In Vivo Persistence of Adoptively-Transferred TIL Cultured With Akti in People With Metastatic Melanoma
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|ClinicalTrials.gov Identifier: NCT02489266|
Recruitment Status : Withdrawn
First Posted : July 3, 2015
Last Update Posted : July 27, 2017
- One cancer therapy involves taking white blood cells from a person, changing them in a lab, and then giving the cells back to the person. These cells are called tumor infiltrating lymphocytes (TIL). Researchers want to grow some of the TIL cells with the drug Akti to see if they live longer than those grown without it.
- To see if TIL cells grown with Akti live longer than those grown without it.
- Adults 18 70 with metastatic melanoma
- Participants will:
- Be screened with tests including scans, x-rays, heart and lung tests, blood and urine tests, and a <TAB>possible colonoscopy.
- Have tumor surgery or biopsy.
- Have a large catheter inserted into a vein in the upper chest.
- Receive leukapheresis for 4 5 hours. Blood is removed through a needle in an arm. White blood cells <TAB>are removed. The rest of the blood is returned by needle in the other arm.
- The cells will be changed in a laboratory.
- Participants will check into the hospital and:
- For 5 days, get 1 2 chemotherapy drugs by catheter.
- For 1 3 days, get the changed cells by catheter.
- For several days, get 2 drugs to stimulate cells, one by injection, the other by catheter.
- For 7 12 days, recover in the hospital.
- After treatment, participants will:
- Take an antibiotic and antiviral for at least 6 months.
- Return to NIH for several 2-day visits for a few years. At each visit, participants will have lab tests, imaging studies, and a physical exam. At some visits, they may have leukapheresis or blood tests.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Melanoma||Biological: AKTi-treated TIL Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldesleukin||Phase 1|
- Adoptive cellular immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) can mediate regression of bulky metastatic melanoma when administered with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
- Regression of tumor in mouse models and humans strongly correlates with anti-tumor T cells that exhibit features of immunologic memory and have a capacity to persist for long periods after adoptive-transfer into tumor-bearing hosts.
- In our preclinical work with TIL, we have identified a pharmacologic inhibitor of AKT that promotes features of immunologic memory in TIL (as evidenced by transcriptomic, proteomic, metabolomic, and functional assays described in the Background section). Consistently, AKT inhibition of human TIL significantly enhances persistence after adoptive-transfer into an immunodeficient mouse model.
- We therefore aim to evaluate whether pharmacologic inhibition of AKT in TIL may enhance persistence after adoptive-transfer into patients with advanced melanoma.
- To determine whether ACT using TIL cultured in a pharmacologic inhibitor of AKT (during ex vivo expansion) results in enhanced in vivo persistence of TIL after adoptive transfer into autologous patients with advanced melanoma.
- Determine the toxicity profile of this treatment regimen.
- Determine whether ACT using a combination of AKTi-treated and conventional TIL can mediate tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors) guidelines in patients with advanced melanoma.
- Age greater than or equal to 18 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
- Patients with metastatic melanoma will undergo ACT in conventional manner, with the exception that half of tumor fragments from which TIL are isolated will be cultured in the presence of a pharmacologic AKT inhibitor. Prior to infusion of TIL, the AKT inhibitor (hereafter AKTi) will be washed from the therapeutic TIL product and will not be systemically administered. Each patient will receive a 1:1 mixture of conventional TIL and AKTi-treated TIL. To evaluate persistence of AKTi-treated and conventional TIL after adoptive co-transfer, we will perform high-throughput deep sequencing of the TCR V-beta CDR3 region of TIL from the infusion-bag and from peripheral blood when sufficient lymphocyte reconstitution (>200 lymphocytes/microliter) has occurred and approximately 4-6 weeks after infusion.
- Up to 20 patients may be enrolled over 20-24 months.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||0 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Trial for the Evaluation of the In Vivo Persistence of Adoptively-transferred Tumor-Infiltrating Lymphocytes Cultured With a Pharmacologic Inhibitor of AKT in Patients With Metastatic Melanoma|
|Study Start Date :||June 24, 2015|
|Actual Primary Completion Date :||June 29, 2016|
|Actual Study Completion Date :||June 29, 2016|
Experimental: Arm 1
Patients will receive cyclophosphamide and fludarabine followed by infusion of the AKTi-treated TIL, followed by high dose aldesleukin.
Biological: AKTi-treated TIL
On day 0, cells will be infused intravenously (IV) over 20-30 minutes (between 1 and 4 days after the last dose of fludarabine).Drug: Cyclophosphamide
Patients will receive Cyclophosphamide 60 mg/kg/day x 2 days.Drug: Fludarabine
Patients will receive Fludarabine 25 mg/m2/day for 5 days.Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).
- Determine whether ACT using TIL cultured in a pharmacologic inhibitor of AktKT (during ex vivo expansion) results in enhanced in vivo persistence of TIL after adoptive transfer into autologous patients with advanced melanoma. [ Time Frame: 4 years ]
- Determine whether ACT using a combination of conventional and AKTi-treated TIL can mediate tumor regression by RECIST guidelines in patients with advanced melanoma [ Time Frame: 4 years ]
- Determine the toxicity profile of this treatment regimen. [ Time Frame: 4 years ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02489266
|Principal Investigator:||Steven A Rosenberg, M.D.||National Cancer Institute (NCI)|