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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Brief Title

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)

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)

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 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- 2
           mcg/kg/dose), followed by 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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Determine MTD and DLTs of s.c. rhIL-15 administered with 3 times per week IV Alemtuzumab

Secondary Outcome

 Clinical response rate and progression free survival

Condition

T-Cell Lymphoma Relapsed

Intervention

IL-15 plus alemtuzumab

Study Arms / Comparison Groups

 1A
Description:  IL-15 for 10 doses over two weeks followed byalemtuzumab for 4 weeks per dosing schema to determine the maximum tolerated dose (MTD)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

11

Start Date

January 19, 2017

Completion Date

June 15, 2021

Primary Completion Date

June 15, 2021

Eligibility Criteria

        -  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 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, 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/T-PLL, 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 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) 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.

               -  If hepatitis C antibody test is positive, then the patient must be tested for the
                  presence of HCV by RT-PCR and be HCV 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-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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Milos Miljkovic, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02689453

Organization ID

160062

Secondary IDs

16-C-0062

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Milos Miljkovic, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

June 17, 2021