Continuous Infusion of rhIL-15 for Adults With Advanced Cancer

NCT01572493 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 12011312-C-0113
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- People with cancer can have a weak immune system as a result of the cancer itself, or from prior treatments. Still, treatments that stimulate the immune system have been shown to be effective against a number of different cancers. Recombinant human interleukin-15 (rhIL-15) is a drug that is designed to boost the immune system. Researchers are interested in seeing if rhIL-15 can strengthen the immune system's response against cancer. The drug will be given through a vein without a break for 10 days (240 hours). Objectives:

• To see rhIL-15 given as a continuous infusion over 10 days can be used to treat advanced cancer
• Identify the side effects associated with this treatment. Eligibility: \- Individuals at least 18 years of age with advanced cancer for which there are no effective treatments. Design:
• Participants screening procedures will include a physical exam and medical history, laboratory (blood) tests and x-rays (Imaging studies) to determine suitability for the protocol.
• Appropriate participants with easily accessible tumor deposits may also be asked to have one pretreatment and one post (cycle 1) treatment tumor biopsy.
• Eligible participants will be admitted to the hospital for the rhIL-15 treatment and will spend about 12 days in the hospital.
• Participants will receive one 10 day infusion each cycle (about every 42 days) for as long as there are no serious side effects and the disease does not progress.
• Participants will continue treatment as long as imaging studies show that the tumor continues to shrink or for two additional cycles after it has disappeared from the x-rays to make that the cancer is completely gone.
• Participants who stop treatment for side effects or because their tumor did not shrink or stopped responding to the treatment will continue to have follow-up visits to monitor the outcome of the rhIL-15 treatment until there is evidence their cancer has progress or they begin another treatment.

Conditions

Lymphoma; Carcinoma

Keywords

Pharmacokinetics of lL-15; Cytokine Therapy; Effects of rhlL-15 on T-cells and NK cells; Immunotherapy

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin-15 (rhIL-15) for 10 Day Dosing

  The MTD is the dose level at which less than one-third of patients (0/3 or 0-1/6 participants) treated at that dose experience a dose-limiting toxicity (DLT), with the next higher dose level demonstrating a one-third or greater number of participants (≥ 2/3 or ≥ 2/6 participants) having DLT. A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probably or definitely related to the study drug by the principal investigator during the first cycle of treatment. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening.

  After one cycle (one cycle is 42 days for 10-day dosing)

• Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin-15 (rhIL-15) for 5 Day Dosing

  The MTD is the dose level at which less than one-third of patients (0/3 or 0-1/6 participants) treated at that dose experience a dose-limiting toxicity (DLT), with the next higher dose level demonstrating a one-third or greater number of participants (≥ 2/3 or ≥ 2/6 participants) having DLT. A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probably or definitely related to the study drug by the principal investigator during the first cycle of treatment. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening.

  After one cycle (one cycle is 21 days for 5-day dosing)

• Number of Participants With Grades 3, 4 or 5 Dose-Limiting Toxicity (DLT) Related to Study Drug

  A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probable or definitely related to the study drug by the principal investigator during the first cycle of treatment; and/or Grade 5 death related to adverse event. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening.

  After one cycle (one cycle is either 42 or 21 days)

Secondary Outcomes (6)

• Clinical Response Rate

  Both cycles 1 and 2 (each cycle is 42 days) for the 10 day treatment, up to 84 days. And clinical responses for the 5-day treatment cohorts (21 day cycle length) were assessed after cycles 2, 4, 6, 8 and so on treatment cycles.

• Time to Progression (TTP)

  From the date of protocol consent until date of progressive disease is documented, up to 263 days

• Maximum Observed Plasma Concentration (Cmax) of Recombinant Human Interleukin-15 (rhIL-15)

  Prior to 1st dose, at 10 minutes after 1st dose, once daily on days 7-10 at completion of treatment, at 10 and 30 minutes after completion of treatment and at 1, 2, 4, and approximately 24 hours after completion of treatment.

• Concentration of Drug in Plasma at Steady State (Css)

  Days 7 through 10

• Area Under the Curve (AUClast)

  Prior to 1st dose, at 10 minutes after 1st dose, once daily on days 7-10 at completion of treatment, at 10 and 30 minutes after completion of treatment and at 1, 2, 4, and approximately 24 hours after completion of treatment.

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  Date treatment consent signed to date off study, approximately 18 months (m)/27 days(d), 3 m, 9 m/13d, 15 m/20d, 28 m/17d, 1 m/23d, 15 m/8d, 4 m/5d, and 6 m/30d for levels 1-9 respectively.

Study Arms (4)

Arm A1 (Dose Escalation, 10-day Dosing)

EXPERIMENTAL

Maximum tolerated dose (MTD) determination in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 10 consecutive days

Biological: rh IL-15 (10 DAYS)

Arm A2 (Dose Expansion, 10-day Dosing)

EXPERIMENTAL

Clinical activity evaluation in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 10 consecutive days

Biological: rh IL-15 (5 DAYS)

Arm B1 (Dose Escalation, 5-day Dosing)

EXPERIMENTAL

Maximum tolerated dose (MTD) determination in subjects with metastatic unresectable cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 5 consecutive days

Biological: rh IL-15 (5 DAYS)

Arm B2 (Dose Expansion, 5-day Dosing)

EXPERIMENTAL

Clinical activity evaluation in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 5 consecutive days

Biological: rh IL-15 (5 DAYS)

Interventions

rh IL-15 (10 DAYS) BIOLOGICAL

Continuous infusion of recombinant human Interleukin-15 (rh IL-15) intravenous (IV) for first 10 days of each cycle

Also known as: Recombinant human Interleukin-15

Arm A1 (Dose Escalation, 10-day Dosing)

rh IL-15 (5 DAYS) BIOLOGICAL

Continuous infusion of recombinant human Interleukin-15 (rh IL-15) for first 5 days of each cycle

Also known as: Recombinant human Interleukin-15

Arm A2 (Dose Expansion, 10-day Dosing); Arm B1 (Dose Escalation, 5-day Dosing); Arm B2 (Dose Expansion, 5-day Dosing)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than or equal to 18 years.
• Patients must have histologically confirmed (by the National Cancer Institute (NCI) Pathology Department) solid tumor malignancy or lymphoma that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are associated with minimal patient survival benefit (as defined the Metabolism Branch physicians or if the patient refuses standard of care treatment). Enrollment of patients with tumors that can be safely biopsied is encouraged.
• Patients must have evaluable or measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan.
• Patients must have recovered to \< grade 1 Common Terminology Criteria for Adverse Events (CTCAE)v4 from toxicity of prior chemotherapy or biologic therapy and must not have had prior chemotherapy or biologic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 8 weeks for 7-hydroxystaurosporine (UCN-01).
• Patients must be at least 1 month since any prior radiation or major surgery.
• Patients on bisphosphonates for any cancer or on hormone therapy for prostate cancer will not need to discontinue this therapy to be eligible. However, patients with prostate cancer will need to have metastatic prostate cancer that has progressed despite hormonal therapy. Castrate testosterone levels occur within hours after castration and within 2 to 3 weeks of a luteinizing hormone-releasing hormone agonist. The current standard is to continue androgen suppression despite progressive disease.
• Diffusing capacity for carbon monoxide (DLCO)/alveolar volume (VA) and forced expiratory volume (FEV)-1.0 \> 60% of predicted on pulmonary function tests.
• Serum creatinine of less than or equal to 1.5 X the upper limit of normal.
• Aspartate aminotransferase (AST) and alanine aminotransferase (AST) \< 2.5 x the upper limit of normal.
• Absolute neutrophil count greater than or equal to 1,500/mm(3) and platelets greater than or equal to 100,000/mm(3).
• Karnofsky performance status greater than or equal to 70% or Eastern Cooperative Oncology Group (ECOG) less than or equal to 1
• Subjects with inactive central nervous system (CNS) metastasis are eligible. Inactive CNS metastasis is defined as: no signs of cerebral edema after successful definitive treatment of brain metastases (surgical resection, whole brain irradiation, stereotactic radiation therapy, or a combination of these) with stable or improved radiographic appearance on magnetic resonance imaging (MRI) scan at least 1 month after completion of treatment.

You may not qualify if:

• Patients who have received any systemic corticosteroid therapy within 3 weeks prior to the start of therapy with the exception of physiological replacement doses of cortisone acetate or equivalent.
• Patients who have received any cytotoxic therapy, immunotherapy, antitumor vaccines, monoclonal antibodies or major surgery in the 4 weeks prior to the start of the study.
• Life expectancy of less than 3 months.
• Patients with more than 30% replacement of hepatic parenchyma by tumor or any history of drug related hepatic encephalopathy.
• History of complex ventricular or supraventricular arrhythmias
• Documented human immunodeficiency virus (HIV), active bacterial infections, active or chronic hepatitis B, or hepatitis C infection.
• Concurrent anticancer therapy (including other investigational agents), with the exception of hormone therapy for prostate cancer.
• Active central nervous system (CNS) metastases (inactive CNS metastases are defined).
• History of severe asthma or presently on chronic inhaled corticosteroid medications (patients with a history of mild asthma controlled with inhaled bronchodilators are eligible).
• History of autoimmune disease, with the exception of an autoimmune event associated with prior ipilimumab (anti-cluster of differentiation 152 (CTLA-4) therapy that has been completely resolved for more than 4 weeks.
• Inability or refusal to practice effective contraception during therapy or the presence of pregnancy or active breastfeeding (men and women of childbearing potential must use an effective method of birth control or abstinence during treatment and for 4 months after completion of treatment).
• Cognitive impairment, history of medical or psychiatric disease, other uncontrolled intercurrent illness, active substance abuse, or social circumstances, which in the view of the Principal Investigator (PI), would preclude safe treatment or the ability to give informed consent.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965-8. doi: 10.1126/science.8178155.

  PMID: 8178155 BACKGROUND

• Bamford RN, Grant AJ, Burton JD, Peters C, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4940-4. doi: 10.1073/pnas.91.11.4940.

  PMID: 8197161 BACKGROUND

• Burton JD, Bamford RN, Peters C, Grant AJ, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA. A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4935-9. doi: 10.1073/pnas.91.11.4935.

  PMID: 8197160 BACKGROUND

• Conlon KC, Potter EL, Pittaluga S, Lee CR, Miljkovic MD, Fleisher TA, Dubois S, Bryant BR, Petrus M, Perera LP, Hsu J, Figg WD, Peer CJ, Shih JH, Yovandich JL, Creekmore SP, Roederer M, Waldmann TA. IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion. Clin Cancer Res. 2019 Aug 15;25(16):4945-4954. doi: 10.1158/1078-0432.CCR-18-3468. Epub 2019 May 29.

  PMID: 31142503 RESULT

• Dubois SP, Miljkovic MD, Fleisher TA, Pittaluga S, Hsu-Albert J, Bryant BR, Petrus MN, Perera LP, Muller JR, Shih JH, Waldmann TA, Conlon KC. Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies. J Immunother Cancer. 2021 Apr;9(4):e002193. doi: 10.1136/jitc-2020-002193.

  PMID: 33883258 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma; Carcinoma

Interventions

Interleukin-15

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Glandular and Epithelial

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Kevin C. Conlon
• Organization: National Cancer Institute

conlonkc@mail.nih.gov

240-858-3570

Study Officials

• Kevin C Conlon, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 5, 2012
• First Posted: April 6, 2012
• Study Start: April 4, 2012
• Primary Completion: June 20, 2019
• Study Completion: July 2, 2019
• Last Updated: March 6, 2023
• Results First Posted: March 6, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)