Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-Small Cell Lung Cancer, or Head and Neck Cancer - Full Text View

Purpose

This phase I trial studies the side effects and best dose of recombinant interleukin-15 in treating patients with advanced melanoma, kidney cancer, non-small cell lung cancer, or head and neck cancer. Recombinant interleukin-15 may kill tumor cells by stopping blood flow to the tumor and by stimulating white blood cells to kill melanoma, kidney, non-small cell lung, and head and neck cancer cells.

Condition	Intervention	Phase
Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma Recurrent Adenoid Cystic Carcinoma of the Oral Cavity Recurrent Basal Cell Carcinoma of the Lip Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity Recurrent Lymphoepithelioma of the Nasopharynx Recurrent Lymphoepithelioma of the Oropharynx Recurrent Melanoma Recurrent Metastatic Squamous Neck Cancer With Occult Primary Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity Recurrent Mucoepidermoid Carcinoma of the Oral Cavity Recurrent Non-small Cell Lung Cancer Recurrent Renal Cell Cancer Recurrent Salivary Gland Cancer Recurrent Squamous Cell Carcinoma of the Hypopharynx Recurrent Squamous Cell Carcinoma of the Larynx Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity Recurrent Squamous Cell Carcinoma of the Nasopharynx Recurrent Squamous Cell Carcinoma of the Oropharynx Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Recurrent Verrucous Carcinoma of the Larynx Recurrent Verrucous Carcinoma of the Oral Cavity Stage III Adenoid Cystic Carcinoma of the Oral Cavity Stage III Basal Cell Carcinoma of the Lip Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity Stage III Lymphoepithelioma of the Nasopharynx Stage III Lymphoepithelioma of the Oropharynx Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity Stage III Mucoepidermoid Carcinoma of the Oral Cavity Stage III Renal Cell Cancer Stage III Salivary Gland Cancer Stage III Squamous Cell Carcinoma of the Hypopharynx Stage III Squamous Cell Carcinoma of the Larynx Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity Stage III Squamous Cell Carcinoma of the Nasopharynx Stage III Squamous Cell Carcinoma of the Oropharynx Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage III Verrucous Carcinoma of the Larynx Stage III Verrucous Carcinoma of the Oral Cavity Stage IIIA Melanoma Stage IIIA Non-small Cell Lung Cancer Stage IIIB Melanoma Stage IIIB Non-small Cell Lung Cancer Stage IIIC Melanoma Stage IV Lymphoepithelioma of the Nasopharynx Stage IV Melanoma Stage IV Non-small Cell Lung Cancer Stage IV Renal Cell Cancer Stage IV Squamous Cell Carcinoma of the Hypopharynx Stage IV Squamous Cell Carcinoma of the Nasopharynx Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity Stage IVA Basal Cell Carcinoma of the Lip Stage IVA Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity Stage IVA Inverted Papilloma of the Paranasal Sinus and Nasal Cavity Stage IVA Lymphoepithelioma of the Oropharynx Stage IVA Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity Stage IVA Mucoepidermoid Carcinoma of the Oral Cavity Stage IVA Salivary Gland Cancer Stage IVA Squamous Cell Carcinoma of the Larynx Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVA Squamous Cell Carcinoma of the Oropharynx Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage IVA Verrucous Carcinoma of the Larynx Stage IVA Verrucous Carcinoma of the Oral Cavity Stage IVB Adenoid Cystic Carcinoma of the Oral Cavity Stage IVB Basal Cell Carcinoma of the Lip Stage IVB Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity Stage IVB Inverted Papilloma of the Paranasal Sinus and Nasal Cavity Stage IVB Lymphoepithelioma of the Oropharynx Stage IVB Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity Stage IVB Mucoepidermoid Carcinoma of the Oral Cavity Stage IVB Salivary Gland Cancer Stage IVB Squamous Cell Carcinoma of the Larynx Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVB Squamous Cell Carcinoma of the Oropharynx Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage IVB Verrucous Carcinoma of the Larynx Stage IVB Verrucous Carcinoma of the Oral Cavity Stage IVC Adenoid Cystic Carcinoma of the Oral Cavity Stage IVC Basal Cell Carcinoma of the Lip Stage IVC Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity Stage IVC Inverted Papilloma of the Paranasal Sinus and Nasal Cavity Stage IVC Lymphoepithelioma of the Oropharynx Stage IVC Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity Stage IVC Mucoepidermoid Carcinoma of the Oral Cavity Stage IVC Salivary Gland Cancer Stage IVC Squamous Cell Carcinoma of the Larynx Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVC Squamous Cell Carcinoma of the Oropharynx Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage IVC Verrucous Carcinoma of the Larynx Stage IVC Verrucous Carcinoma of the Oral Cavity Tongue Cancer	Biological: recombinant interleukin-15 Other: pharmacological study Other: laboratory biomarker analysis	Phase 1

