Clinical Trials /

Genetically Modified T-Cells Followed by Aldesleukin in Treating Patients With Stage III-IV Melanoma

NCT01955460

Description:

This pilot phase I trial studies the side effects and best dose of genetically modified T-cells followed by aldesleukin in treating patients with stage III-IV melanoma. T-cells are a type of white blood cell that help the body fight infections. Genes that may help the T-cells recognize melanoma cells are placed into the T-cells in the laboratory. Adding these genes to the T cells may help them kill more tumor cells when they are put back in the body. Aldesleukin may enhance this effect by stimulating white blood cells to kill more melanoma cells.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Lymphodepletion Plus Adoptive Cell Transfer With TGF-beta Resistant (DNRII) and NGFR Transduced T-Cells Followed by High Dose Interleukin-2 in Participants With Metastatic Melanoma
  • Official Title: A Pilot Study of Lymphodepletion Plus Adoptive Cell Transfer With TGF-beta Resistant (DNRII) and NGFR Transduced T-Cells Followed by High Dose Interleukin-2 in Participants With Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 2012-0758
  • SECONDARY ID: RP110553-P4
  • SECONDARY ID: NCI-2014-01211
  • NCT ID: NCT01955460

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
CyclophosphamideCytoxan, NeosarT-Cells + Chemotherapy
MesnaMesnexT-Cells + Chemotherapy
Fludarabine monophosphateFludarabine phosphate, FludaraT-Cells + Chemotherapy
T-CellsT-Cells + Chemotherapy
Interleukin-2 (IL-2)Aldesleukin, IL-2, ProleukinT-Cells + Chemotherapy

Purpose

This is a pilot study to assess the feasibility and safety of producing sufficient quantities of T-cells injected with the genes TGFb-DNR and NGFR that can be given in combination with chemotherapy (cyclophosphamide and fludarabine) and aldesleukin to patients with metastatic melanoma. This study involves gene therapy. T-cells are types of white blood cells that help your body fight infections. They may recognize and kill melanoma cells. Researchers want to grow your T-cells in a laboratory, inject them with TGFb-DNR and NGFR genes which may help them recognize tumor cells, and then give them back to you by vein. This may help to control melanoma.

Detailed Description

      15 patients will be treated. Patients will receive T-cells transduced with DNRII as well as
      T- cells transduced with NGFR (as a control gene).

      All participants will receive the same dose level of cyclophosphamide, fludarabine, and
      aldesleukin.

      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, as explained below.

      On Days -7 and -6, you will receive cyclophosphamide by vein over about 2 hours. You will
      also receive furosemide by vein over about 60 minutes to try to increase the amount of urine
      your body makes.

      On Day -7, you will receive mesna by vein non-stop over about 24 hours. Mesna is given to
      help protect the bladder from side effects of cyclophosphamide.

      You will take trimethoprim and sulfamethoxazole (SMX) by mouth 2 times a day, starting on
      Day -7 and continuing for at least 6 months after chemotherapy. SMX is given to lower your
      risk of side effects.

      On Days -5 to -1, you will receive fludarabine by vein over about 15-30 minutes.

      On Day 0, you will receive TGFb-DNR and NGFR T-cells through a central venous catheter (CVC)
      for up to 4 hours, or possibly more if your doctor thinks it is needed. 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. Other catheters may be needed in one 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 the risks in more detail.

      Starting on Day 0:

        -  You will receive levofloxacin with or without food by mouth or by vein over about 60
           minutes 1 time a day until your white blood cell count rises. Levofloxacin is designed
           to prevent infection caused by bacteria.

        -  You will take fluconazole by mouth 1 time a day for 6 months after chemotherapy.
           Fluconazole is designed to treat fungal infections.

        -  You will take Valtrex by mouth (or acyclovir by vein over about 60 minutes if you are
           unable to take Valtrex by mouth) 1 time a day for 6 months after chemotherapy. These
           drugs treat infections caused by the herpes viruses.

      On Days 1-5, you will receive aldesleukin by catheter over about 15 minutes every 8-16 hours
      for up to 15 doses. On Days 22-26, you will receive aldesleukin by catheter over about 15
      minutes every 8-16 hours for up to 15 doses. You will only receive aldesleukin if your
      platelet counts are high enough.

      You will be in the hospital over the course of about 7 days each time you receive
      aldesleukin. You will be expected to stay in the Houston area for at least 14 days in order
      to take part in the chemotherapy and cell infusion parts of the study.

      You will be given standard drugs to help decrease the risk of side effects and/or to treat
      side effects (such as allergic reactions, nausea/vomiting, or low blood cell counts). These
      drugs may include Tylenol (acetaminophen), ondansetron, and filgrastim). You may ask the
      study staff for information about their risks.

      Study Visits:

      Every 1-2 days during Days -7 to 26, blood (about 3 teaspoons) will be drawn for routine
      tests. Every day during this time, you will have a physical exam.

      On Day 0:

      Your vital signs will be measured before the TGFb-DNR and NGFR T-cell infusion, every 15
      minutes (+/- 10 minutes) during the infusion, and then 1 time an hour (+/- 30 minutes) for 4
      hours after the infusion.

      On Days 3 and 21 (+/- 7 days) after the T-cell infusion, blood (about 2 teaspoons) sample
      will be drawn check for the presence of CMV. The study staff will check your CMV levels at
      Day 3 (+/- 24 hours) and Day 21 (+/- 7days) after TIL infusion as an added precaution.

      On Day 6 (+/- 3 days) and Day 21 (+/- 7 days) if possible, blood (about 4½ tablespoons) will
      be drawn to test the level and activity of the cells.

      At about 6 and 12 weeks, the following tests and procedures will be performed:

        -  You will have a physical exam, including measurement of your vital signs and weight.

        -  Blood (about 4½ tablespoons) will be drawn to test the frequency and activity of the
           T-cells.

        -  You will have a CT or PET/CT scan of the chest, abdomen, and pelvis to check the status
           of the disease.

        -  You will have an MRI or CT scan of the brain to check the status of the disease.

        -  You will have any other tests that the study doctor thinks are needed.

      Length of Study Drug Dosing:

      You may receive up to 2 rounds of the study drugs (up to 24 weeks total). 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 once you have completed the follow-up visits.

      Long-Term Follow-Up:

      At about 6 and 12 months after you stop receiving the study drugs and T-cells, blood (about
      1 tablespoon) will be drawn to check the activity of the T-cells.

      After the first 12 months, you will return to MD Anderson once a year for at least 5 years.
      The following tests and procedures will be performed:

        -  You will have a physical exam.

        -  Blood (about 4 tablespoons) will be drawn for routine tests.

        -  You will have a CT or PET/CT scan of the chest, abdomen, and pelvis.

        -  You will have an MRI or CT scan of the brain.

      This is an investigational study. TGFb-DNR and NGFR T-cells are not FDA approved or
      commercially available. They are currently being used for research purposes only.

      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
      investigational to give cyclophosphamide and fludarabine to patients with metastatic
      melanoma.

      Aldesleukin is FDA approved and commercially available for the treatment of metastatic
      melanoma and a type of kidney cancer.

      The study doctor can explain how the study drug(s) are designed to work.

      Up to 15 participants will be enrolled in this study. All will take part at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
T-Cells + ChemotherapyExperimentalPatients receive T-cells transduced with DNRII as well as T- cells transduced with NGFR (as a control gene). Cytoxan administered at 60 mg/kg/day by vein over approximately 2 hours on Days -7 and -6. Mesna 60 mg/kg by vein over 24 hours on Days -7 and -6. Fludarabine 25 mg/m2 by vein daily over approximately 15-30 minutes on Days -5 to -1. On day 0, all patients receive the assigned dose level of transduced DNRII TIL, with an equal number of transduced NGFR TIL, up to a total of 1.5 x 10^11 TIL in NS. Twelve (12) to sixteen (16) hours after completing the T cell infusion, all patients receive high dose interleukin-2 (IL-2) on an inpatient basis at the standard dose of 720,000 IU/kg as an intravenous bolus over an approximate 15 minute period every 8-16 hours for up to 15 doses on Days 1 to 5 and 22-26.
  • Cyclophosphamide
  • Mesna
  • Fludarabine monophosphate
  • Interleukin-2 (IL-2)

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have metastatic melanoma or stage III in-transit, subcutaneous, or
             regional nodal disease (turnstile I).

