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)

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).

- Up to 30 patients will be enrolled in this study.

- 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;

- 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 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.