Patient case: 64-year-old male with bladder cancer; genetic feature: FGFR3 (S249C)

Clinical trial: NK Cells to Prevent Disease Relapse for Patients High Risk Myeloid Malignancies

Summary: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.
  The goal of this clinical research study is to learn about the safety of giving a kind of immune cells called "natural killer" (NK) cells with standard chemotherapy and an allogeneic stem cell transplant (using cells from a donor). Researchers also want to learn the highest tolerable dose of NK cells that can be given.
  Immune system cells (such as NK cells) are made by the body to attack foreign or cancerous cells. Researchers believe that the NK cells you receive from the donor may react against the leukemia cells in your body, help eliminate leukemia, and prevent disease relapse.
  This is an investigational study. The study drugs are FDA approved and commercially available for the treatment of blood cancers and/or stem cell transplant. The way the researchers process the NK cells and the infusion of them is investigational and is not FDA approved.
  Up to 45 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description: Dose Levels:
  If you agree to take part in this study, you will be assigned to a dose level of NK cells based on when you joined this study. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue for up to 6 dose levels, until the highest tolerable dose of NK cells is found.
  The day you receive the stem cell transplant is called Day 0. The days before you receive your stem cell transplant are named with a minus sign (-). The days after you receive the stem cell transplant are named with a plus sign (+).
  You will receive 1 of 2 chemotherapy treatments that will be chosen by your doctor. The treatment will be selected based on your age and health. The types include a high-dose regimen and a reduced-intensity regimen.
  Study Drug Administration (High Dose Regimen):
  On Day -8, you will be admitted to the hospital and given fluids by vein.
  On Day -7, you will receive melphalan by vein over 30 minutes.
  On Days -7 through -4, you will receive fludarabine by vein over 1 hour. Fludarabine and melphalan are given to treat the cancer and lower the immune system in order to lower the risk of the body rejecting the NK cells.
  On Day -3, you will receive total body irradiation (TBI). TBI involves the delivery of high doses of radiation designed to destroy cancer cells and/or lower the immune system in order to lower the risk of the body rejecting the new stem cells.
  On Day -2 or Day -1, you will receive NK cells by vein over 30 minutes.
  On Day -1, you will "rest" (not receive chemotherapy).
  On Day 0, you will receive the donor's stem cells by vein. The infusion will last anywhere from about 30 minutes to several hours.
  On Days +3 and +4, you will receive cyclophosphamide by vein over 3 hours. Cyclophosphamide is given to lower the immune system in order to lower the risk of graft-versus-host disease (GVHD -- when transplanted immune tissue, such as donor NK and stem cells, attacks the tissues of the recipient's body). You will also receive mesna by vein over 30 minutes every 4 hours for a total of 10 mesna doses on Days +3 and +4. Mesna is given to lower the risk of side effects to the bladder caused by cyclophosphamide.
  Starting on Day +5, you will receive tacrolimus and mycophenolate mofetil (MMF) to help lower the risk of GVHD. Tacrolimus will be given by vein non-stop for about 2 weeks. After the 2 weeks of taking tacrolimus by vein, you will take tacrolimus by mouth as a pill for at least 4 months after the transplant. MMF will be given by mouth, 3 times a day, usually for about 6-7 months.
  Starting on Day +7, you will receive filgrastim-sndz as an injection under the skin 1 time a day, until your blood cell levels are high enough. Filgrastim-sndz is designed to help with the growth of a type of healthy white blood cells that fight infection.
  On Day +7 (+/- 1 day) and once about 3-12 weeks later, you will receive NK cells by vein over 30 minutes.
  You will be given standard drugs 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 Drug Administration (Reduced Intensity Regimen) If your study doctor thinks it is needed due to illness or your age, you will receive a reduced intensity regimen.
  On Day -9, you will be admitted to the hospital and given fluids by vein.
  On Day -8, you will receive melphalan by vein over 30 minutes.
  On Days -7 through -4, you will receive fludarabine by vein over 1 hour.
  On Day -3, you will receive total body irradiation (TBI). TBI involves the delivery of high doses of radiation designed to destroy cancer cells and/or lower the immune system in order to lower the risk of the body rejecting the new stem cells.
  On Day -2 or Day -1, you will receive NK cells by vein over 30 minutes.
  On Day -1, you will "rest" (not receive chemotherapy).
  On Day 0, you will receive the donor's stem cells by vein. The infusion will last anywhere from about 30 minutes to several hours.
  On Days +3 and +4, you will receive cyclophosphamide by vein over 3 hours. You will also receive mesna by vein over 30 minutes every 4 hours for a total of 10 mesna doses on Days +3 and +4. Mesna is given to lower the risk of side effects to the bladder.
  Starting on Day +5, you will receive tacrolimus and MMF to help lower the risk of GVHD. Tacrolimus will be given by vein non-stop for about 2 weeks. After the 2 weeks of taking tacrolimus by vein, you will take tacrolimus by mouth as a pill for at least 4 months after the transplant. MMF will be given by mouth, 3 times a day, usually for about 6-7 months.
  Starting on Day +7, you will receive filgrastim-sndz as an injection under the skin 1 time a day, until your blood cell levels are high enough. Filgrastim-sndz is designed to help with the growth of white blood cells.
  On Day +7 (+/- 1 day) and once about 3-12 weeks later, you will receive NK cells by vein over 30 minutes.
  You will be given standard drugs 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 Testing:
  Before you are sent home from the hospital and/or clinic, you will receive additional written instructions. These instructions will include how often you will come to the hospital/clinic, which standard drugs you will take at home, and what side effects you may have and what to do for them.
  After finishing the chemotherapy and cell infusion, your follow-up care will be routine standard of care follow-up that all patients receiving allogeneic stem cell transplantation receive. At each visit, you will have a physical exam. You will be asked about any side effects you may have had. Blood (about 1 tablespoon) will be drawn for routine tests. If the doctor thinks it is needed, you will have a bone marrow aspiration to check the status of the disease. To collect a bone marrow aspirate, an area of the hip or other site is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle.
  Blood (up to about 4 tablespoons) will be drawn to test the genetic makeup and function of the infused NK cells and to check the status of the disease about once a week for the first 4 weeks after the transplant, before the 3rd NK cell infusion and about 1 week later, and then about 3, 6, and 12 months after the transplant, if possible. This may be repeated, if your doctor thinks it is needed.
  Length of Treatment:
  Your active participation in this study will be over 12 months after the transplant. You will be off study 2 years after the transplant. Between Years 1 and 2 after the transplant, the study staff may check your medical record to see how you are doing. You may be taken off study early if the doctor thinks it is in your best interest, if the disease gets worse or comes back requiring further treatment, if intolerable side effects occur, if not enough NK cells can be collected, or if you are unable to follow study directions.
  If for any reason you want to leave the study early, you must talk to the study doctor. It may be life-threatening to leave the study after you have started to receive the study drugs but before you receive the stem cell transplant because your blood cell counts will be dangerously low.

