Tumor-Infiltrating Lymphocytes After Combination Chemotherapy in Treating Patients With Metastatic Melanoma
Condition: Stage III Cutaneous Melanoma AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Metastatic Melanoma
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Aldesleukin; Cyclophosphamide; Fludarabine Phosphate; Laboratory Biomarker Analysis; Therapeutic Tumor Infiltrating Lymphocytes
Intervention description: Given IV; Given IV; Given IV; Correlative studies; Undergo TIL infusion
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well tumor-infiltrating lymphocytes (TIL) after combination
      chemotherapy works in treating patients with melanoma that has spread to other places in the
      body. Biological therapies, such as TIL, may stimulate the immune system in different ways
      and stop tumor cells from growing. Drugs used in chemotherapy, such as cyclophosphamide and
      fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by
      killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving
      TIL after combination chemotherapy may kill more tumor cells.
    

Eligibility criteria:

        Inclusion Criteria:

        Step I Inclusion Criteria:

          -  Stage IV melanoma or stage III melanoma that is unlikely to be cured by surgery

          -  Able to tolerate high-dose cyclophosphamide, fludarabine and high-dose IL-2

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Patients must have a magnetic resonance imaging (MRI), computed tomography (CT), or
             positron emission tomography (PET) of the brain within 2 months before consenting if
             known history of brain metastasis or if clinically indicated; if new lesions are
             present, principal investigator (PI) or designee should make final determination
             regarding enrollment

          -  Patients must have a site of metastatic disease that can be safely resected or
             biopsied for tissue sufficient for TIL harvest

        Step II Inclusion Criteria:

          -  Patients must have measurable metastatic melanoma

          -  Able to tolerate high-dose cyclophosphamide, fludarabine, and high-dose IL-2

          -  ECOG performance status of 0-1

          -  Patients must have brain imaging by MRI, CT or PET within 30 days prior to
             lymphodepletion; patients may have asymptomatic brain lesions that are =< 1 cm each,
             lesions that are > 1 cm that have been irradiated and in the opinion of the
             investigator no longer represents active disease will also be allowed

          -  A functional cardiac test (e.g., stress treadmill, stress thallium, multigated
             acquisition scan (MUGA), dobutamine echocardiogram) to rule out cardiac ischemia
             within 4 months prior to lymphodepletion is required for all patients

          -  Pulmonary function tests (PFTs) are required of all patients within 4 months prior to
             lymphodepletion; forced expiratory volume (FEV)1 and forced vital capacity (FVC) must
             be >= 65% predicted and diffusion lung capacity for carbon monoxide (DLCO) must be >=
             50% predicted

          -  Patients must have their tumor sent for v-Raf murine sarcoma viral oncogene homolog
             B1(BRAF) mutational analysis

          -  Patients must have adequate TIL (at least 40 x 10^6 cells at the pre-expansion stage)

        Exclusion Criteria:

        Step I Exclusion Criteria:

          -  Men or women of reproductive ability who are unwilling to use effective contraception
             or abstinence for 4 months after treatment

          -  Calculated creatinine clearance (estimated glomerular filtration rate [eGFR]) < 60
             ml/min; EGFR values can be determined by either Modification of Diet in Renal Disease
             (MDRD) or Cockcroft-Gault equation based on the investigator's discretion

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 x upper limit of
             normal

          -  Total bilirubin > 2.0 mg/dl, except in patients with Gilbert's syndrome whose total
             bilirubin must not exceed 3.0 mg/dl) deemed by investigator to be irreversible

          -  FEV1 < 65% predicted, FVC < 65% of predicted, DLCO (corrected for hemoglobin [Hgb]) <
             50% predicted); pulmonary function tests (PFTs) within 4 months prior to consent for
             Step I will be required for patients with underlying risk factors such as smoking
             history > 10 pack years, or a history of pre-existing symptomatic lung disease (not
             including melanoma metastases to the lung)

          -  Pre-existing known cardiovascular abnormalities as defined by any one of the
             following:

