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Human Interleukin-15 and Obinutuzumab in Treating Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Trial Status: Active

This phase I trial studies the side effects and best dose of human interleukin-15 when given together with obinutuzumab in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Human interleukin-15 is a man-made version of a small protein (cytokine) that is naturally produced in the body by white blood cells and increases the activity and strength of the immune system. Human interleukin-15 may boost or strengthen the immune system as it fights against cancer. Immunotherapy with obinutuzumab, may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Giving human interleukin-15 and obinutuzumab together may work better in treating patients with chronic lymphocytic leukemia compared to existing treatment.

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, National Cancer Institute (NCI)
  • Measurable or evaluable disease
  • Patients must have received prior treatment required as follows: CLL that is refractory or relapsed following therapy with a BTK inhibitor OR have relapsed/refractory CLL and are intolerant of BTK inhibitor 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 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 < 100 x 10^9/L) * Massive (i.e., >= 6 cm below the left costal margin) or progressive or symptomatic splenomegaly * Massive nodes (i.e., >= 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy * Progressive lymphocytosis with an increase of >= 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 >= 10% within the previous 6 months ** Significant fatigue (ie, Eastern Cooperative Oncology Group [ECOG] performance scale 2 or worse; cannot work or unable to perform usual activities) ** Fevers 38.0 degrees Celsius (C) for 2 or more weeks without evidence of infection ** Night sweats for >= 1 month without evidence of infection
  • ECOG performance status =< 1 (Karnofsky >= 80%) or =< 2 (Karnofsky >= 60%) if the decrease in the performance status is CLL-related and constitutes a criterion for active treatment
  • Absolute neutrophil count (ANC) >= 750 /mcL
  • Platelets >= 50,000 / mcL (transfusions not permitted)
  • Hemoglobin >= 9 g/dL (transfusions permitted)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN)
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< 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]) =< 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 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 =< 2, or other grade =< 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 =< 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

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: ACTIVE
Contact: Milos Miljkovic
Phone: 800-411-1222

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

I. To evaluate the potential antitumor activity of the combination of rhIL-15 and obinutuzumab by assessing the clinical response rate, minimal residual disease (MRD) status, progression-free survival, and overall survival in patients with relapsed and refractory chronic lymphocytic leukemia (CLL).

II. To define the effects of rhIL-15 on the antibody-dependent cellular cytotoxicity (ADCC) mediated by obinutuzumab using ex vivo peripheral blood mononuclear cells (PBMCs).

III. To characterize the biological effects of rhIL-15 administered with obinutuzumab on the percentages and absolute numbers of circulating lymphocytes (T and natural killer [NK] cells) and the T-cell subsets (including naive, central, and effector memory subsets) by flow cytometry.

EXPLORATORY OBJECTIVE:

I. To identify biomarkers predictive of response to rhIL-15 and obinutuzumab treatment.

OUTLINE: This is a dose-escalation study of recombinant human interleukin-15.

Patients receive recombinant human interleukin-15 intravenously (IV) continuously over 24 hours on days 1-5. Patients also receive obinutuzumab IV over 4 hours on days 4, 5, 11, and 18 of cycle 1 and on day 4 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, every 6 months for 4 years, and annually until disease progression or start of new anti-cancer therapy. Patients are then followed up every 3-6 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Milos Miljkovic

  • Primary ID 10241
  • Secondary IDs NCI-2019-00768, 19-C-0024, 19-C-0024 A
  • Clinicaltrials.gov ID NCT03759184