Eligibility: Inclusion Criteria:
  1. Patients age 18 to 65 years old. Eligibility for pediatric patients will be determined in conjunction with an MDACC pediatrician. Patients age 2-17 years old may be enrolled after at least 4 adults (ages 18-65 years old) have been treated without toxicity, as defined in the Statistical Considerations section.
  2. Patient with no matched related donor who has a related haploidentical donor identified (</= 7/8 allele match at the A, B, C,DR loci) who is willing to undergo a bone marrow harvest and an NK cell collection approximately 2 weeks of the recipient's admission for transplant. The donor must be 16 years of age or older and weigh at least 110 pounds.
  3. Patients with one of the following diseases: Acute myeloid leukemia (AML): a. First complete remission with high-risk features defined as: (i) Greater than 1 cycle of induction therapy required to achieve remission; (ii) Preceding myelodysplastic syndrome (MDS); (iii) Presence of FLT3 mutations or internal tandem duplication or other mutations associated with poor-risk AML (e.g. DNMT3A, TET2); (iv) FAB M6 or M7 classification; (v) Adverse cytogenetics: -5, del 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype [> 3 abnormalities]; (vi) Treatment-related AML, or b. Second or greater remission; patients beyond second remission have to be in CR at transplant to be eligible, or c. Primary induction failure with partial response to therapy who achieve adequate cytoreduction.
  4. Patients with myelodysplastic syndromes (MDS): a. De novo MDS with intermediate or high-risk IPSS scores. Patients with intermediate-1 features should have failed to respond to hypomethylating agent therapy, or b. Patients with treatment-related MDS.
  5. Chronic myeloid leukemia (CML): a. Failed to achieve cytogenetic remission or have cytogenetic relapse after treatment with at least 2 tyrosine kinase inhibitors, or b. Accelerated phase or blast phase at any time.
  6. Performance score of at least 70% by Karnofsky or 0 to 1 by ECOG (age >/= 12 years), or Lansky Play-Performance Scale of at least 70% or greater (age <12 years).
  7. Adequate major organ system function as demonstrated by: Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockcroft-Gault formula).
  8. Bilirubin equal or less than 1.5 mg/dl except for Gilbert's disease. ALT or AST equal or less than 200 IU/ml for adults. Conjugated (direct) bilirubin less than 2x upper limit of normal.
  9. Left ventricular ejection fraction equal or greater than 40%.
  10. Diffusing capacity for carbon monoxide (DLCO) equal or greater than 50% predicted corrected for hemoglobin. For children </= 7 years of age who are unable to perform PFT, oxygen saturation >/= 92% on room air by pulse oximetry.
  11. Patient or patient's legal representative, parent(s) or guardian should provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years.
  Exclusion Criteria:
  1. HIV positive; active hepatitis B or C.
  2. Uncontrolled infections; PI is the final arbiter of this criterion.
  3. Liver cirrhosis.
  4. CNS involvement within 3 months.
  5. Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.
  6. Inability to comply with medical therapy or follow-up.

Relevance to patient case: not relevant