Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia
Condition: Leukemia; Lymphocytic; Chronic; B-Cell
MeSH terms: Leukemia
Intervention: rhIL-15; rhIL-15; Obinutuzumab
Intervention description: Continuous intravenous (civ) Interleukin-15 (IL-15) at dose levels of 0.5,1 or 2 mcg/kg/day on days 1-5 of cycles 1-6; Continuous intravenous (civ) Interleukin-15 (IL-15) at the maximum tolerated dose or the maximum administered dose of 2 mcg/kg/day on days 1-5 of cycles 1-6; Intravenous (IV) Obinutuzumab will be administered at a dose of 100 mg on day 4, 900 mg on day 5, 1,000 mg on day 11, and 1,000 mg on day 18 of cycle 1: then 1,000 mg on day 4 of each subsequent cycle
Intervention MeSH terms: Obinutuzumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Monoclonal Antibody Treatment; Recombinant Human Interleukin-15; Lymphoid Malignancy; Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

Summary:

      Background:

      Chronic lymphocytic leukemia (CLL) is a blood cancer. Recombinant human interleukin 15
      (IL-15) is a manmade protein. Obinutuzumab is a protein made to deactivate cancer cells.
      Researchers want to see if treating people with CLL with both proteins improves their
      outcomes.

      Objectives:

      To find the safe dose of IL-15 with Obinutuzumab. To identify its effects, including on the
      immune system and cancer.

      Eligibility:

      Adults at least 18 years old who have certain CLL that standard therapy has failed

      Design:

      Participants will be screened with:

        -  Medical history

        -  Physical exam

        -  Evaluation of ability to do daily activities

        -  Blood, heart, and urine tests

      Participants may also be screened with:

        -  A small amount of bone marrow removed by needle in the hipbone

        -  Scans of the body and/or brain

      The study will be done in 28-day cycles for up to 6 cycles.

      Participants will get the study drugs through a catheter and pump.

      Cycle 1: Participants will be seen in the clinic during week 1. They will get:

        -  IL-15 as a continuous intravenous infusion over 24 hours on days 1-5 and 3 dose levels
           will be evaluated: dose level 1; 0.5 mcg/kg/day; dose level 2: 1 mcg/kg/day and dose
           level 3: 2 mcg/kg/day.

        -  Obinutuzumab as a 4-hour infusion in escalating doses during the course of the first
           cycle 100 mg on day 4, 900 mg on day 5, 1000 mg on day 11 and day 18.

      Cycles 2 through 6: Participants will come to the clinic days 1-5 and get IL-15 as in cycle 1
      and Obinutuzumab 1000 mg on day 4 of each treatment cycle.

      During the study, participants:

        -  Will repeat screening tests

        -  Will get standard medicines for side effects

        -  May give blood, saliva, and tumor samples for research

      After treatment, participants will have follow-up visits every 3 months for 1 year, then
      every 6 months for up to 5 years. After that, participants may be called or emailed.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have a confirmed diagnosis of chronic lymphocytic leukemia/small
             lymphocytic lymphoma that expresses cluster of differentiation 20 (CD20) as confirmed
             by new/fresh peripheral blood sample collection and review by Laboratory of Pathology,
             National Cancer Institute (NCI)

          -  Measurable or evaluable disease

          -  Patients must have received prior treatment required as follows: chronic lymphocyte
             leukemia (CLL) that is refractory or relapsed following therapy with a Bruton's
             tyrosine kinase (BTK) inhibitor OR have relapsed/refractory CLL and are intolerant of
             BTK inhibitor therapy; in addition, patients with deletion 17p (del(17p) must also be
             refractory or relapsed after, or intolerant to, therapy with Venetoclax; patients who
             have received prior Obinutuzumab are eligible regardless of response to the drug.

          -  Active disease requiring treatment, as defined by at least one of the following (per
             the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 consensus
             criteria):

               -  Evidence of progressive marrow failure as manifested by the development of, or
                  worsening of, anemia (hemoglobin (Hb) <10 g/dL) and/or thrombocytopenia (platelet
                  counts <100x10^9/L).

               -  Massive (i.e., greater than or equal to 6 centimeters (cm) below the left costal
                  margin) or progressive or symptomatic splenomegaly.

               -  Massive nodes (i.e., greater than or equal to 10 cm in longest diameter) or
                  progressive or symptomatic lymphadenopathy.

               -  Progressive lymphocytosis with an increase of greater than or equal to 50% over a
                  2-month period, or lymphocyte doubling time (LDT) <6 months.

