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Clinical Trial 16992

Study Title
A Phase II Clinical Trial of Vemurafenib with Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Patients with Metastatic Melanoma

Summary
The investigators want to find out more about the effects of an investigational combination of medicines, which includes special immune cells (T-cells). A T-cell is a type of lymphocyte, or white blood cell. Lymphocytes are a kind of white blood cell that protect the body from viral infections, help other cells fight bacterial and fungal infections, produce antibodies, fight cancers, and coordinate the activities of other cells in the immune system.


Inclusion Criteria
  • Age greater than or equal to 18 years
  • Patients must have unresectable metastatic stage IV melanoma or stage III intransit or regional nodal disease and in the opinion of the PI or treating Coinvestigator is an acceptable candidate for ACT.
  • Residual measurable disease after resection of target lesion(s) for TIL growth
  • Tumor must have a B-RAF V600E, D or K mutation by pyrosequencing, Cobas assay, or equivalent (43)
  • Clinical performance status of ECOG 0 - 1. ECOG performance status of 0-1 will be inferred if the patient's level of energy is ≥ 50% of baseline.
  • Patients may be treatment-naïve or may have been previously treated for metastatic disease.
  • Women of childbearing potential (defined as having a menstrual cycle within the past 12 months and not having had a surgical procedure to accomplish sterilization) must have a negative serum pregnancy test within seven days of starting the Vemurafenib.
  • Adequate renal, hepatic and hematologic function, including creatinine of less than or equal to 1.7 gm/dL, 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, AST and ALT of less than 3X institutional upper limit of normal, hemoglobin of 8 gm/dL or more, WBC of 3000 per mcL and total granulocytes of 1000 per mcL or more, and platelets of 100,000 per mcL or more.
  • Patients must have a positive screening EBV antibody titre on screening test.
  • Patients with antibiotic allergies per se are not excluded; although the production of TIL for adoptive transfer includes antibiotics, extensive washing after harvest will minimize systemic exposure to antibiotics.
  • At screening, patients with ≤ 3 untreated central nervous system (CNS) metastases may be included provided none of the untreated lesions are > 1 cm in greatest dimension, and there is no peri-tumoral edema present on brain imaging (MRI or CT if MRI is contraindicated).
  • At screening, patients with ≤ 3 treated CNS metastases treated with either surgical resection and/or radiation therapy may be included. Patients may be included if the largest lesion is ≤ 1 cm, and there is no evidence of progressive CNS disease on brain imaging at least 28 days after treatment.
  • At screening, patients may be included if the largest lesion is > 1 cm or > 3 in number, if the patient has underdone treatment with surgery and/or radiation therapy and there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment.
  • At screening, patients must have no known history of congenital long QT syndrome and must have a corrected mean QTc interval ≤ 450 msec at baseline.
  • No evidence of ongoing cardiac dysrhythmia ≥ grade 2 (NCI CTCAE, v4.0)
  • All laboratory and imaging studies must be completed and satisfactory within 30 days of signing the consent document, with the exceptions of: negative serum pregnancy test for women of child-bearing potential must be negative within 7 days of starting Vemurafenib, HLA-typing which will not be repeated if performed previously, and PFTs/cardiac stress tests whose results are valid for 6 months if performed previously.
Exclusion Criteria
  • Patients with active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illness of the cardiovascular, respiratory or immune system, which in the opinion of the PI or treating Coinvestigator is not acceptable risk for ACT, are excluded.
  • Patients testing positive for HIV titre, Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody, HTLV I or II antibody, or both RPR and FTA positive are excluded.
  • Patients who are pregnant or nursing are excluded.
  • Patients needing chronic, immunosuppressive systemic steroids are excluded
  • Patients with autoimmune diseases that require immunosuppressive medications are excluded.
  • 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
  • Patients with > 3 untreated CNS metastases or evidence of peri-tumoral edema will be excluded.
  • Patients with ≤ 3 untreated CNS metastases but with at least one lesion >1 cm or peri-tumoral edema will be excluded.
  • Patients with congenital long QT syndrome are excluded.
  • Patients with invasive malignancy other than melanoma at the time of enrollment and within 2 years prior to the first Vemurafenib administration are excluded, except for adequately treated (with curative intent) basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years.
  • Patients who are unable to swallow pills are excluded.
  • Patients with treated CNS metastases > 1 cm or > 3 in number will be excluded if there is evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy
  • Patients unable to comprehend and give informed consent are excluded.
  • Previous BRAF inhibitor treatment.
  • Male patients with female partners of childbearing potential who do not agree to use two FDA-accepted forms of contraception during sexual intercourse with women of child-bearing potential from the start of Vemurafenib and up to at least 6 months after discontinuing Vemurafenib are excluded.
  • Female patients of childbearing potential who do not agree to use two FDA forms of contraception during sexual intercourse from the start of Vemurafenib and up to at least 6 months after discontinuing Vemurafenib are excluded.
The co-primary objectives of this study will be to improve the drop-out rate in patients undergoing ACT, and to improve the 12 month PR + CR rate based upon RECIST 1.1 criteria on an intention-to-treat basis. A secondary objective is an evaluation of progression-free survival.
See other Clinical Trials
  • Conditions
    Cutaneous
     
  • Interventions
    cyclophosphamide; fludarabine; IL-2; cytoxan; RO5185426; TIL; Vemurafenib; Zelboraf
  • Study Type
    Therapeutic
  • Phase of Study:
    Phase II
  • Recruitment Status
    Open

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