Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Neoplasms by Histologic Type

Hematologic Diseases

Chronic Graft Versus Host Disease

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Obinutuzumab

Immunoglobulins

Antineoplastic Agents, Immunological

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)

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)

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

rhIL-15

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

Kevin C Conlon, M.D.

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.

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.

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

Phase 1 Trial of Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Here is the number of treatment-emergent AEs related to rhIL-15 assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. A treatment emergent AE is defined as

Here is the number of treatment-emergent AEs related to Obinutuzumab assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. A treatment emergent AE is defined as

A DLT is defined as a grade 3-5 toxicity if not incontrovertibly due to disease progression or an extraneous cause, and deemed possibly, probably, or definitely related to interleukin-15 by the principal investigator during the first 28 days of treatment. Some exceptions are grade 3 or 4 lymphocytopenia or neutropenia without clinical signs of infection grade 2 or above, grade 3 or 4 thrombocytopenia lasting fewer than 5 days and not associated with bleeding or purpura. Transient (\<24 hours) grade 3 hypoalbuminemia, hypokalemia, hypomagnesemia, hyponatremia or hypophosphatemia which responds to medical intervention. Grade 3 is severe, grade 4 is life-threatening, and grade 5 is death related to adverse event.

A DLT is defined as a grade 3-5 toxicity if not incontrovertibly due to disease progression or an extraneous cause, and deemed possibly, probably, or definitely related to Obinutuzumab by the principal investigator during the first 28 days of treatment. Some exceptions are grade 3 or 4 lymphocytopenia or neutropenia without clinical signs of infection grade 2 or above, grade 3 or 4 thrombocytopenia lasting fewer than 5 days and not associated with bleeding or purpura. Transient (\<24 hours) grade 3 hypoalbuminemia, hypokalemia, hypomagnesemia, hyponatremia or hypophosphatemia which responds to medical intervention. Grade 3 is severe, grade 4 is life-threatening, and grade 5 is death related to adverse event.

The MTD is the dose level at which no more than 1 of up to 6 participants experience a dose limiting toxicity (DLT) during the DLT evaluation window, or the dose at which at least 2 of ≤ 6 participants have DLT. A DLT is defined as a grade 3-5 toxicity if not incontrovertibly due to disease progression or an extraneous cause, and deemed possibly, probably, or definitely related to interleukin-15 by the principal investigator during the first 28 days of treatment.

The MTD is the dose level at which no more than 1 of up to 6 participants experience a dose limiting toxicity (DLT) during the DLT evaluation window, or the dose at which at least 2 of ≤ 6 participants have DLT. A DLT is defined as a grade 3-5 toxicity if not incontrovertibly due to disease progression or an extraneous cause, and deemed possibly, probably, or definitely related to Obinutuzumab by the principal investigator during the first 28 days of treatment.

DOR is measured from the time measurement criteria are met for complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) whichever is recorded first until the first date that recurrent of progressive disease is objectively documented, death, or in the absence of progressive disease (PD), date of last assessment. Response was assessed by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines. Complete response (CR) is disease related constitutional symptoms resolved; partial response (PR) is two criteria from Group A (e.g. lymphadenopathy or liver and/or spleen size) if abnormal at baseline plus one of the criteria from Group B (e.g. platelet count) must be met; complete response with incomplete marrow recovery (CRi) is CR with incomplete hematopoietic recovery; stable disease (SD) is defined as not achieving CR or PR, and PD is development of transformation to a more aggressive histology.

Overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence. OS was estimated using the Kaplan-Meier curves and a 95% confidence interval. Response was assessed by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines. Complete response (CR) is disease related constitutional symptoms resolved; Partial response (PR) is two criteria from Group A (e.g. lymphadenopathy or liver and/or spleen size) if abnormal at baseline plus one of the criteria from Group B (e.g. platelet count) must be met, requires the absence of growth factor or transfusion support; Complete response with incomplete marrow recovery (CRi) is CR with incomplete hematopoietic recovery; Stable disease (SD) is defined as not achieving CR or PR, but not fulfilling the criteria for progressive disease (PD); and PD is one criteria from Group A or B are met or development of transformation to a more aggressive histology.

EFS is defined as the duration of time from the date of study enrollment until time of disease lapse, disease progression, alternative therapy for lymphoma given, or death, whichever comes first. EFS was estimated using the Kaplan-Meier curves and a 95% confidence interval. Progression was assessed by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines and is defined as one criterion from Group A (e.g., lymphadenopathy or liver and/or spleen size) or B (e.g., platelet count) are met or development of transformation to a more aggressive histology.

OS is defined as the date of on-study to the date of death from any cause or last follow up.

PFS is defined as the duration of time measurement criteria are met for complete response (CR), complete response with incomplete marrow recovery (CRi), and partial response (PR), whichever is recorded first. PFS was estimated using the Kaplan-Meier curves and a 95% confidence interval. Response was assessed by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines. CR is disease related constitutional symptoms resolved; PR is two criteria from Group A (e.g. lymphadenopathy or liver and/or spleen size) if abnormal at baseline plus one of the criteria from Group B (e.g. platelet count) must be met, requires the absence of growth factor or transfusion support; CRi is CR with incomplete hematopoietic recovery; and progressive disease is one criteria from Group A or B are met or development of transformation to a more aggressive histology.

National Cancer Institute (NCI)

Principal Investigator

Each cycle of treatment is 28 days or 4 weeks, and a maximum of 6 cycles will be administered.

Participant was treated with continuous intravenous (civ) interleukin-15 (IL-15) on dose level 1 with 0.5 mcg/kg/day on days 1-5 of cycles 1-6.

Obinutuzumab (IV) 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.

Arm 1 - Dose Escalation - Dose Level 1

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Kevin Conlon

Number of Treatment-emergent Adverse Events (AEs) Related to Recombinant Human Interleukin-15 (rhIL-15)

Number of Treatment-emergent Adverse Events (AEs) Related to Obinutuzumab

Grade 3 Possibly Related

Grade 3 Probably Related

Grade 3 Definitely Related

Grade 4 Possibly Related

Grade 4 Probably Related

Grade 4 Definitely Related

Grade 5 Possibly Related

Grade 5 Probably Related

Grade 5 Definitely Related

Number of Participants With a Grades 3-5 Dose-limiting Toxicity (DLT) of Continuous Intravenous (CIV) Recombinant Human Interleukin-15 (rhIL-15) Treatment

Number of Participants With a Grade 3-5 Dose-limiting Toxicity (DLT) With Intravenous (IV) Obinutuzumab Treatment

This outcome measure was not done. The MTD was not found because the study was closed after \> 1 year of inactivity and only one participant was enrolled.

Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin-15 (rhIL-15) Administration

Maximum Tolerated Dose (MTD) of Intravenous (IV) Obinutuzumab Treatment

Duration of Response (DOR)

Complete Response

Complete Response with incomplete marrow recovery

Partial Response

Stable Disease

Progressive Disease

Overall Response Rate

There is no confidence interval with 1 sample result.

Event-free Survival (EFS)

There is no full range with 1 sample result.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia	NCT03759184	Leukemia Lymphocytic Chronic B-Cell	rhIL-15 rhIL-15 Obinutuzumab	18 Years -	National Institutes of Health Clinical Center (CC)
Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia	NCT03759184	Leukemia Lymphocytic Chronic B-Cell	rhIL-15 rhIL-15 Obinutuzumab	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for monoclonal antibody treatment