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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)

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ClinicalTrials.gov Identifier: NCT02689453
Recruitment Status : Recruiting
First Posted : February 24, 2016
Last Update Posted : August 9, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( 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.


Condition or disease Intervention/treatment Phase
Leukemia, Adult T-Cell HTLV I Associated T Cell Leukemia Adult T-Cell Leukemia (ATL) Peripheral T-Cell Lymphoma (PTCL) Cutaneous T Cell Lymphoma (CTCL) Biological: IL-15 plus alemtuzumab Phase 1

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 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
  • ECOG Performance Status less than or equal to 1
  • Diagnosis of adult T-cell leukemia (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 SC rhIL-15 in combination with alemtuzumab using a standard 3 + 3 dose escalation.
  • Treatment will include s.c. rhIL015 daily (M-F) weeks 1 and 2 (dose levels 0.5- 3 mcg/kg/dose), followed by IV alemtuzumab beginning in week 3 (escalating doses followed by standard dosing in weeks 4-6).

and 6: 30 mg three times a week (Monday, Wednesday and Friday.)

-Up to 24 patients will be enrolled in this study.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : January 19, 2017
Estimated Primary Completion Date : January 31, 2023
Estimated Study Completion Date : January 31, 2025


Arm Intervention/treatment
Experimental: 1A
IL-15 for 10 doses over two weeks followed byalemtuzumab for 4 weeks
Biological: IL-15 plus alemtuzumab
rhIL-15 by s.c. injection Monday-Friday over two weeks; followed by alemtuzumab three times a week for a total of 4 weeks of alemtuzumab treatment.

Experimental: 1B
IL-15 for 10 doses over two weeks followed by alemtuzumab for 4 weeks at the maximum tolerateddose (MTD)
Biological: IL-15 plus alemtuzumab
rhIL-15 by s.c. injection Monday-Friday over two weeks; followed by alemtuzumab three times a week for a total of 4 weeks of alemtuzumab treatment.




Primary Outcome Measures :
  1. Determine MTD and DLTs of s.c. rhIL-15 administered with 3 times per week IV Alemtuzumab [ Time Frame: after 6 weeks of treatment ]
    Adverse events will be tabulated/reported by type, grade, and frequency.


Secondary Outcome Measures :
  1. Clinical response rate and progression free survival [ Time Frame: after 6 weeks of treatment ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Inclusion Criteria

  • Age (Bullet) 18 years; no upper age limit.
  • Patients diagnosed with a leukemia or lymphoma as follows:

    • Chronic or acute leukemia forms of HTLV-1 associated adult T-cell leukemia (see Appendix 2 for the characteristics of patients with the various stages of ATL);
    • 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)

NOTE: Diagnosis must be validated by the Pathology Department, NCI.

-Patients must have measurable or evaluable disease.

NOTE: All patients with greater than 10% abnormal CD4+ homogeneous CD3low strongly CD25+ expressing cells, or greater than 5% S(SqrRoot)(Copyright)zary cells, among the PBMCs in the peripheral blood will be deemed to have evaluable disease.

  • Abnormal T cells must be 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 ATL; those with CTCL or PTCL who have 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).
  • DLCO/VA and 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
    • AST and 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.
  • 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 3 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) 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 HIV, active bacterial infections, active or chronic hepatitis B, hepatitis C.

    • Positive hepatitis B serology indicative of previous immunization (i.e., HBsAb positive and HBcAb negative) or a fully resolved acute hepatitis B infection is not an exclusion criterion.
    • Positive hepatitis C serology is an exclusion criterion.

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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02689453


Contacts
Contact: Maureen E Edgerly, R.N. (240) 760-6013 NCIMO_Referrals@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Milos Miljkovic, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02689453     History of Changes
Other Study ID Numbers: 160062
16-C-0062
First Posted: February 24, 2016    Key Record Dates
Last Update Posted: August 9, 2018
Last Verified: August 6, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
T-cell Lymphoproliferative Disorder
CD4/CD25 Expressing T-cells in Blood and Lymphoid Tissues
Anti-CD52 Monoclonal Antibody
Antibody Dependent Cellular Cytotoxicity

Additional relevant MeSH terms:
Lymphoma
Leukemia
Lymphoma, T-Cell
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma, T-Cell, Peripheral
Lymphoma, T-Cell, Cutaneous
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Antibodies
Alemtuzumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents