Patient case: 45-year-old female with Melanoma. Genetic variant: BRAF (V600E), CDKN2A Deletion. Other conditions: None.

Clinical trial: Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization in Patients With Metastatic Melanoma

Summary: Objectives:
  The primary objective will be to determine whether patients receiving the combination of dendritic cells and high dose IL-2 have sustained persistence of infused T cells compared to patients treated with T cells and high dose IL-2 alone.
  Secondary endpoints will include evaluations for tumor response and studies to determine whether dendritic cells enhance the infused T cells in anti-tumor activity and their ability to migrate to the tumor site. In addition, we will evaluate the characteristics of the infused T cells that correspond with effectiveness in vivo.

Detailed description: Leptomeningeal Disease: (Cohort D):
  Study Visits:
  You are expected to stay in the Houston area for at least 21 days in order to take part in this study.
  During this study, you will have the following tests and procedures:
  -  You will have an MRI of the complete spine and brain within 1 week before starting the therapy, at Week 4 (+/- 3 days), and at 8 weeks (+/- 3 days) after the Day 1 IT TIL infusion. You will also have MRIs of the brain and entire spine every 2 months (+/- 1 week)
  -  At baseline, before starting maintenance therapy with IL-2, and then every 2 months after that, you will have a CT CAP and/or PET/CT to evaluate the status of the disease.
  -  You will have a neurological exam (tests to check the functioning of your nerves, including tests of your balance and reflexes) within 1 week before the Day 1 IT TIL infusion and before starting maintenance therapy with IL-2.
  -  Blood (about 4 1/2 tablespoons each time) will be taken before surgery to remove your tumor or tumor biopsy, before the treatment starts and again on Days 4, 8, 11, 15, 18, 21, 28, 35, 42 (+7 days), and at each follow-up visit (+/- 7 days). These blood samples will be collected to evaluate the activity of the T-cells and their ability to attack the tumor.
  -  On days that you receive TIL, CSF will be collected through the Ommaya reservoir before the infusion of IT TIL to match the amount of TIL that is being infused.
  -  You will have a neurocognitive exam (tests to check your memory and thinking abilities, for example) within 1 week before Day 1 of IT TIL infusion and before starting maintenance therapy.
  -  You will complete a questionnaire about your symptoms within 1 week before Day 1 and before starting maintenance therapy. The questionnaire and visit should not take more than 3 hours.
  CSF will be collected for routine tests through either the Ommaya reservoir or a spinal tap within 4 weeks before Day 1 and then 1 time a week for 8 weeks.
  °Blood (about 4.5 tablespoons) will be drawn to monitor and track the TIL presence in the blood as compared to the CSF 1 week before the first IT TIL infusion and on Day 15 and in Week 5.
  During your inpatient stay/observation on Days 1-21:
  -  You will have a physical exam within 24 hours before Day 1 and Day 15 IT TIL infusion
  -  Vital signs will be checked every 4 hours for the first 24 hours after each TIL infusion, and then every 8 hours on all other days.
  -  You will have a neurological exam before IT TIL infusion, at 60-120 minutes after the infusion, and again at 24 (+/- 3 hour) hours after the infusion.
  -  If possible, 14 teaspoons of blood will be collected 1 week before the first IT TIL infusion on Day 15 and in Week 5 to monitor and track the presence of TIL in the blood as compared to the CSF.
  -  If possible, 10 teaspoons of blood will be collected Week 4 and every 4 weeks after for a total of 16 weeks to monitor and track the TIL presence in the blood as compared to the CSF.
  Length of Treatment:
  Depending on what your doctor thinks it is in your best interest, you might be asked to come back on a monthly or bi-monthly basis for IL-2 treatment. You will no longer be able to take the IT IL or IL-2 study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Follow-Up Visits:
  Follow-up visits will be scheduled depending on your treatment schedule. Each time you come for follow-up, up to 2 tablespoons of spinal fluid and up to 10 teaspoons of blood will be collected for research purposes. As standard of care for all patients with LMD, you will have an MRI of the brain and the spine, as well as either CT or PET/CT of your body to also monitor the rest of your disease.
  This is an investigational study. The medications being used in this study are FDA approved. IL-2 is a commercially available drug. However, its use together with T-cells in this study is experimental. The T-cells are authorized for use only in research. A total of 30 patients will take part in this portion of the study. All will be enrolled at MD Anderson.
