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Tumor-Infiltrating Lymphocytes After Combination Chemotherapy in Treating Patients With Metastatic Melanoma

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Recurrent Melanoma of the Skin; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

Intervention: Aldesleukin (Biological); Cyclophosphamide (Drug); Fludarabine Phosphate (Drug); Laboratory Biomarker Analysis (Other); Therapeutic Tumor Infiltrating Lymphocytes (Biological)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Sylvia Lee, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

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 or by stopping them from dividing. Giving TIL after combination chemotherapy may kill more tumor cells.

Clinical Details

Official title: Cellular Adoptive Immunotherapy Using Autologous Tumor-Infiltrating Lymphocytes Following Lymphodepletion With Cyclophosphamide and Fludarabine for Patients With Metastatic Melanoma

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Clinical response, assessed using Response Evaluation Criteria in Solid Tumors 1.1 definitions for complete response, partial response, stable disease, and progressive disease

Secondary outcome:

In vivo persistence of adoptively transferred T cells following TIL infusion

Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Percent expression of biomarkers

Detailed description: PRIMARY OBJECTIVES: I. Examine the anti-tumor efficacy of cellular adoptive immunotherapy in metastatic melanoma patients using autologous tumor-infiltrating lymphocytes with a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine (fludarabine phosphate), and followed by adjuvant high-dose interleukin (IL)-2 (aldesleukin). SECONDARY OBJECTIVES: I. Determine the in vivo persistence of transferred tumor-infiltrating lymphocytes. II. Examine the safety of cellular adoptive immunotherapy in melanoma patients using autologous tumor-infiltrating lymphocytes, preceded by a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine, and followed by adjuvant high-dose IL-2. III. Evaluate for molecular tumor markers and immunohistochemical features that correlate with in vivo persistence and anti-tumor efficacy. OUTLINE:

Patients receive cyclophosphamide intravenously (IV) on days - 7 to -6 and fludarabine

phosphate IV on days - 5 to -1. Patients undergo TIL infusion over 30-60 minutes on day 0 and

receive aldesleukin IV every 8 hours on days 1-5 for up to a maximum of 14 doses. After completion of study treatment, patients are followed up at 6, 12, and 24 weeks.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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 an 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 at time of lymphodepletion

- 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, 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

- 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 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 Modification of Diet in Renal Disease (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

Locations and Contacts

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
Sylvia M. Lee, Phone: 206-288-2274, Email: leesm@u.washington.edu
Sylvia M. Lee, Principal Investigator
Additional Information

Starting date: July 2013
Last updated: July 21, 2015

Page last updated: August 23, 2015

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