Subcutaneous Recombinant Human IL-15 (s.c. rhIL-15) and Alemtuzumab for People With Refractory or Relapsed Chronic and Acute Adult T-cell Leukemia (ATL)

NCT02689453 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 16006216-C-0062
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Adult T-cell leukemia (ATL) is a rare blood cancer. Researchers want to see if a combination of two drugs - recombinant human interleukin 15 (rhIL-15) and alemtuzumab - is a better treatment for ATL. Objectives: To test if giving rhIL-15 combined with alemtuzumab improves the outcome of therapy for ATL. Also, to determine the safe dose of this combination and identify side effects and effects on the immune system. Eligibility: Adults 18 years and older with chronic or acute ATL who have not been helped by other treatments. Design: Participants will be screened with tests that are mostly part of their usual cancer care. They will sign a separate consent form for this. Weeks 1 and 2: Participants will have a total of 10 visits. They will:

• Get rhIL-15 under the skin by needle.
• Have a physical exam and vital signs measured.
• Give blood samples.
• Answer questions about their health and their medicines. Week 3: Participants will stay in the clinic. They will:
• Get alemtuzumab infusions in a vein through a small catheter on days 1, 2, 3, and 5.
• Take medicines to decrease side effects.
• Have a computed tomography (CT) scan to evaluate the treatment.
• Have a physical exam and vital signs measured.
• Give blood samples. Answer questions about their health and medicines. Weeks 4, 5, and 6 will repeat week 3, without the CT scan. Some patients will just have outpatient visits these weeks. After treatment, participants will have follow-up visits every few months for up to 2 years. At these visits, participants will give blood samples and have CT scans.

Conditions

T-Cell Lymphoma Relapsed; Adult T-Cell Leukemia (ATL); Peripheral T-Cell Lymphoma (PTCL); Cutaneous T Cell Lymphoma (CTCL); T-Cell Prolymphocytic Leukemia

Keywords

T-cell Lymphoproliferative Disorder; CD4/CD25 Expressing T-cells in Blood and Lymphoid Tissues; Anti-CD52 Monoclonal Antibody; Antibody Dependent Cellular Cytotoxicity

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) of Subcutaneous Recombinant Human IL-15 (s.c. rhIL-15)

  MTD is defined as the dose level at which no more than 1 of up to 6 participants experience a dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and the dose below that at which at least 2 (of≤6) participants have DLT as a result of the drug. A DLT is defined as any grade 3 or 4 toxicity possibly, probably or definitely related to the rhIL-15 treatment that occurs during the first 6 weeks of treatment with some exceptions such as grade 3 or 4 lymphopenia, and grade 3 neutropenia for example.

  6 weeks

• Number of Dose-limiting Toxicities (DLTs) of Subcutaneous Recombinant Human IL-15 (s.c. rhIL-15) Administered With 3 Times Per Week Intravenous (IV) Alemtuzumab

  A DLT is defined as any grade 3 or 4 toxicity possibly, probably or definitely related to the rhIL-15 treatment that occurs during the first 6 weeks of treatment with some exceptions such as grade 3 or 4 lymphopenia, and grade 3 neutropenia for example.

  6 weeks

• Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to Subcutaneous (s.c. rhIL-15) by Grade Who Have Refractory or Relapsed Chronic and Acute Adult T-cell Leukemia (ATL)Cancer

  Here is the number of participants with serious adverse events possibly, probably, and/or definitely related to IL-15 (s.c. rhIL-15) by Grade assessed by the Common Terminology Criteria for Adverse Events (CTCAE 5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.

  Date treatment consent signed to date off study, approximately 16 months and 14 days for level 1, 18 months and 12 days for level 2, and 14 months and 24 days for level 3.

Secondary Outcomes (4)

• Number of Participants With a Clinical Response

  At 3 weeks of treatment and again at 6 weeks of treatment

• Progression Free Survival (PFS)

  Restaging by computerized tomography (CT) occurred at the end of week 3 and week 6 during treatment, then every 60 days for 6 months, and every 90 days for up to 2 years after finishing treatment.

• Percentages of Circulating Lymphocytes (T and NK Cells) and the T-cell Subsets

  At 6 weeks of treatment

• Plasma Levels of Pro-inflammatory Cytokines

  At 6 weeks of treatment

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 16 months and 14 days for level 1, 18 months and 12 days for level 2, and 14 months and 24 days for level 3.

Study Arms (2)

1A-Interleukin 15 (IL-15) Followed by Alemtuzumab

EXPERIMENTAL

IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks per dosing schema to determine the maximum tolerated dose (MTD)

Biological: IL-15 plus; Biological: alemtuzumab

1B - Interleukin-15 (IL-15) Followed by Alemtuzumab at the Maximum Tolerated Dose

EXPERIMENTAL

IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks at the maximum tolerated dose (MTD)

Biological: IL-15 plus; Biological: alemtuzumab

Interventions

IL-15 plus BIOLOGICAL

Recombinant Human IL-15 (subcutaneous (s.c.) rhIL-15) by s.c. injection Monday-Friday over two weeks.

Also known as: Interleukin-15

1A-Interleukin 15 (IL-15) Followed by Alemtuzumab; 1B - Interleukin-15 (IL-15) Followed by Alemtuzumab at the Maximum Tolerated Dose

alemtuzumab BIOLOGICAL

Alemtuzumab three times a week for a total of 4 weeks of alemtuzumab treatment.

Also known as: Campath

1A-Interleukin 15 (IL-15) Followed by Alemtuzumab; 1B - Interleukin-15 (IL-15) Followed by Alemtuzumab at the Maximum Tolerated Dose

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; no upper age limit.
• Patients diagnosed with a leukemia or lymphoma as follows:
• Chronic or acute leukemia forms of Human T-cell lymphotropic virus type 1 (HTLV-1) associated adult T-cell leukemia;
• Peripheral T-cell lymphoma (angioimmunoblastic, hepatosplenic, or not otherwise specified); or,
• Cutaneous T-cell lymphoma stage III or IV with circulating monoclonal cells (B1 or B2) and/or erythrodermia (T4)
• T-cell prolymphocytic leukemia (T-PLL)
• NOTE: Diagnosis must be validated by the Pathology Department, National Cancer Institute (NCI).
• Patients must have measurable or evaluable disease.
• NOTE: All patients with greater than 10% abnormal cluster of differentiation 4 (CD4+) homogeneous cluster of differentiation 3 (CD3) low strongly cluster of differentiation 25 (CD25+) expressing cells, or greater than 5% Szary cells/T-PLL, among the peripheral blood mononuclear cells (PBMCs) in the peripheral blood will be deemed to have evaluable disease.
• Abnormal T cells must be cluster of differentiation 52 (CD52+) as assessed by flow cytometry or immunohistochemistry.
• Patients must have a life expectancy of greater than or equal to 2 months.
• Patients must have been refractory or relapsed following front line therapy for Adult T-cell Leukemia (ATL); those with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL) who have cluster of differentiation 30 (CD30+) disease must have progressed during or after treatment with brentuximab vedotin, or are unable to receive treatment due to allergy or intolerance.
• Patients must have recovered to less than grade 1 or to baseline from toxicity of prior chemotherapy or biologic therapy and must not have had major surgery, chemotherapy, radiation or biologic therapy within 2 weeks prior to beginning treatment. NOTE: Exceptions to this include events not considered to place the subject at unacceptable risk of participation in the opinion of the PI (e.g., alopecia).
• Carbon monoxide diffusing capacity alveolar volume (DLCO/VA) and forced expiratory volume (FEV) 1.0 \> 50% of predicted on pulmonary function tests.
• Adequate laboratory parameters, as follows:

You may not qualify if:

• Patients who have received any systemic corticosteroid therapy within 4 weeks prior to the start of therapy, or 12 weeks if given to treat graft versus host disease (GVHD), with the exception of physiological replacement doses of cortisone acetate or equivalent.
• Patients who have undergone allogeneic stem cell transplantation and have required systemic treatment for GVHD (including but not limited to oral or parenteral corticosteroids, ibrutinib, and extracorporeal phototherapy) within the last 12 weeks
• Clinical evidence of (parenchymal or meningeal) central nervous system (CNS) involvement or metastasis. In subjects suspected of having CNS disease, a magnetic resonance imaging (MRI) scan of the brain and lumbar puncture should be done to confirm.
• Documented human immunodeficiency virus (HIV), active bacterial infections, active or chronic hepatitis B, hepatitis C.
• If hepatitis C antibody test is positive, then the patient must be tested for the presence of hepatitis C virus (HCV) by reverse transcription polymerase chain reaction (RT-PCR) and be HCV ribonucleic acid (RNA) negative
• NOTE: HIV-positive patients are excluded from the study. Alemtuzumab may produce a different pattern of toxicities in patients with HIV infection; in addition, the depletion of T cells produced by alemtuzumab may have adverse effects on HIV-positive individuals.
• Concurrent anticancer therapy (including other investigational agents).
• History of severe asthma or presently on chronic inhaled corticosteroid medications (patients with a history of mild asthma not requiring corticosteroid therapy are eligible).
• Patients with smoldering and lymphomatous ATL.
• Pregnant or nursing patients.
• Patients who have previously received alemtuzumab are ineligible. NOTE: Patients with relapsed T-cell prolymphocytic leukemia (T-PLL) who have achieved at least a partial response to prior alemtuzumab are eligible.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, moderate/severe graft versus host disease, cognitive impairment, active substance abuse, or psychiatric illness/social situations that, in the view of the Investigator, would preclude safe treatment or the ability to give informed consent and limit compliance with study requirements.

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 (3)

• Miljkovic MD, Dubois SP, Muller JR, Bryant B, Ma E, Conlon KC, Waldmann TA. Interleukin-15 augments NK cell-mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies. Blood Adv. 2023 Feb 14;7(3):384-394. doi: 10.1182/bloodadvances.2021006440.

  PMID: 35475910 DERIVED

• 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

• Waldmann TA, Dubois S, Miljkovic MD, Conlon KC. IL-15 in the Combination Immunotherapy of Cancer. Front Immunol. 2020 May 19;11:868. doi: 10.3389/fimmu.2020.00868. eCollection 2020.

  PMID: 32508818 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia-Lymphoma, Adult T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, T-Cell, Cutaneous; Leukemia, Prolymphocytic, T-Cell

Interventions

Interleukin-15; Alemtuzumab

Condition Hierarchy (Ancestors)

Leukemia, T-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Leukemia, Prolymphocytic

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins

Results Point of Contact

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

conlonkc@mail.nih.gov

240-858-3570

Study Officials

• Kevin 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: February 20, 2016
• First Posted: February 24, 2016
• Study Start: January 19, 2017
• Primary Completion: June 15, 2021
• Study Completion: June 15, 2021
• Last Updated: April 29, 2022
• Results First Posted: April 29, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)