Clinical Trials /

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

NCT03759184

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia
  • Official Title: Pilot Trial of Hunan IL-15 (rhIL-15) and Obinutuzumab for Refractory and Relapsed Chronic Lymphocytic Leukemia (CLL)

Clinical Trial IDs

  • ORG STUDY ID: 190024
  • SECONDARY ID: 19-C-0024
  • NCT ID: NCT03759184

Conditions

  • Leukemia
  • Lymphocytic
  • Chronic
  • B-Cell

Interventions

DrugSynonymsArms
rhIL-151
obinutuzumab1

Purpose

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.

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-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 >= 18 years old

        -  ECOG performance status less than or equal to 1

        -  Diagnosis of chronic lymphocytic leukemia (CLL) with >= 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 ibrutinib
           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, 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.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalDOSE ESCALATION: IL-15 by 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 MTD
  • rhIL-15
  • obinutuzumab
2ExperimentalDOSE EXPANSION: 3 to 6 patients to receive IL-15 by civ infusion at the 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)
  • rhIL-15
  • obinutuzumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  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 ibrutinib OR have relapsed/refractory
             CLL and are intolerant of ibrutinib 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., >=6 cm below the left costal margin) or progressive or symptomatic
                  splenomegaly.

               -  Massive nodes (i.e., >=10 cm in longest diameter) or progressive or symptomatic
                  lymphadenopathy.

               -  Progressive lymphocytosis with an increase of >=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 >=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 >=1 month without evidence of infection.

          -  >=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 <1 (Karnofsky >80%)

          -  Adequate organ function as evidenced by the following laboratory parameters:

               -  Absolute neutrophil count (ANC) >= 750 /mcL

               -  Platelets >= 50,000 / mcL (transfusions not permitted)

               -  Hemoglobin >= 9 g/dL (transfusions permitted)

               -  Serum creatinine <= 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 or Legally Authorized Representative (LAR) 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
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the safety, toxicity profile, dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of civ rhIL-15 administration in combination with IV obinutuzumab treatment
Time Frame:28 days or 4 weeks (cycle 1)
Safety Issue:
Description:Frequency (number and percentage) of treatmentemergent AEs

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

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

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