Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies
Condition: Peripheral T-cell Lymphoma NOS; Mycosis Fungoides; Sezary Syndrome; Anaplastic Large Cell Lymphoma
MeSH terms: Mycoses; Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Mycosis Fungoides; Sezary Syndrome; Lymphoma, Large-Cell, Anaplastic
Intervention: rhIL-15; rhIL-15; Avelumab
Intervention description: Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a starting dose level of 1 mcg/kg/day, a second dose level of 2 mcg/kg/day, a third dose level at 3 mcg/kg/day, and a fourth dose level at 4 mcg/kg/day on days 1-5 of each of six cycles.; Interleukin-15 (IL-15) will be administered by continuous intravenous infusion at the maximum tolerated dose (MTD) or maximum administered dose (MAD) on days 1-5 of each of six cycles; Avelumab (intravenous (IV) over 1 hour) will be administered at a dose of 10 mg/kg on days 8 and 22 of each of six cycles.
Intervention MeSH terms: Avelumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: T-cell Lymphoproliferative Disorder; Cutaneous T-Cell Lymphoma; Anti-PD-L1 monoclonal antibody; Antibody Dependent Cellular Cytotoxicity (ADCC)

Summary:

      Background:

      Some T-cell lymphomas and leukemias do not respond to standard treatment. Researchers hope to
      develop a treatment that works better than current treatments.

      Objective:

      To test if interleukin (IL-5) combined with avelumab is safe and effective for treating
      certain cancers.

      Eligibility:

      People ages 18 and older with relapsed T-cell leukemias and lymphomas for which no standard
      treatment exists or standard treatment has failed

      Design:

      Participants will be screened with:

        -  Medical history

        -  Physical exam

        -  Blood, urine, heart, and lung tests

        -  Possible tumor biopsy

        -  Bone marrow biopsy: A small needle will be inserted into the hipbone to take out a small
           amount of marrow.

        -  Computed tomography (CT) or positron emission tomography (PET) scans and magnetic
           resonance imaging (MRI): Participants will lie in a machine that takes pictures of the
           body.

      Participants will get the study drugs for 6 cycles of 28 days each. They will have a midline
      catheter inserted: A tube will be inserted into a vein in the upper chest. They will get
      Interleukin-15 (IL-5) as a constant infusion over the first 5 days of every cycle. They will
      get avelumab on days 8 and 22 of each cycle. They will be hospitalized for the first week of
      the first cycle.

      Participants will have tests throughout the study:

        -  Blood and urine tests

        -  Another tumor biopsy if their disease gets worse

        -  Scans every 8 weeks

        -  Possible repeat MRI

        -  Another bone marrow biopsy at the end of treatment, if there was lymphoma in the bone
           marrow before treatment, and they responded to treatment everywhere else.

      After they finish treatment, participants will have visits every 60 days for the first 6
      months. Then visits will be every 90 days for 2 years, and then every 6 months for 2 years.
      Visits will include blood tests and may include scans.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically proven relapsed/refractory T-cell
             lymphoma other than adult T-cell leukemia/lymphoma (ATLL), angioimmunoblastic T-cell
             lymphoma (AITL), peripheral T-cell lymphoma T follicular helper phenotype (PTCL-TFH),
             or enteropathy-associated T-cell lymphoma (EATL), confirmed by the Laboratory of
             Pathology, National Cancer Institute (NCI)

          -  Patients with CD30 (also known as TNFRSF8) + mycosis fungoides/Sezary syndrome (MF/SS)
             or CD30+ anaplastic large cell lymphoma (ALCL) must have relapsed after or become
             intolerant to treatment with brentuximab vedotin.

          -  A formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be
             available for performance of correlative studies. NOTE: Patients must be willing to
             have a tumor biopsy if prior tissue or adequate archival tissue is not available
             (i.e., post-enrollment and prior to treatment).

