Conditions: Leukemia Lymphocytic Chronic B-Cell
Keywords: Monoclonal Antibody Treatment Recombinant Human Interleukin-15 Lymphoid Malignancy Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 1
Healthy volunteers: no

Brief 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.

Detailed description:
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-cluster of differentiation 20 (CD20) monoclonal antibody thought to engage the immune system by directly activating antibody-dependent, cell mediated 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 cluster of differentiation 8 (CD8) + memory T-cells. 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 recombinant human Interleukin-15 (rhIL-15); BL/6 mice inoculated with EL4 murine T-cell lymphoma expressing human cluster of differentiation 20 (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
* Eastern Cooperative Oncology Group (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 expressing CD20
* Patients must have measurable or evaluable disease
* Patients must have CLL that is refractory or relapsed following therapy with a Bruton's tyrosine kinase (BTK) inhibitor OR have relapsed/refractory CLL and are intolerant to BTK inhibitor therapy; patients with deletion 17p (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 manufacturers 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.

Arms:
arm 1: DOSE ESCALATION: Interleukin-15 (IL-15) by continuous intravenous (civ) infusion at escalating doses of 0.5, 1, and 2 mcg/kg/day on days 1-5 of each 4-week cycle (max 6 cycles), with Obinutuzumab by IV infusion 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 the first cycle; then 1,000 mg on day 4 of each subsequent cycle, to determine the maximum tolerated dose (MTD) arm 2: DOSE EXPANSION: 3 to 6 patients to receive interleukin-15 (IL-15) by continuous intravenous (civ) infusion at the maximum tolerated dose (MTD) on days 1-5 of cycles 1-6 with Obinutuzumab by IV infusion 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 the first cycle; then 1,000 mg on day 4 of each subsequent cycle (Total 9 patients at MTD)

Interventions: intervention 1: rhIL-15 intervention 2: rhIL-15 intervention 3: Obinutuzumab
Intervention descriptions: intervention 1: 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 intervention 2: 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 intervention 3: 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

Protocol document:
Prot_SAP_000.pdf: 
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