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

Background:

- Of the several drugs and drug combinations approved for treatment of relapsed and
refractory chronic lymphocytic leukemia (CLL), the reported complete response rates are
no greater than 30%.

- Obinutuzumab is a glycoengineered, humanized type 2 anti-CD20 monoclonal antibody
thought to engage the immune system by directly activating antibody-dependent,
cellmediated cytotoxicity (ADCC); it is approved for treatment of chronic lymphocytic
leukemia in combination with chlorambucil.

- The key mediators of ADCC are polymorphonuclear neutrophils, monocytes, and natural
killer (NK) cells.

- Recombinant human Interleukin-15 (rhIL-15) is a stimulatory cytokine that promotes the
differentiation and activation of NK cells, monocytes, and long-term CD8+ memory Tcells.
In a Phase I trial, administration of rhIL-15 as a 5-day continuous intravenous infusion
(civ) was associated with up to 45-fold increase in the number of NK cells at well
tolerated dose levels.

- Preclinical murine lymphoid malignancy models have shown increased efficacy of
monoclonal antibodies when administered together with rhIL-15; BL/6 mice inoculated with
EL4-CD20 cells (a syngeneic lymphoma line); including significant prolongation of
survival with the IL-15/Rituximab combination compared to either drug given as single
agent (90% v. 30% alive at 75 days).

Objectives:

- To determine the safety, toxicity profile, dose-limiting toxicity (DLT) and the maximum
tolerated dose (MTD) of civ rhIL-15 administration in combination with intravenous (IV)
obinutuzumab treatment

Eligibility:

- Age greater than or equal to 18 years old

- ECOG performance status less than or equal to 1

- Diagnosis of chronic lymphocytic leukemia (CLL) with greater than or equal to 50% of B
cells xpressing CD20

- Patients must have measurable or evaluable disease

- Patients must have CLL that is refractory or relapsed following therapy with ibrutinib
OR have relapsed/refractory CLL and are intolerant to ibrutinib therapy; patients with
del(17p) must also be refractory or relapsed after, or intolerant to, therapy with
venetoclax

- Adequate organ function parameters as defined within the protocol

- Active disease requiring treatment, as defined within the protocol

Design:

- This is a single institution non-randomized Phase I dose escalation study evaluating
increasing doses of civ rhIL-15 in combination with obinutuzumab using a standard 3 + 3
dose escalation design.

- On days 1-5 of each 4-week cycle, rhIL-15 will be administered by civ at dose levels
0.5, 1, and 2 mcg/kg/day.

- During the first cycle, obinutuzumab will be administered at a dose of 100 mg by IV on
day 4, 900 mg on day 5, 1,000 mg on day 11, and 1,000 mg on day 18; then 1,000 mg on day
4 of each subsequent cycle.

- Infusion reaction, antimicrobial, and tumor lysis syndrome prophylaxis will be
administered per manufacturer s recommendations.

- Treatment will continue up to 6 cycles, or until unacceptable toxicity or progressive
disease.

- Up to 24 patients will be enrolled in the study.

- INCLUSION CRITERIA:

- Patients must have a confirmed diagnosis of chronic lymphocytic leukemia/small
lymphocytic lymphoma that expresses CD20 as confirmed by new/fresh peripheral blood
sample collection and review by Laboratory of Pathology, NCI

- Measurable or evaluable disease

- Patients must have received prior treatment required as follows: CLL that is
refractory or relapsed following therapy with ibrutinib OR have relapsed/refractory
CLL and are intolerant of ibrutinib therapy; in addition, patients with 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
IWCLL 2018 consensus criteria):

- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia (Hb <10 g/dL) and/or thrombocytopenia (platelet counts <100
(SqrRoot) 10^9/L).

- Massive (i.e., greater than or equal to 6 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 (eg, 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 (ie, ECOG performance scale 2 or worse; cannot work or
unable to perform usual activities).

- Fevers 38.0 degree 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%)

- 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 ULN for patients with total bilirubin levels > 1.5 ULN

- AST (SGOT) and ALT (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 (HCG blood or urine) during screening.

- Ability of patient or Legally Authorized Representative (LAR) 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., 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 HIV infection, PCR evidence for
active or chronic hepatitis B or hepatitis C, or positive screening HBV/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