Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia

* 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