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase 1 Study of Recombinant Human IL15 (rhIL15) in Adults With Advanced Solid Tumors: Melanoma, Renal Cell, Non-Small Cell Lung and Head and Neck Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: neuroblastoma

MedlinePlus related topics: Benign Tumors Cancer Head and Neck Cancer Kidney Cancer Lung Cancer Melanoma Tonsils and Adenoids

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

MTD defined as the next lower dose in which 1 or more patients experiences a dose limiting toxicity (DLT) defined as grade 3 or 4 toxicity graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Total white blood cell (WBC) count [ Time Frame: Up to 4 months ] [ Designated as safety issue: No ]
The absolute increase in each cell subset as well as the variance in change across each dose level (mean, median, and standard error [SE]/standard deviation [SD] will be reported for each dose level and absolute lymphocyte count (ALC), circulating NK count, and circulating CD4/CD8 cell counts).
Absolute lymphocyte count [ Time Frame: Up to 4 months ] [ Designated as safety issue: No ]
The absolute increase in each cell subset as well as the variance in change across each dose level (mean, median, and SE/SD will be reported for each dose level and ALC, circulating NK count, and circulating CD4/CD8 cell counts).
Total number of T cells and NK cells, as well as activated T cells, T cell subsets and NK cell subsets assessed by flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
The percentage of cells positive for the marker and/or mean fluorescence intensity (MFI) at time points after rhIL15 administration will be compared to baseline and the change will be calculated as %after/ %baseline or MFI after/ MFI baseline.
Total number of T cells and NK cells, as well as activated T cells, T cell subsets and NK cell subsets assessed by flow cytometric analysis of PBMCs [ Time Frame: Day 11 ] [ Designated as safety issue: No ]
The percentage of cells positive for the marker and/or MFI at time points after rhIL15 administration will be compared to baseline and the change will be calculated as %after/ %baseline or MFI after/ MFI baseline.
T cell subset response to recall viral antigens including CMV and influenza A virus, determined by enzyme-linked immunosorbent spot (ELISPOT) assay [ Time Frame: Baseline ] [ Designated as safety issue: No ]
The absolute change in responses for each patient will be calculated by subtracting the spot forming cells (SFC)/million PBMC at day 11 from the SFC/million PBMC at baseline for each antigen.
T cell subset response to recall viral antigens including CMV and influenza A virus, determined by ELISPOT assay [ Time Frame: Day 11 ] [ Designated as safety issue: No ]
The absolute change in responses for each patient will be calculated by subtracting the SFC/million PBMC at day 11 from the SFC/million PBMC at baseline for each antigen.
T cell responses to non- physiologic stimuli including PMA [ Time Frame: Baseline ] [ Designated as safety issue: No ]
The absolute change in responses for each patient will be calculated by subtracting the SFC/million PBMC at day 11 from the SFC/million PBMC at baseline for each antigen.
T cell responses to non- physiologic stimuli including PMA [ Time Frame: Day 11 ] [ Designated as safety issue: No ]
The absolute change in responses for each patient will be calculated by subtracting the SFC/million PBMC at day 11 from the SFC/million PBMC at baseline for each antigen.
NK cell function measured using flow cytometric analysis of cytokine secretion and expression of degranulation marker CD107a [ Time Frame: Baseline ] [ Designated as safety issue: No ]
The absolute change in responses for each patient will be calculated by subtracting the SFC/million PBMC at day 11 from the SFC/million PBMC at baseline for each antigen.
NK cell function measured using flow cytometric analysis of cytokine secretion and expression of degranulation marker CD107a [ Time Frame: Day 11 ] [ Designated as safety issue: No ]
The absolute change in responses for each patient will be calculated by subtracting the SFC/million PBMC at day 11 from the SFC/million PBMC at baseline for each antigen.
Overall response rate (ORR) based on RECIST criteria [ Time Frame: Day 56 ] [ Designated as safety issue: No ]
Percentages and exact 2-sided 95% confidence intervals of the numbers in each of the overall response categories (complete response, partial response, stable disease and progressive disease) will be calculated for each dose cohort.
Serum PK of IL15 and IL15 receptor-alpha [ Time Frame: Pre-dose, 10 minute, 1, 4, and 24 hours ] [ Designated as safety issue: No ]
IL15 and IL15 receptor-alpha levels will be plotted over time for each dose group. The number and percentage of patients developing auto-antibodies to IL15 will be tabulated by dose cohort.
Presence of auto-antibodies, assessed by ELISA [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Presence of auto-antibodies, assessed by ELISA [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
Presence of auto-antibodies, assessed by ELISA [ Time Frame: Day 11 ] [ Designated as safety issue: No ]

