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Leukemia, Lymphocytic, Chronic, B-CellPhase 1/2NCT02912754

Ruxolitinib Combined With Ibrutinib in Chronic Lymphocytic Leukemia Patients

A Phase 1/2 study testing ruxolitinib and ibrutinib in people with Leukemia, Lymphocytic, Chronic, B-Cell, run by Sunnybrook Health Sciences Centre at 2 sites in Canada.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

This study involves adding the kinase inhibitor Ruxolitinib to Ibrutinib to treat Chronic Lymphocytic Leukemia (CLL). Read more about this study

Who is it for?
Ages 19 years and older
Conditions the study is for
Leukemia, Lymphocytic, Chronic, B-Cell
What is being tested?
ruxolitinib and ibrutinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
2 sitesCanada
Study dates
Mar 2017to Aug 2019
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 19 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of CLL meeting published diagnostic criteria.
  • CLL currently being treated with Ibrutinib due to relapsed/refractory disease or primary del17p cytogenetic lesions at a daily dose of 420 mg and:
  • failure of plasma b2M levels to decrease below 2.5 mg/L after 6 months after starting Ibrutinib.
  • persistent lymphocytosis (>5x106 cells/L) and splenomegaly or lymphadenopathy (marker node >1.5 cm on CT scans) after 1 year of taking Ibrutinib.
  • Not currently treated with other agents for CLL.
  • Serum bilirubin, and alanine transferase less than or equal to twice the upper limit of normal.
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  • Platelets >75x109/L. Absolute neutrophil count (ANC)>.75x109/L. Hemoglobin greater than or equal to 65 g/L
  • Age >18 years old
  • Eastern Cooperative Oncology Group (ECOG) < 2

Who cannot join

  • Patients with inadequate bone marrow reserve at baseline visit as demonstrated by at least one of the following: a. ANC<.75x109/L b. platelets <75x109/L without the assistance of growth factors, thrombopoietic factors, or platelet transfusions. C. hemoglobin <65 g/L despite transfusions.
  • Patients who have or have had progressive multifocal leukoencephalopathy (PML).
  • Patients with clinically significant bacterial, fungal, parasitic or viral infection, which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
  • Patients with known active hepatitis A, B, C or who are HIV-positive or who are at risk for hepatitis B virus (HBV) reactivation. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive. Prior test results obtained as part of standard of care prior to alloSCT that confirm a subject is immune and not at risk for reactivation (ie, hepatitis B surface antigen negative, surface antibody positive) may be used for purposes of eligibility and tests do not need to be repeated. Subjects with prior positive serology results must have negative polymerase chain reaction results. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment.
  • Primary immunodeficiency such as X-linked agammaglobulinemia or common variable immunodeficiency.
  • Patients with active and inactive ('latent') tuberculosis infection.
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  • Involvement of the central nervous system by lymphoma or leukemia.
  • Richter's transformation or prolymphocytic leukemia.
  • Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
  • Use of glucocorticoids above the equivalent of 10 mg of prednisone daily within 4 weeks prior to treatment.
  • Major surgery within 4 weeks prior to treatment.
  • Patients with a history of malignancy in the past 3 years except for treated, early-stage squamous or basal cell carcinoma.
  • History or current diagnosis of uncontrolled or significant cardiac disease, including any of the following: a. myocardial infarction within last 6 months. b. uncontrolled congestive heart failure. c. unstable angina within last 6 months. d. exertional angina. e. clinically significant (symptomatic) cardiac arrhythmias (eg. bradyarrhythmias, sustained ventricular tachycardia, and clinically significant second or third degree block without a pacemaker).
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • Renal failure requiring dialysis or serum creatinine >176.8 microM and patients with moderate (creatinine clearance of 30-50 ml/min) and severe (creatinine clearance<30 ml/min) renal impairment with platelet counts less than 100,000/ml.
  • Patients with mild, moderate, or severe hepatic impairment or inadequate liver function defined by any of direct bilirubin, alanine amino transferase (ALT), or aspartate aminotransferase (AST)>2.5 x upper limit of normal (ULN).
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
  • Patients with known hypersensitivity to ruxolitinib or other JAK1/2 inhibitors, or to their excipients.
  • Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 30 days of screening or 5 half-lives (whichever is longer) prior to the first dose of study drug.
  • Significant concurrent, uncontrolled medical condition which, in the investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.
  • Subjects who are unable to comprehend or are unwilling to sign an informed consent form (ICF).
  • Sexually active males who do not agree to use condoms during intercourse while taking ruxolitinib and for 3 months after stopping treatment (N.B. the mean elimination half-life of ruxolitinib is around 3 hours) and not father a child in this period. Vasectomized men must also agree to use a condom during intercourse to prevent delivery of ruxolitinib via seminal fluid.
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human choriogonadotropin (HCG) laboratory test (>5 mIU/ml).
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study duration inclusive of 30 day safety follow up. Highly effective contraception methods include:
  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. Incase of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  • Male sterilization (at least 6 months prior to screening). the vasectomized male partner should be the sole partner for that subject.
  • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
  • Use of strong CYP3A4 inhibitors for patients in the phase I component of the trial.

Trial locations and contacts

2 sites in 1 country.