          -  Disease must be measurable with at least one measurable lesion by response evaluation
             criteria in lymphoma (RECIL) 2017 or Modified Severity-Weighted Assessment Tool
             (mSWAT) criteria or have an abnormal clonal T-cell population detectable by peripheral
             blood flow cytometry

          -  Age greater than or equal to 18 years

        NOTE: Because no dosing or adverse event data are currently available on the use of rhIL-15
        in combination with avelumab in patients <18 years of age, children are excluded from this
        study, but will be eligible for future pediatric trials

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1

          -  Adequate organ and marrow function as defined:

               -  Absolute neutrophil count greater than 1,000/mcL

               -  Absolute lymphocyte count greater than or equal to 500/mcL

               -  Hemoglobin greater than or equal to 9 g/dL

               -  Platelets greater than 100,000/mcL

               -  Total bilirubin less than or equal to 1.5 X institutional upper limit of normal
                  (ULN)

               -  Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase
                  (SGOT)/Alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT)
                  less than or equal to 2.5 X institutional ULN

               -  Serum creatinine less than or equal to 1.5 X institutional ULN OR

               -  Creatinine clearance greater than or equal to 50 mL/min/1.73 m^2 for patients
                  with creatinine levels greater than 1.5 institutional ULN

          -  Negative serum or urine pregnancy test at screening for women of childbearing
             potential (WOCBP)

        NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone
        successful surgical sterilization or who is not postmenopausal. WOCBP must have a negative
        pregnancy test (human chorionic gonadotropin (HCG) blood or urine) during screening.

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation, and 30 days after completion of rhIL-15 and
             avelumab administration. Should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document

        EXCLUSION CRITERIA:

          -  Patients with the following T-cell leukemias/lymphomas: adult T-cell leukemia/lymphoma
             (ATLL), angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma T
             follicular helper phenotype (PTCL-TFH), and enteropathy-associated T-cell lymphoma
             (EATL).

          -  Chemotherapy and anti-tumor antibodies within 4 weeks (6 weeks for nitrosoureas or
             mitomycin C); other tumor-directed systemic therapy and radiation therapy within 2
             weeks.

          -  Persisting toxicity related to prior therapy of grade > 1, with the exception of the
             following: alopecia, sensory neuropathy grade less than or equal to 2, or other grade
             less than or equal to 2 not constituting a safety risk based on investigator's
             judgment

          -  Patients who are receiving any other investigational agents

          -  Patients who have had prior therapy with any antibody/drug targeting programmed cell
             death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) Tcell coregulatory proteins
             (immune checkpoints)

          -  Current use of immunosuppressive medication, EXCEPT for the following:

               -  Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
                  intra-articular injection)

               -  Systemic corticosteroids at physiologic doses less than or equal to 10 mg/day of
                  prednisone or equivalent; or,

               -  Steroids as premedication for hypersensitivity reactions (e.g., computed
                  tomography (CT) scan premedication)

          -  Patients with known central nervous system (CNS) involvement should be excluded from
             this clinical trial because of their poor prognosis and because they often develop
             progressive neurologic dysfunction that would confound the evaluation of neurologic
             and other adverse events

          -  Patients with previous malignant disease other than the target malignancy within the
             last 5 years with the exception of basal or squamous cell carcinoma of the skin or
             cervical carcinoma in situ

          -  Patients with history of any organ transplantation, including allogenic stem cell
             transplantation

          -  Received a live vaccine within 4 weeks of the first dose of avelumab. Vaccination with
             a live vaccine while on trial is prohibited. NOTE: Seasonal influenza vaccines for
             injection are generally inactivated flu vaccines and are allowed; however intranasal
             influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

          -  Patients with history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to recombinant human Interleukin-15 (rhIL-15) or
             avelumab

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection requiring systemic therapy, or psychiatric illness/social
             situations that would limit compliance with study requirements

          -  Inability or refusal to practice effective contraception during therapy or the
             presence of pregnancy or active breastfeeding. Based on its mechanism of action,
             avelumab can cause fetal harm when administered to a pregnant woman. Animal studies
             have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk
             of immune-mediated rejection of the developing fetus resulting in fetal death. These
             potential risks may also apply to other agents used in this study

          -  Patients with active bacterial infections, documented human immunodeficiency virus
             (HIV) infection or positive screening serology, polymerase chain reaction (PCR)
             evidence for active or chronic hepatitis B or hepatitis C, or positive screening
             hepatitis B virus (HBV)/hepatitis C virus (HCV) serology without documentation of
             successful curative treatment

          -  Patients with active or history of any autoimmune disease, unrelated to their
             malignancy, including asthma requiring chronic inhaled or oral corticosteroids, or
             with history of asthma requiring mechanical ventilation; patients with a history of
             mild asthma that are on or can be switched to non-corticosteroid bronchodilator
             regimens are eligible

          -  Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease:
             cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial
             infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure
             (greater than or equal to New York Heart Association Classification Class II), or
             serious cardiac arrhythmia requiring medication

          -  Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study