  Tissue Harvest and Screening: (Turnstile I):
  Tissue Harvest:
  If you are found to be eligible to take part in this study, a biopsy procedure of the tumor will be performed. A whole or part of your tumor will be cut and removed using high enough pain medication. This biopsy is being done to help attempt to grow the T-cells necessary for the treatment. Your T-cells will be grown in the laboratory with the help of radiation-exposed cells from other blood donors. These donor cells are tested to be negative for currently screened infectious diseases. If researchers are unable to grow enough cells or if your tumor does not have enough of the necessary components, you will not continue on study and other treatment options will be discussed with you.
  If the growth of these cells is successful, you will be able to continue on the study. There is up to a 6-week waiting period between the biopsy and continuing to the next phase of this study. You will be allowed to participate in other treatment plans during this time period.
  If there are any abnormal results, the study doctor or a research staff member will discuss this with you.
  This is an investigational study. The T-cell and vaccine therapy are authorized for use only in research.
  A total of up to 189 patients will take part in this study. All will be enrolled at MD Anderson
  Treatment Consent: (Turnstile II):
  Study Visits:
  You will have blood samples collected to evaluate the activity of the T-cells and their ability to attack the tumor. Blood samples (about 4-1/2 tablespoons each time) will be taken before surgery to remove your tumor. If you are not scheduled to have surgery, you may have a biopsy of you tumor. Blood ( 4-1/2 tablespoons) will also be drawn before chemotherapy starts and again on Days 7, 14, 21, 28, 35, 42 (+7 days), and at each follow-up visit (+/- 7 days). This blood will be collected to evaluate the activity of your T-cells.
  You will return in 8 weeks for follow-up assessments, as part of the Melanoma Department's standard of care.
  If your blood tests show that you had Cytomegalovirus (CMV) in the past, you will have an additional blood (about 2 teaspoons) sample drawn after the T-cell infusion to check for the presence of CMV. The study staff will check your CMV levels at Day 3 (+/- 24 hours) and Day 21 (+/- 7 days) after TIL infusion as an added precaution.
  Some of the T-cells that you receive may come from donors who have tested positive for CMV in the past. However, these donors will be treated for CMV before their cells are collected, and the cells will also be tested to check for CMV before they are given to you.
  At about 6 weeks (+ 7 days) and at 12 weeks (+ 7 days) after you receive the T-cell and/or vaccine infusion (for each cycle), you will return to the clinic for a physical exam and for repeat scans to evaluate the size of your tumors.
  If possible, you will also have blood samples (about 4 1/2 tablespoons) drawn on all follow-up visits to check the effects of the T-cells on your blood cells.
  If the doctor thinks it is needed, you will receive pentamidine by vein over 1 hour every 21 days for 6 months after lymphodepletion. If you cannot receive pentamidine, you will take atovaquone by mouth.
  Length of Treatment:
  You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  End-of-Treatment Visit:
  You will return in 8 weeks for follow-up evaluations per the Melanoma Department's standard of care.
  Re-Treatment:
  If you have stable disease or a partial response to treatment, you may be re-treated on the same schedule that you received before. Before this occurs, you will need to be evaluated again. A maximum of 1 re-treatment course may be given for each participant.
  This is an investigational study. IL-2 was recently approved by the FDA for the treatment of metastatic melanoma. IL-2 is a hormone naturally found in the body that boosts the immune system. It is made in the lab, but from a normal human gene.
  The T-cell and vaccine therapy are authorized for use only in research. A total of up to 189 patients will take part in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients must have metastatic melanoma, uveal melanoma or stage III in-transit or regional nodal disease. (Turnstile I)
  2. Patients must receive an MRI/CT of the brain or PET/CT within 6 months of consenting. If new lesions are present, PI or his designee should make final determination regarding enrollment. (Turnstile I)
  3. Age greater than or equal to 12 years. (Turnstile I)
  4. Clinical performance status of ECOG 0-2. (Turnstile I)
  5. Patients previously treated with immunotherapy, targeted therapy, or no therapy will be eligible. Patients receiving cytotoxic agents will be evaluated by the PI or his designee as to suitable eligibility. (Turnstile I)
  6. Patients must be HLA-A2 for cohort A. (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
  7. Patients must have adequate TIL available. (Turnstile II)
  8. Patients must have measurable metastatic melanoma. (Turnstile II - Chemotherapy/Cell Infusion -Inclusion Criteria).
  9. Patients may have brain lesions which measure </= 1cm each. Lesions that are >1 cm that have been treated with SRS and in the opinion of the PI or his designee no longer represents active disease will also be allowed. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  10. Patients of both genders must practice birth control for four months after receiving the preparative regimen. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  11. Patients must have a documented negative pregnancy test (urine or serum) for women who have menstruation in the past 12 months and without sterilization surgery.
  12. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), 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. (Turnstile II)
  13. Pregnancy testing will be performed within 7 days prior to treatment. (Turnstile II)
  14. Clinical performance status of ECOG 0 - 2 at the time of chemotherapy infusion. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
  15. Absolute neutrophil count greater than or equal to 750/mm3. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  16. Platelet count greater than or equal to 75,000/mm3. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  17. Hemoglobin greater than or equal to 8.0 g/dl. (Turnstile II - Chemotherapy/Cell Infusion).
  18. Serum ALT less than three times the upper limit of normal. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
  19. Serum creatinine less than or equal to 1.6 mg/dl. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
  20. Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl. (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria).
  21. Patients in Cohort A will be randomized to receive either TIL alone or TIL plus Dendritic cells.
  22. A stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) within 6 months of lymphodepletion. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
  23. Pulmonary function tests (FEV1>65% or FVC>65%of predicted) within 6 months of lymphodepletion. (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria).
  24. MRI/CT of the brain within 42 days of lymphodepletion. CT scan of chest/abdomen/pelvis or PET/CT within 30 days of lymphodepletion. Exception: Patients randomized to receive dendritic cells may have an MRI of the brain within 30 days of lymphodepletion. (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
  25. Patients must be receiving a B-RAF inhibitor and failed to achieve PR or CR or have progressive disease in response to B-RAF treatment (Cohort C).
  26. i. Patients with MRI evidence of LMD, with or without evidence of malignant cells in CSF ("positive cytology"), or ii. Patients with evidence of malignant cells in the CSF (positive cytology), with or without MRI evidence of LMD, or iii. Patients with surgically-proven LMD (leptomeningeal involvement on pathology review) +/- MRI or CSF evidence by MRI or CSF cytology (Cohort D)
  27. a. Many patients present with concomitant systemic disease outside of the central nervous system. Extra-CNS disease status should meet the following criteria: i. Patients with concomitant systemic disease under control with current or prior systemic treatment, as per primary treating physician ii. Patients without any evidence of systemic disease, either receiving systemic treatment or on active observation (Cohort D)
  28. c. Previous Therapies i. Patients who are currently being treated with IT IL-2 for LMD are eligible. No wash out period is required. ii. Patients who have been previously treated with other IT therapies are eligible, as long as there is at least a 2 week wash out period iii. Patients who have previously received therapy with systemic TIL therapy are eligible.
  29. (contd #28) iv. Patients with VP shunts must have VP shunts with on/off valves and must be expected to tolerate VP shunt valve off for more than 6 hours Patients who have received CNS irradiation, including whole brain radiation or stereotactic radiosurgery, are eligible, if they are at least 1 weeks post CNS-irradiation (Cohort D)Patients who are currently being treated with IT IL-2 for LMD are eligible. No wash out period is required. (Cohort D)
  30. d. Other Requirements i. Patients must be able to give informed consent ii. Patients must have ECOG performance status 0, 1 or 2 and/or KPS > 50 iii. Patients must be able to swallow iv. Patients must be able to sit up with or without assistance v. Patients must be able to undergo contrast-enhanced MRI. (Cohort D)
  Exclusion Criteria:
  1. Has had prior systemic cancer cytotoxic chemotherapy within the past four weeks at the time of the start of the lymphodepletion regimen.
  2. Has had prior B-RAF or MEK targeted therapy within 7 days prior to the start of the lymphodepletion regimen (Cohort A and Cohort B).
  3. Is not receiving B-RAF treatment (Cohort C) (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  4. Achieves PR or CR in response to B-RAF treatment (Cohort C).
  5. Women who are pregnant or nursing will be excluded because of the potentially dangerous effects of the preparative chemotherapy on the fetus. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  6. 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 test and/or abnormal PFT. PI or his designee shall make the final determination regarding appropriateness of enrollment.(Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  7. Any form of primary or secondary immunodeficiency. Must have recovered immune competence after chemotherapy or radiation therapy as evidenced by lymphocyte counts (> 500/mm3), WBC (> 3,000/mm3) or absence of opportunistic infections. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  8. Require steroid therapy or steroid-containing compounds, or have used systemic steroids in the past 30 days, or have used topical or inhalational steroids in the past 2 weeks prior to lymphodepletion. Exception: Patients on physiologic dose of steroid (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  9. Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  10. Patients with rapidly advancing systemic disease, especially those without good options of systemic treatment for their disease outside the CNS. (Cohort D)
  11. Patients with rapidly advancing parenchymal brain metastases (Cohort D)
  12. Pregnant patients (Cohort D)
  13. Patients with rapid decline in neurological function as documented on exam and/or as per clinical judgment of treating physician (Cohort D)

Relevance to patient case: not relevant