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)

Study Overview
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Brief Summary
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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.

Detailed Description
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Background: A previous trial alemtuzumab (CAMPATH-1) in patients with chronic, acute and lymphomatous subtype HTLV-1 associated ATL showed appreciable initial activity but no clear long-term impact. Antibody dependent cellular cytotoxicity (ADCC) with polymorphonuclear neutrophils (PMNs), monocytes and natural killer (NK) cells acting as the effector cells is alemtuzumab s primary in vivo mechanism of action for depleting malignant leukemic or lymphomatous cells. The immunologic effects of Interleukin-15 (IL-15), a stimulatory cytokine that promotes the differentiation and activation of NK cells, monocytes and long-term cluster of differentiation 8 (CD8+) memory Tcells, has been assessed in several phase I trials in cancer patients. Administration of recombinant human (rh) IL-15 as an intravenous bolus (IVB), continuous intravenous infusion (CIV) or subcutaneous injections (SC) into adult cancer patients has produced 5 to 50 fold expansion in the number of circulating NK cells at well tolerated doses in these patients. Preclinical murine lymphoid malignancy models have shown efficacy from the administration of IL-15 and monoclonal antibodies, with improved survival compared to controls. Objective: -To determine the safety, toxicity profile and the maximum tolerated dose (MTD) of s.c. rhIL-15 in combination with standard three times per week IV alemtuzumab treatment. Eligibility: Age greater than or equal to 18 years old Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 1 Diagnosis of adult T-cell leukemia (Human T-cell lymphotropic virus type 1 (HTLV-1) associated, chronic or acute), peripheral T-cell lymphoma (angioimmunoblastic, hepatosplenic, or not otherwise specified), cutaneous T-cell lymphoma (Stage III or IV, with leukemia involvement or erythrodemia), or T-cell prolymphocytic leukemia (T-PLL) Measurable or evaluable disease Adequate organ and bone marrow function as defined in the protocol. Design: This is a single institution nonrandomized Phase I dose escalation study evaluating increasing doses of subcutaneous (SC) rhIL-15 in combination with alemtuzumab using a standard 3 + 3 dose escalation. Treatment will include s.c. rhIL015 daily Monday-Friday (M-F) weeks 1 and 2 (dose levels 0.5- 2 mcg/kg/dose), followed by intravenous (IV) alemtuzumab beginning in week 3 (escalating doses followed by standard dosing in weeks 4-6). Up to 30 patients will be enrolled in this study.

Official Title
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A Phase I Study of Subcutaneous Recombinant Human IL-15 (S.C. Rhil-15) and Alemtuzumab for Patients With Refractory or Relapsed Chronic and Acute Adult T-Cell Leukemia (ATL)

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

Intervention / Treatment
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* Biological: IL-15 plus
* Biological: alemtuzumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Inclusion Criteria 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: Serum creatinine of less than or equal to 1.5 x the upper limit of normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 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. Eastern Cooperative Oncology Group (ECOG) less than or equal to 1. Patients must be able to understand and sign an Informed Consent Form. All patients must use adequate contraception during participation in this trial and for 4 months following completing therapy. EXCLUSION CRITERIA: 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. Positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antigen (HBsAb) positive and hepatitis B core antibody (HBcAb) negative) or a fully resolved acute hepatitis B infection is not an exclusion criterion. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1A-Interleukin 15 (IL-15) Followed by Alemtuzumab<br>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<br>* Recombinant Human IL-15 (subcutaneous (s.c.) rhIL-15) by s.c. injection Monday-Friday over two weeks.<br>* Other names: Interleukin-15;Biological: alemtuzumab<br>* Alemtuzumab three times a week for a total of 4 weeks of alemtuzumab treatment.<br>* Other names: Campath;|
| Experimental: 1B - Interleukin-15 (IL-15) Followed by Alemtuzumab at the Maximum Tolerated Dose<br>IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks at the maximum tolerated dose (MTD) | Biological: IL-15 plus<br>* Recombinant Human IL-15 (subcutaneous (s.c.) rhIL-15) by s.c. injection Monday-Friday over two weeks.<br>* Other names: Interleukin-15;Biological: alemtuzumab<br>* Alemtuzumab three times a week for a total of 4 weeks of alemtuzumab treatment.<br>* Other names: Campath;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Clinical Response | Clinical response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and reported along with a 95% confidence interval. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. | At 3 weeks of treatment and again at 6 weeks of treatment | 
| Progression Free Survival (PFS) | PFS was measured from the date of protocol consent until death or progressive disease occurs. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and reported along with a 95% confidence interval. Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions. | 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 | Biological effects of rhIL-15 administered with alemtuzumab on the percentages of circulating lymphocytes (T and NK cells) and the T-cell subsets naïve, central and effector memory subsets (based on expression of cluster of differentiation 52 (CD52), neural cell adhesion molecule (CD56), cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8), memory T cells (CD45RO), memory T cells (CD45RA), cluster of differentiation 28 (CD28), apoptosis antigen 1 (CD95), C-C Chemokine Receptor 4 (CD194), C-C Motif Chemokine Receptor 7 (CCR7) and L-selectin (CD62L) using flow cytometry. | At 6 weeks of treatment | 
| Plasma Levels of Pro-inflammatory Cytokines | Plasma levels of pro-inflammatory cytokines using flow cytometry. | At 6 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T-cell Lymphoproliferative Disorder, CD4/CD25 Expressing T-cells in Blood and Lymphoid Tissues, Anti-CD52 Monoclonal Antibody, Antibody Dependent Cellular Cytotoxicity