrollment.

Relevance to patient case: not relevant