          2. Patients must have a lesion amenable to resection for the generation of TIL
             (Turnstile I).

          3. Patients must receive an MRI/CT/PET of the brain within 6 months of signing informed
             consent. If new lesions are present, patient must have definitive treatment. PI or
             his designee should make final determination regarding enrollment (Turnstile I).

          4. Age greater than or equal to 12 years (Turnstile I).

          5. Clinical performance status of ECOG 0-2 within 30 days of signing informed consent
             (Turnstile I).

          6. Patients previously treated with immunotherapy, targeted therapy, or no therapy
             (treatment naive) will be eligible (Turnstile I).

          7. Patients receiving cytotoxic agents will be evaluated by the PI or his designee for
             eligibility suitability (Turnstile I).

          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) (Turnstile I).

          9. Patients must have adequate TIL available (Turnstile II). Pre-REP TIL generated in
             the similar clinical trial 2004-0069 may also be utilized for Turnstile II.

         10. Patients must have at least one biopsiable measurable metastatic melanoma, lesion >
             or = to1cm (Turnstile II).

         11. Patients may have brain lesions </= 1cm each. The PI or designee will approve the
             treatment. (Turnstile II)

         12. 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 menstruation in the past 12 months and without
             sterilization surgery (Turnstile II).

         13. 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).

         14. Patients with 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 menses at any time in the preceding 12
             consecutive months (Turnstile II).

         15. Clinical performance status of ECOG 0-2 within 30 days of signing Informed Consent
             (Turnstile II).

         16. Absolute neutrophil count greater than or equal to 1000/mm3 (Turnstile II).

         17. Platelet count greater than or equal to 100,000/mm3 (Turnstile II).

         18. Hemoglobin greater than or equal to 8.0 g/dl (Turnstile II).

         19. Serum ALT less than three times the upper limit of normal (Turnstile II).

         20. Serum creatinine less than or equal to 1.6 mg/dl (Turnstile II).

         21. 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).

         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).

         23. Pulmonary function tests (FEV1>65% or FVC>65%of predicted) within 6 months of
             lymphodepletion (Turnstile II).

         24. MRI/CT/PET of the brain within 30 days of lymphodepletion (Turnstile II).

        Exclusion Criteria:

          1. 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 (Turnstile I).

          2. Primary immunodeficiency and need for chronic steroid therapy, however prednisone is
             allowed at < 10 mg/day. (Turnstile I)

          3. Patients who are pregnant or nursing (Turnstile I).

          4. Presence of a significant psychiatric disease, which in the opinion of the principal
             investigator or his designee, would prevent adequate informed consent (Turnstile I).

          5. Has had prior systemic cancer therapy within the past four weeks or B-RAF or MEK
             inhibitors within 7 days at the time of the start of the lymphodepletion regimen
             (Turnstile II).

          6. Women who are pregnant will be excluded because of the potentially dangerous effects
             of the preparative chemotherapy on the fetus (Turnstile II).

          7. 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 (Turnstile II).

          8. 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).

          9. Require steroid therapy or steroid-containing compounds, or have used systemic
             steroids in the past 4 weeks, or have used topical or inhalational steroids in the
             past 2 weeks prior to lymphodepletion; the exception being patients on chronic
             physiologic dose of steroid (Turnstile II).

         10. 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Feasibility of Producing Sufficient Quantities of TFGâ-DNRII and NGFR Transduced TIL for Treatment of Metastatic Melanoma
Time Frame:12 weeks
Safety Issue:
Description:Feasibility defined as the production of virally transduced T cells and treatment of patients with these cells. Trial considered successful if the treatment is feasible in at least 12 patients.

Secondary Outcome Measures

Measure:Response of Autologous TGFb Resistant (DNRII Transduced) and NGFR Transduced TIL in Participants with Metastatic Melanoma
Time Frame:6 and 12 weeks
Safety Issue:
Description:Tumor response to therapy in this study done by using immune-related response criteria (irRC) which is a modified version of WHO criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Melanoma
  • Metastatic
  • T-cells
  • Autologous tumor infiltrating lymphocytes
  • TIL
  • DNRII
  • NGFR
  • Cyclophosphamide
  • Cytoxan
  • Neosar
  • Mesna
  • Mesnex
  • Fludarabine
  • Fludarabine phosphate
  • Fludara
  • Interleukin-2
  • IL-2
  • Aldesleukin
  • Proleukin

Last Updated

December 12, 2016