Estimated Enrollment:	30
Study Start Date:	February 2013
Estimated Primary Completion Date:	December 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Treatment (recombinant interleukin-15) Patients receive recombinant interleukin-15 SC daily on days 1-5 and 8-12. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.	Biological: recombinant interleukin-15 Given SC Other Names: IL15 interleukin 15 Other: pharmacological study Correlative studies Other Name: pharmacological studies Other: laboratory biomarker analysis Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of recombinant human IL15 (recombinant interleukin-15) (rhIL15) administered subcutaneous.

SECONDARY OBJECTIVES:

I. To determine the effect of the dose schedules of rhIL15 on the number and phenotype of peripheral blood mononuclear cells including total white blood cell count, absolute lymphocyte count (ALC), total number of T cells and natural killer (NK) cells, as well as activated T cells, T cell subsets and NK cell subsets.

II. To determine the effect of the dose schedules of rhIL15 on the function of peripheral blood mononuclear cells including T cell subset response to recall viral antigens including cytomegalovirus (CMV) and influenza A virus, T cell responses to non- physiologic stimuli including: phytohemagglutinin (PHA), and NK cell cytokine (interferon gamma [IFN-y]) secretion and degranulation by cluster of differentiation 107a (CD107a) expression.

III. To assess tumor response rate by objective response rate (ORR). IV. To assess the immunogenicity, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of National Cancer Institute (NCI) rhIL15.

OUTLINE: This is a dose-escalation study.

Patients receive recombinant interleukin-15 subcutaneously (SC) daily on days 1-5 and 8-12. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 24 weeks.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients must have histological or cytological confirmed malignancy in the following disease groups: melanoma, non-small cell lung carcinoma, renal cell carcinoma or head and neck carcinoma, for which no standard effective or curative options are available
Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Documented evidence of disease progression during 6 month period prior to the time of enrollment
Prior therapy requirements:
- At least >= 1 prior completed chemotherapy regimen
- At least 4 weeks from last dose of prior chemotherapy with resolution of the acute toxic effects of the therapy
- At least 2 weeks from completion of prior radiation therapy
- At least 4 weeks from last dose of prior investigational therapy
- Not receiving any current anti-cancer therapy
- At least 4 weeks from last dose of interferon or interleukin (IL)-2 therapy
- At least 12 weeks from completion of antibody therapy with anti-checkpoint antibodies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and anti-programmed cell death 1 (PD1)
- At least 4 weeks from last dose of prior other biologic agents
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Karnofsky >= 70%)
Absolute lymphocytes >= 800/mcL
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Total bilirubin within normal institutional limits
Prothrombin time (PT)/partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN)
Hemoglobin (Hgb) >= 10 g/dL
Alkaline phosphatase =< 2.5 x ULN
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional upper limit of normal
Serum creatinine < 1.5 x ULN or creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
Thyroid function thyroxine (T4), thyroid stimulating hormone (TSH) within normal limits; pre-existing hypothyroidism is acceptable as long as patient has been stable on thyroid replacement for four months prior to entering the study
No known central nervous system (CNS) metastases or neurological symptoms possibly related to active CNS metastasis
Females of childbearing potential must have a negative pregnancy test within 48 hours prior to initiation of protocol therapy; note: subjects are considered not of child bearing potential if they are surgically sterile, they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy or they are postmenopausal; menopause is the age associated with complete cessation of menstrual cycles, menses, and implies the loss of reproductive potential; by a practical definition, it assumes menopause after 1 year without menses with an appropriate clinical profile at the appropriate age
Ability to understand and the willingness to sign a written informed consent document
No history of any hematopoietic malignancy
No active (as defined by requiring immunosuppressive therapy) or history of clinically significant autoimmune disease (as defined by previously requiring immunosuppressive therapy)
No evidence of a clinically significant active infection
No systemic or inhaled corticosteroids or immunosuppressive therapy within 30 days prior to initiation of protocol therapy; note: use of topical corticosteroids and/or eye drops containing glucocorticosteroids is acceptable
No history of severe asthma, as defined by prior or current use of systemic corticosteroids for disease control, with the exception of physiological replacement doses of cortisone acetate or equivalent, as defined by a dose of 10mg or less; note: history of mild asthma not requiring daily therapy is eligible
No history of pulmonary disease such as emphysema or chronic obstructive pulmonary disease (COPD), (forced expiratory volume in one second [FEV1] >= 2L or >= 75% of predicted for height and age); pulmonary function tests (PFTs) are required in patients with significant pulmonary or smoking history
No history of human immunodeficiency virus (HIV), active or chronic hepatitis B, hepatitis C or human T-cell lymphotropic virus (HTLV-I) infection; note: a positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antibody [HBsAb] positive and hepatitis B core antibody [HBcAb] negative), or a fully resolved acute hepatitis B virus (HBV) infection is not an exclusion criterion
Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal, barrier method of birth control or abstinence) from the time the consent is signed, during the duration of study participation and 4 months after discontinuation of protocol therapy
Females must not be breastfeeding
No evidence of clinically significant congestive heart failure, (ejection fraction of 45% or greater)
No platelet or blood transfusions within two weeks of obtaining baseline laboratory values
No blood modifiers while enrolled in the study (growth factors such as erythropoiesis-stimulating agent [ESA], filgrastim [G-CSF], platelet or blood transfusions)

