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

  • STATUS
    Recruiting
  • End date
    Sep 1, 2021
  • participants needed
    24
  • sponsor
    National Cancer Institute (NCI)
Updated on 2 December 2020
Investigator
Maureen E Edgerly, R.N.
Primary Contact
National Institutes of Health Clinical Center (9.7 mi away) Contact
cancer
lymphoid leukemia
hematologic malignancy
anemia
chronic lymphocytic leukemia
lymphoma
thrombocytopenia

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 stay in the clinic for week 1. They will get:

  • IL-15 as a continuous intravenous infusion over 24 hours on days 1-5
  • Obinutuzumab as an infusion on 4 days, over about 4 hours. The doses for this will increase.

Other cycles: Participants will come to the clinic days 1 5 and get IL-15 as in cycle 1. They will get obinutuzumab on day 4.

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.

...

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-CD20 monoclonal antibody thought to engage the immune system by directly activating antibody-dependent, cellmediated 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 CD8+ memory Tcells. 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 rhIL-15; BL/6 mice inoculated with 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
  • 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 xpressing 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 ibrutinib therapy; patients with del(17p) must also be refractory or relapsed after, or intolerant to BTK inhibitor therapy; patients with 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 manufacturer s 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.

Details
Treatment Obinutuzumab, rhIL-15
Clinical Study IdentifierNCT03759184
SponsorNational Cancer Institute (NCI)
Last Modified on2 December 2020

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Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Chronic or Lymphocyte or Leukemia (Pediatric) or B lymphocyte or leukemia?
Do you have any of these conditions: Leukemia (Pediatric) or B lymphocyte or leukemias or leukemia or Lymphocyte or Chronic?
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, 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 IWCLL 2018 consensus criteria)
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (Hb <10 g/dL) and/or thrombocytopenia (platelet counts <100 (SqrRoot) 10^9/L)
Massive (i.e., greater than or equal to 6 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 (eg, 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 (ie, ECOG performance scale 2 or worse; cannot work or unable to perform usual activities)
Fevers 38.0 degree 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 ULN for patients with total bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (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 (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., 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 HIV infection, PCR evidence for active or chronic hepatitis B or hepatitis C, or positive screening HBV/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
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