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

NCT03759184 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 19002419-C-0024
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Leukemia; Lymphocytic; Chronic; B-Cell

Keywords

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

Outcome Measures

Primary Outcomes (6)

• 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

  28 days or 4 weeks (cycle 1)

• 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

  28 days or 4 weeks (cycle 1)

• 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.

  28 days or 4 weeks (cycle 1)

• 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.

  28 days or 4 weeks (cycle 1)

• 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.

  28 days or 4 weeks (cycle 1)

• 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.

  28 days or 4 weeks (cycle 1)

Secondary Outcomes (5)

• Duration of Response (DOR)

  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

• Overall Response Rate

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

• Event-free Survival (EFS)

  Approximately 8 months

• Overall Survival (OS)

  Approximately 27 months

• Progression-free Survival (PFS)

  Approximately 8 months

Other Outcomes (1)

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

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

Study Arms (2)

Arm 1 -DOSE ESCALATION

EXPERIMENTAL

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)

Drug: rhIL-15; Biological: Obinutuzumab

Arm 2 - DOSE EXPANSION

EXPERIMENTAL

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)

Drug: rhIL-15; Biological: Obinutuzumab

Interventions

rhIL-15 DRUG

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

Also known as: Recombinant human interleukin-15

Arm 1 -DOSE ESCALATION

Obinutuzumab BIOLOGICAL

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

Also known as: Gazyva

Arm 1 -DOSE ESCALATION; Arm 2 - DOSE EXPANSION

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• 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.

  PMID: 33883258 DERIVED

• 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.

  PMID: 32508818 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia; Bronchiolitis Obliterans Syndrome

Interventions

Interleukin-15; obinutuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Kevin Conlon
• Organization: National Cancer Institute

conlonkc@mail.nih.gov

240-858-3570

Study Officials

• Kevin C Conlon, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 28, 2018
• First Posted: November 29, 2018
• Study Start: July 11, 2019
• Primary Completion: December 15, 2019
• Study Completion: October 22, 2021
• Last Updated: March 22, 2022
• Results First Posted: March 10, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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.
• 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.

Locations

US (1)