               -  Autoimmune complications including anemia or thrombocytopenia poorly responsive
                  to corticosteroids.

               -  Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung,
                  spine).

               -  Disease-related symptoms as defined by any of the following:

                    -  Unintentional weight loss greater than or equal to 10% within the previous 6
                       months.

                    -  Significant fatigue (i.e., Eastern Cooperative Oncology Group (ECOG)
                       performance scale 2 or worse; cannot work or unable to perform usual
                       activities).

                    -  Fevers 38.0 degree Celsius (C) for 2 or more weeks without evidence of
                       infection.

                    -  Night sweats for greater than or equal to 1 month without evidence of
                       infection.

          -  greater than or equal to 18 years of age on day of signing informed consent

        NOTE: Because no dosing or adverse event data are currently available on the use of rhIL-15
        in combination with Obinutuzumab in patients <18 years of age, children are excluded from
        this study, but will be eligible for future pediatric trials

          -  ECOG performance status less than or equal to 1 (Karnofsky greater than or equal to
             80%; or less than or equal to 2 (Karnofsky >60%) if the decrease in the performance
             status is CLL-related and constitutes a criterion for active treatment

          -  Adequate organ function as evidenced by the following laboratory parameters:

               -  Absolute neutrophil count (ANC) greater than or equal to 750 /mcL

               -  Platelets greater than or equal to 50,000 / mcL (transfusions not permitted)

               -  Hemoglobin greater than or equal to 9 g/dL (transfusions permitted)

               -  Serum creatinine less than or equal to 1.5 X upper limit of normal (ULN)

               -  Serum total bilirubin less than or equal to 1.5 X ULN OR Direct bilirubin less
                  than or equal to upper limit of normal (ULN) for patients with total bilirubin
                  levels > 1.5 ULN

               -  Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase (SGOT)
                  and alanine aminotransferase (ALT) Serum glutamate-pyruvate transaminase (SGPT)
                  less than or equal to 3 X ULN

          -  Women of child-bearing potential (WOCBP) and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry and for the duration of study treatment, and for at least 18 months after the
             last dose of Obinutuzumab. The effects of rhIL-15 and Obinutuzumab on the developing
             human fetus are unknown. Additionally, CD20-depleting agents are known to produce
             opportunistic infections, causing fetal B-cell depletion in animal studies, and may be
             teratogenic. 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.

        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.

        - Ability of patient to understand and the willingness to sign a written informed consent
        document.

        EXCLUSION CRITERIA:

          -  Current or prior anti-cancer treatment prior to the first dose of rhIL-15 as defined
             below:

               -  Chemotherapy, targeted small molecule therapy, or other anti-cancer treatment not
                  otherwise specified below within 2 weeks

               -  Radiation therapy within 2 weeks

               -  Anti-cancer monoclonal antibody (mAb) treatment within 4 weeks

               -  Use of an investigational agent (e.g., biologic, drug, or other) within 4 weeks

               -  Allogeneic stem cell transplant within 100 days

               -  Systemic treatment for graft versus host disease (GVHD), including but not
                  limited to oral or parenteral corticosteroids, ibrutinib, and extracorporeal
                  phototherapy, within the last 12 weeks

          -  Persisting toxicity related to prior therapy (including GVHD) of grade > 1, with the
             exception of the following: alopecia or 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

          -  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)

          -  Presence of Richter's transformation.

          -  Patients requiring immediate cytoreduction, if they had no prior treatment with a drug
             that has an established clinical benefit.

          -  Presence of uncontrolled intercurrent illnesses including but not limited to ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, cognitive impairment, active substance abuse, or psychiatric
             illness/social situations that in the view of the Investigator would preclude safe
             treatment and limit compliance with study requirements

          -  Presence of active bacterial infections, documented human immunodeficiency virus (HIV)
             infection, 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

          -  Asthma requiring chronic inhaled or oral corticosteroids, or 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

          -  Active or history of any autoimmune disease thought to be unrelated to their CLL

          -  Inability or refusal to practice effective contraception during therapy or the
             presence of pregnancy or active breastfeeding. Because there is no significant
             preclinical information regarding the risks to a fetus or a newborn infant, all
             pregnant or breastfeeding woman will be excluded from participation in this trial

          -  Received a live vaccine within 30 days of planned start of study therapy. 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

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to rhIL-15 or Obinutuzumab, unless felt to be in the best interests of the
             patient in the opinion of the investigator

          -  Known additional malignancy that requires active systemic treatment