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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01807182
First received: March 6, 2013
Last updated: September 12, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Recurrent Melanoma
Stage IIIA Melanoma
Stage IIIB Melanoma
Stage IIIC Melanoma
Stage IV Melanoma
Drug: cyclophosphamide
Drug: fludarabine phosphate
Biological: therapeutic tumor infiltrating lymphocytes
Biological: aldesleukin
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Cellular Adoptive Immunotherapy Using Autologous Tumor-Infiltrating Lymphocytes Following Lymphodepletion With Cyclophosphamide and Fludarabine for Patients With Metastatic Melanoma

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Clinical response, assessed using Response Evaluation Criteria in Solid Tumors 1.1 definitions for complete response, partial response, stable disease, and progressive disease [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • In vivo persistence of adoptively transferred T cells following TIL infusion [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]
  • Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: Yes ]
  • Percent expression of biomarkers [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]
    Logistic regression will be used to assess these correlations.


Estimated Enrollment: 40
Study Start Date: July 2013
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (TIL, combination chemotherapy, aldesleukin)
Patients receive cyclophosphamide 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.
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: therapeutic tumor infiltrating lymphocytes
Undergo TIL infusion
Other Name: tumor infiltrating lymphocytes
Biological: aldesleukin
Given IV
Other Names:
  • IL-2
  • Proleukin
  • recombinant human interleukin-2
  • recombinant interleukin-2
Other: laboratory biomarker analysis
Correlative studies

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • A stress cardiac test (e.g., stress treadmill, stress thallium, stress multi gated acquisition scan [MUGA], dobutamine echocardiogram) to rule out cardiac ischemia within 4 months before Step I is required for patients with a history of cardiac disease
  • 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 up to 2 asymptomatic brain lesions < 1cm each; 1-3 lesions that are > 1cm that have been irradiated and in the opinion of the investigator no longer represents active disease will also be allowed
  • A stress cardiac test (e.g., stress treadmill, stress thallium, stress 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:
  • Pregnant women, nursing mothers, 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]) < 60ml/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); PFTs within 4 months prior to consent for Step I will be required for patients with underlying risk factors such as smoking history, or history of lung disease
  • Significant 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 this 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 principal investigator (PI) or sub-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 7 days prior to entry; patients of both genders must practice birth control during treatment and for four months after treatment
  • Calculated creatinine clearance (eGFR) < 60ml/min
  • 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)
  • Significant 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% (echocardiogram or MUGA), although any patient with an ejection fraction between 45-49% must receive clearance by a cardiologist to be eligible for this trial
  • Absolute neutrophil count less than 1000/mm^3
  • Platelet count less than 100,000/mm^3
  • Hemoglobin less than 10.0g/dl
  • Untreated central nervous system metastases that are either symptomatic or greater than 1 cm at time of therapy; 1-3 lesions that are > 1cm that have been treated with stereotactic radiosurgery (SRS) 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., 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) or topical steroids within 2 weeks prior to lymphodepletion
  • Any other significant medical or psychological conditions that would make the patient unsuitable candidate for cell therapy at the discretion of the PI
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01807182

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Sylvia M. Lee    206-667-2218      
Principal Investigator: Sylvia M. Lee         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Sylvia Lee Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01807182     History of Changes
Other Study ID Numbers: 2643.00, NCI-2013-00486, 2643.00, P30CA015704
Study First Received: March 6, 2013
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Nevi and Melanomas
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Aldesleukin
Interleukin-2
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents

ClinicalTrials.gov processed this record on September 16, 2014