               -  Congestive heart failure

               -  Clinically significant hypotension

               -  Cardiac ischemia, or symptoms of coronary artery disease

               -  Presence of cardiac arrhythmias on electrocardiogram (EKG) requiring drug therapy

               -  Ejection fraction < 45% (echocardiogram or MUGA), although any patient with an
                  ejection fraction between 45-49% must receive clearance by a cardiologist to be
                  eligible for Step II of the trial

          -  Clinically significant autoimmune disorders or conditions of immunosuppression;
             patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency
             virus (HIV)-1 associated complex or known to be HIV antibody seropositive or known to
             be recently polymerase chain reaction (PCR)+ for hepatitis B or C are not eligible for
             this study; the severely depressed or altered immune system found in these patients
             and the possibility of premature death would compromise study objectives

          -  Patients with active systemic infection requiring intravenous antibiotics

          -  Clinically significant psychiatric disease which, in the opinion of the PI or
             sub-investigator (I), would render immunotherapy and its potential sequelae unsafe or
             compliance with procedural requirements unlikely

        Step II Exclusion Criteria:

          -  Pregnant women, nursing mothers, men or women of reproductive ability who are
             unwilling to use effective contraception or abstinence; women of childbearing
             potential must have a negative pregnancy test within 14 days prior to entry; patients
             of both genders must practice birth control during treatment and for four months after
             treatment

          -  Calculated creatinine clearance (eGFR) < 60 ml/min; EGFR values can be determined by
             either MDRD or Cockcroft-Gault equation based on the investigator's discretion

          -  AST/ALT > 3 x upper limit of normal

          -  Total bilirubin > 2.0 mg/dl, except in patients with Gilbert's syndrome whose total
             bilirubin must not exceed 3.0 mg/dl)

          -  Clinically significant pulmonary dysfunction (FEV1 < 65% predicted or FVC < 65% of
             predicted, DLCO (corrected for Hgb) < 50% predicted)

          -  Pre-existing known cardiovascular abnormalities as defined by any one of the
             following:

               -  Congestive heart failure

               -  Clinically significant hypotension

               -  Cardiac ischemia, or symptoms of coronary artery disease

               -  Presence of cardiac arrhythmias on EKG requiring drug therapy

               -  Ejection fraction < 45%, although any patient with an ejection fraction between
                  45-49% must receive clearance by a cardiologist to be eligible for Step II of
                  this trial

          -  Absolute neutrophil count less than 1000/mm^3

          -  Platelet count less than 100,000/mm^3

          -  Hemoglobin less than 10.0 g/dl

          -  Untreated central nervous system metastases that are either symptomatic or greater
             than 1 cm at time of therapy; lesions that are > 1cm that have been irradiated and in
             the opinion of the PI or sub-I no longer represent active disease may be allowed

          -  Patients with systemic infections requiring active therapy within 72 hours of
             lymphodepletion

          -  Systemic cancer therapy (standard or experimental), including cytotoxic chemotherapy
             or IL-2, received less than 4 weeks or checkpoint blocking agents (e.g., cytotoxic
             T-lymphocyte protein [CTLA]-4 or programmed cell death protein [PD]1/PD-ligand [L]1
             inhibitors) received less than 6 weeks prior to lymphodepletion, with the exception of
             targeted therapies

          -  Commercially available, molecularly targeted therapies (e.g., dabrafenib, trametinib,
             vemurafenib, imatinib) taken within 7 days prior to lymphodepletion

          -  Clinically significant autoimmune disorders or conditions of immunosuppression;
             patients with AIDS or HIV-1 associated complex or known to HIV antibody seropositive
             or known to be recently PCR+ for hepatitis B or C virus are not eligible for this
             study; virology testing will be done within 6 months of T cell infusion; the severely
             depressed or altered immune system found in these patients and the possibility of
             premature death would compromise study objectives

          -  Prior treatment with systemic steroids within 4 weeks prior to lymphodepletion (except
             for physiologic replacement doses for adrenal insufficiency, premedication for
             contrast allergies for scans, and for drug fever related to targeted therapy)

          -  Any other significant medical or psychological conditions that would make the patient
             unsuitable candidate for cell therapy at the discretion of the PI