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

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ClinicalTrials.gov Identifier: NCT03759184
Recruitment Status : Recruiting
First Posted : November 29, 2018
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE November 28, 2018
First Posted Date  ICMJE November 29, 2018
Last Update Posted Date July 16, 2019
Actual Study Start Date  ICMJE July 11, 2019
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 28, 2018)
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) ]
Frequency (number and percentage) of treatmentemergent AEs
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03759184 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia
Official Title  ICMJE Pilot Trial of Human IL-15 (rhIL-15) and Obinutuzumab for Refractory and Relapsed Chronic Lymphocytic Leukemia (CLL)
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 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 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 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia
  • Lymphocytic
  • Chronic
  • B-Cell
Intervention  ICMJE
  • Drug: rhIL-15
    civ IL-15 at dose levels of 0.5,1 or 2 mcg/kg/day on days 1-5 of cycles 1-6
  • Biological: obinutuzumab
    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
Study Arms  ICMJE
  • Experimental: 1
    DOSE 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
    Interventions:
    • Drug: rhIL-15
    • Biological: obinutuzumab
  • Experimental: 2
    DOSE 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)
    Interventions:
    • Drug: rhIL-15
    • Biological: obinutuzumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 28, 2018)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2021
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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., 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%)
  • 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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Maureen E Edgerly, R.N. (240) 760-6013 edgerlym@pbmac.nci.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03759184
Other Study ID Numbers  ICMJE 190024
19-C-0024
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Milos Miljkovic, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date May 20, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP