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)

Phase 1

Completed

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

Interventions: Biological: IL-15 plus
Biological: alemtuzumab

Registration Number: NCT02689453

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1A-Interleukin 15 (IL-15) Followed by Alemtuzumab	alemtuzumab	IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks per dosing schema to determine the maximum tolerated dose (MTD)
1A-Interleukin 15 (IL-15) Followed by Alemtuzumab	IL-15 plus	IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks per dosing schema to determine the maximum tolerated dose (MTD)
1B - Interleukin-15 (IL-15) Followed by Alemtuzumab at the Maximum Tolerated Dose	alemtuzumab	IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks at the maximum tolerated dose (MTD)
1B - Interleukin-15 (IL-15) Followed by Alemtuzumab at the Maximum Tolerated Dose	IL-15 plus	IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks at the maximum tolerated dose (MTD)

Primary Outcome Measures

Name	Time	Method
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	6 weeks	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.
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	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.	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.
Maximum Tolerated Dose (MTD) of Subcutaneous Recombinant Human IL-15 (s.c. rhIL-15)	6 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With a Clinical Response	At 3 weeks of treatment and again at 6 weeks of treatment	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.
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.	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.
Percentages of Circulating Lymphocytes (T and NK Cells) and the T-cell Subsets	At 6 weeks of treatment	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.
Plasma Levels of Pro-inflammatory Cytokines	At 6 weeks of treatment	Plasma levels of pro-inflammatory cytokines using flow cytometry.