Canada2 sites

  • Sunnybrook Odette Cancer Center

    Toronto, Ontario, M4N 3M5

    Geetha Geetha Yogendran, BSc, 416-480-5000 ext. 89565, geetha.yogendran@sunnybrook.ca

    Lindsay McCaw, MSc, 416-480-6100 ext. 4244, lindsay.mccaw@sunnybrook.ca

  • Sunnybrook Odette Cancer Center

    Toronto, Ontario, M4N3M5

Other trials in Canada

About this study

Official title: A Phase I/II Trial of Ruxolitinib in Chronic Lymphocytic Leukemia Patients at Risk for Progression on Ibrutinib

This study involves adding the kinase inhibitor Ruxolitinib to Ibrutinib to treat Chronic Lymphocytic Leukemia (CLL).

Read the detailed description

Ibrutinib is an effective drug that can extend the lives of CLL patients but it is not curative as a single agent and may eventually select for more aggressive disease. Survival of CLL cells in the presence of Ibrutinib may be enabled by signals from the microenvironment where the leukemia cells originate. These signals are transmitted into the cells by Janus Kinases (JAKs) such as janus kinase 1 (JAK1) and janus kinase 2 (JAK2). According, JAK inhibitors may overcome the cytoprotective properties of the CLL microenvironment and help to improve outcomes with Ibrutinib.

The JAK2 inhibitor Ruxolitinib is licensed for use in myelofibrosis and polycythemia rubra vera and its toxicity and efficacy as a single agent in CLL has been studied in two previous clinical trials. As a single agent, Ruxolitinib was inferior to Ibrutinib. However, Ruxolitinib was shown to cooperate with Ibrutinib and increase killing of CLL cells in vitro. Based on these observations, it is hypothesized that Ruxolitinib will significantly improve the therapeutic efficacy of single-agent Ibrutinib.

This is a single center phase I/II trial to determine the efficacy and safety of ruxolitinib tablets in CLL patients being treated until progression with Ibrutinib and considered at risk to progress on the basis of persistent lymphocytosis and lymphadenopathy after 1 year of Ibrutinib or elevated beta-2-microglobulin (b2M) levels after 6 months of Ibrutinib. Ruxolitinib will be administered for 21 days of a 35-day cycle to be repeated 6 more times.

Being tested
ruxolitinib, ibrutinib
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ruxolitinibDrug

    Also called jakafi

    ruxolitinib will be added to ibrutinib or 3 out of 5 weeks per cycle

  • ibrutinibDrug

    Also called imbruvica

    patients will be taking ibrutinib for at least 6 months and will continue to take it at the same dose and schedule while taking ruxolitinib

Study groups in NCT02912754
Study groupRoleWhat they receive
Ibrutinib plus RuxolitinibExperimentalPatients taking ibrutinib for relapsed CLL will add ruxolitinib twice per day at the dose identified in a preliminary phase I trial for 7 cycles (3 weeks on/2 weeks off).
Receives: Drug: ruxolitinib; Drug: ibrutinib
Ibrutinib aloneNo interventionPatients will continue to take Ibrutinib for the equivalent period of time.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. maximum tolerated dose (MTD) of ruxolitinib in combination with Ibrutinib.

    identify the MTD of ruxolitinib with ibrutinib

    Measured: 2 years

Secondary outcomes (1)

  1. ability of Ruxolitinib to increase the depth of response to Ibrutinib

    identify the number of complete responses that occur when ruxolitinib is added to ibrutinib

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Sep 2016 (estimated)
  2. Study startMar 2017 (estimated)
  3. Primary completionDec 2018 (estimated)
  4. Study completionAug 2019 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
36 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02912754
Sponsor's protocol ID
CINC424XCA05T
Status last verified
Sep 2016
First submitted
19 Sep 2016
Last updated
13 Mar 2017
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: the results from the study will be published in peer-review journals

Publications

  • Oppermann S, Lam AJ, Tung S, Shi Y, McCaw L, Wang G, Ylanko J, Leber B, Andrews D, Spaner DE. Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells. Oncotarget. 2016 Nov 8;7(45):72608-72621. doi: 10.18632/oncotarget.11618.

    PubMed 27579615

  • Spaner DE, Wang G, McCaw L, Li Y, Disperati P, Cussen MA, Shi Y. Activity of the Janus kinase inhibitor ruxolitinib in chronic lymphocytic leukemia: results of a phase II trial. Haematologica. 2016 May;101(5):e192-5. doi: 10.3324/haematol.2015.135418. Epub 2016 Jan 27. No abstract available.

    PubMed 26819050

  • Xia M, Luo TY, Shi Y, Wang G, Tsui H, Harari D, Spaner DE. Effect of Ibrutinib on the IFN Response of Chronic Lymphocytic Leukemia Cells. J Immunol. 2020 Nov 15;205(10):2629-2639. doi: 10.4049/jimmunol.2000478. Epub 2020 Oct 16.

    PubMed 33067379

  • Spaner DE, McCaw L, Wang G, Tsui H, Shi Y. Persistent janus kinase-signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial. Cancer Med. 2019 Apr;8(4):1540-1550. doi: 10.1002/cam4.2042. Epub 2019 Mar 7.

    PubMed 30843659

  • Shi Y, Wang G, Muhowski EM, McCaw L, Wang C, Bjarnason G, Woyach JA, Spaner DE. Ibrutinib reprograms the glucocorticoid receptor in chronic lymphocytic leukemia cells. Leukemia. 2019 Jul;33(7):1650-1662. doi: 10.1038/s41375-019-0381-4. Epub 2019 Jan 29.

    PubMed 30696950

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing ruxolitinib and ibrutinib in people with Leukemia, Lymphocytic, Chronic, B-Cell, run by Sunnybrook Health Sciences Centre at 2 sites in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 13 Mar 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

maximum tolerated dose (MTD) of ruxolitinib in combination with Ibrutinib. (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02912754, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2017.

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