Exclusion Criteria:

Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C), or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
Class II or greater congestive heart failure as described in the New York Heart Association Functional Classification criteria
Patients with primary brain cancer or known brain metastases should be excluded from this clinical trial
Patients who have received prior anti-CTLA4 or anti-PD1 therapy less than 12 weeks prior to enrollment
Patients who have received prior biologic agents less than 4 weeks prior to enrollment
Patients who have received prior interferon or IL-2 therapy less than 4 weeks prior to enrollment
Patients who are receiving any other investigational agents
ECOG score greater than 1 (Karnofsky < 70%)
HIV-positive patients
Positive hepatitis C serology
Inability to home monitor blood pressure
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01727076

Locations

United States, California
Stanford University Hospitals and Clinics	Not yet recruiting
Stanford, California, United States, 94305
Contact: Holbrook Kohrt 650-723-8222 kohrt@stanford.edu
Principal Investigator: Holbrook Kohrt
United States, Maryland
National Cancer Institute Cancer Prevention Study	Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: Thomas A. Waldmann 800-411-1222 tawald@mail.nih.gov
Principal Investigator: Thomas A. Waldmann
National Institutes of Health	Active, not recruiting
Bethesda, Maryland, United States, 20892
United States, Minnesota
Masonic Cancer Center, University of Minnesota	Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Jeffrey S. Miller 612-625-7409 mille011@umn.edu
Principal Investigator: Jeffrey S. Miller
University of Minnesota Medical Center-Fairview	Active, not recruiting
Minneapolis, Minnesota, United States, 55455
United States, Washington
Cancer Immunotherapy Trials Network	Not yet recruiting
Seattle, Washington, United States, 98109
Contact: Jeffrey S. Miller 612-625-7409 mille011@umn.edu
Principal Investigator: Jeffrey S. Miller
University of Washington Medical Center	Not yet recruiting
Seattle, Washington, United States, 98195
Contact: John A. Thompson 206-288-2044 jat@u.washington.edu
Principal Investigator: John A. Thompson
United States, Wisconsin
University of Wisconsin Hospital and Clinics	Not yet recruiting
Madison, Wisconsin, United States, 53792
Contact: Paul M. Sondel 608-263-6420 pmsondel@humonc.wisc.edu
Principal Investigator: Paul M. Sondel

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Jeffrey Miller

Cancer Immunotherapy Trials Network

More Information

No publications provided

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT01727076 History of Changes
Other Study ID Numbers:	NCI-2012-02205, CITN11-02, U01CA154967
Study First Received:	November 12, 2012
Last Updated:	April 12, 2013
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Melanoma
Nevi and Melanomas
Carcinoma
Carcinoma, Basal Cell
Carcinoma, Non-Small-Cell Lung
Carcinoma, Renal Cell
Carcinoma, Squamous Cell
Carcinoma, Adenoid Cystic
Granuloma
Head and Neck Neoplasms
Laryngeal Diseases
Lung Neoplasms
Papilloma
Tongue Neoplasms
Carcinoma, Mucoepidermoid

Carcinoma, Verrucous
Esthesioneuroblastoma, Olfactory
Papilloma, Inverted
Neoplasms, Unknown Primary
Salivary Gland Neoplasms
Hypopharyngeal Neoplasms
Laryngeal Neoplasms
Paranasal Sinus Neoplasms
Oropharyngeal Neoplasms
Nasopharyngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Basal Cell
Carcinoma, Bronchogenic

ClinicalTrials.gov processed this record on May 23, 2013