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

Primary Purpose

Leukemia, Lymphocytic, Chronic

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

rhIL-15

Obinutuzumab

About this trial

This is an interventional treatment trial for Leukemia focused on measuring Monoclonal Antibody Treatment, Recombinant Human Interleukin-15, Lymphoid Malignancy, Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm 1 -DOSE ESCALATION

Arm 2 - DOSE EXPANSION

Arm Description

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)

Outcomes

Primary Outcome Measures

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

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

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

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

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

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.

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

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.

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

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.

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

Secondary Outcome Measures

Duration of Response (DOR)

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 Rate

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.

Event-free Survival (EFS)

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.

Overall Survival (OS)

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

Progression-free Survival (PFS)

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.

Full Information

NCT ID

NCT03759184

First Posted

November 28, 2018

Last Updated

March 11, 2022

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT03759184

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Terminated

Why Stopped

The study was closed after > 1 year of inactivity.

Study Start Date

July 11, 2019 (Actual)

Primary Completion Date

December 15, 2019 (Actual)

Study Completion Date

October 22, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leukemia, Lymphocytic, Chronic, B-Cell

Keywords

Monoclonal Antibody Treatment, Recombinant Human Interleukin-15, Lymphoid Malignancy, Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1 -DOSE ESCALATION

Arm Type

Experimental

Arm Description

Arm Title

Arm 2 - DOSE EXPANSION

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

rhIL-15

Other Intervention Name(s)

Recombinant human interleukin-15

Intervention Description

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 Type

Drug

Intervention Name(s)

rhIL-15

Other Intervention Name(s)

Recombinant human interleukin-15

Intervention Description

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 Type

Biological

Intervention Name(s)

Obinutuzumab

Other Intervention Name(s)

Gazyva

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

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

Time Frame

28 days or 4 weeks (cycle 1)

Title

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

Description

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

Time Frame

28 days or 4 weeks (cycle 1)

Title

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

Description

Time Frame

28 days or 4 weeks (cycle 1)

Title

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

Description

Time Frame

28 days or 4 weeks (cycle 1)

Title

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

Description

Time Frame

28 days or 4 weeks (cycle 1)

Title

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

Description

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.

Time Frame

28 days or 4 weeks (cycle 1)

Secondary Outcome Measure Information:

Title

Duration of Response (DOR)

Description

Time Frame

time measurement criteria are met for CR, CRi, or PR whichever is recorded first until the first date that recurrent of progressive disease is objectively documented or death, approximately 27 months

Title

Overall Response Rate

Description

Time Frame

6 cycles (each cycle is 28 days or 4 weeks)

Title

Event-free Survival (EFS)

Description

Time Frame

Approximately 8 months

Title

Overall Survival (OS)

Description

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

Time Frame

Approximately 27 months

Title

Progression-free Survival (PFS)

Description

Time Frame

Approximately 8 months

Other Pre-specified Outcome Measures:

Title

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Description

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.

Time Frame

Date treatment consent signed to date off study, approximately 27 months and 11 days.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kevin C Conlon, M.D.

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

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

IPD Sharing Time Frame

Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genome Data Sharing (GDS) plan for as long as database is active.

IPD Sharing Access Criteria

Clinical data will be made available via subscription to Biomedical Translational Research (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Citations:

PubMed Identifier

33883258

Citation

Dubois SP, Miljkovic MD, Fleisher TA, Pittaluga S, Hsu-Albert J, Bryant BR, Petrus MN, Perera LP, Muller JR, Shih JH, Waldmann TA, Conlon KC. Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies. J Immunother Cancer. 2021 Apr;9(4):e002193. doi: 10.1136/jitc-2020-002193.

Results Reference

derived

PubMed Identifier

32508818

Citation

Waldmann TA, Dubois S, Miljkovic MD, Conlon KC. IL-15 in the Combination Immunotherapy of Cancer. Front Immunol. 2020 May 19;11:868. doi: 10.3389/fimmu.2020.00868. eCollection 2020.

Results Reference

derived

Links:

URL

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-C-0024.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

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

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