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Chronic Phase Chronic Myeloid LeukemiaPhase 1/2NCT01914484

Phase I/II Study of Nilotinib/Ruxolitinb Therapy for TKI Resistant Ph-Leukemia

A Phase 1/2 study testing Nilotinib and Ruxolitinib in people with Chronic Phase Chronic Myeloid Leukemia and Accelerated Phase Chronic Myeloid Leukemia, run by University Health Network, Toronto at 1 site in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies with BCR-ABL kinase inhibition activity. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nilotinib and Ruxolitinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
1 siteCanada
Study dates
1 Aug 2013to 31 Dec 2018
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 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have Chronic Myeloid Leukemia in any phase (CP, AP, or BP of any phenotype) or Ph+ Acute Lymphoblasic Leukemia. The confirmation of Ph+ chromosome can be substituted by the presence of BCR/ABL transcript by PCR test at diagnosis.
  • Patients must be previously treated with and resistant, or intolerant, to 2 or more lines of treatment including imatinib, dasatinib, or other investigational agent. Patient who have CML-CP who were previously treated with and resistant to only dasatinib are also included. At least 2 weeks must have elapsed from the last date of treatment to the first dose of study treatment. Patients who have received Nilotinib for more than 4 consecutive weeks will be excluded.
  • Must be ≥18 years old.
  • Provide written informed consent.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  • Minimum life expectancy of 3 months or more.
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  • Adequate organ liver and renal functions:
  • Total bilirubin ≤ 1.5 x ULN. Does not apply to patients with isolated hyperbilirubinemia (e.g., Gilbert's Disease) of grade < 3;
  • Alanine aminotransferase (ALT) ≤ 2.5x ULN or or ≤ 5.0 x ULN if considered due to leukemia.
  • Creatinine ≤ 2.5 mg/dL.
  • Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukemia;
  • Serum lipase and amylase ≤ 1.5 x ULN
  • Normal serum levels ≥ LLN (lower limit of normal) or corrected to within normal limits with supplements, prior to the first dose of study medication, of potassium, magnesium and calcium;
  • Female patients of childbearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test within 2 weeks prior to enrollment. Male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post menopausal. Post menopausal is defined as at least 12 consecutive months without menses.
  • Ability and willingness to comply with study procedures and schedule, in the Investigator's opinion.

Who cannot join

  • Received Tyrosine Kinase Inhibitor therapy within 7 days prior to receiving the first dose of Ruxolitinib+Nilotinib, with the exception of patients who have previously received Nilotinib who must have stopped Nilotinib 4 weeks prior to receiving the first dose of Ruxolitinib+Nilotinib.
  • Patients who have not recovered (> grade 1 by NCI CTCAE, v. 4.03) from AEs (except alopecia) due to agents previously administered.
  • Patients who received other therapies as follows:
  • For CP and AP patients:
  • Received any of the following within 2 weeks prior to receiving first dose of Ruxolitinib + Nilotinib:
  • Hydroxyurea (within 7 days of first dose)
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  • anagrelide
  • interferon
  • cytarabine
  • immunotherapy
  • any other cytotoxic chemotherapy, radiotherapy, or investigational therapy
  • For BP patients:
  • Received any of the following within 2 weeks prior to receiving first dose of Ruxolitinib + Nilotinib:
  • chemotherapy other than hydroxyurea
  • anagrelide
  • interferon
  • cytarabine
  • immunotherapy
  • any other cytotoxic chemotherapy, radiotherapy, or investigational therapy
  • For Ph+ ALL patients:
  • Received any of the following within 2 weeks prior to the first dose of Ruxolitinib+Nilotinib:
  • corticosteroids
  • vincristine
  • Hydroxyurea (within 7 days of first dose)
  • anagrelide
  • interferon
  • cytarabine
  • immunotherapy
  • any other cytotoxic chemotherapy, radiotherapy, or investigational therapy
  • Underwent autologous or allogeneic stem cell transplant within 60 days prior to receiving the first dose of Ruxolitinib+Nilotinib; any evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.
  • Patients with any of the following:
  • Have prolonged QT (QTc >450 ms) or take medications that are known to be associated with Torsades de Pointes, or potentially prolonging QT.
  • Long QT syndrome or familiar history of long QT syndrome Persistent significant bradicardia (<50bpm) Experienced a myocardial infarction within 12 months of registration
  • Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
  • Have previously been treated with Ruxolitinib.
  • Patients with CML CP are excluded if they are in MCyR.
  • Patients with CML AP, CML BP, or Ph+ ALL are excluded if they are in MCyR.
  • Have active central nervous system (CNS) disease as evidenced by cytology or pathology. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture. In the absence of clinical CNS disease, lumbar puncture is not required.
  • Have significant or active cardiovascular disease or significant bleeding disorder unrelated to CML or Ph+ ALL.
  • Have a history of pancreatitis or alcohol abuse.
  • Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
  • Have malabsorption syndrome or other gastrointestinal illness that could affect the absorption of the study drug.
  • Patients with inadequate bone marrow reserve within 2 weeks prior to start study drug as demonstrated by:
  • Absolute neutrophil count (ANC) that is ≤ 1000/µL.
  • Platelet count that is < 125,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
  • Patients with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason.
  • Patients with coagulation parameters (PT, PTT, INR) ≥ 1.5 ULN within 2 weeks prior to starting study drug.
  • Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy.
  • Patients with HLA matched donor and eligible for allogeneic transplantation for CML treatment.
  • Patient being treated concurrently with any of the following prohibited medications:
  • JAK inhibitor
  • Any investigational medication other than the study drugs. Use of such medications within 14 days or 6 half-lives, whichever is longer, prior to the first dose of study drug is prohibited
  • Potent inducers and inhibitors of CYP3A4• Use of HU, interferon, thalidomide, busulfan, lenalidomide, anagrelide, is not permitted at any time beginning 28 days prior to the first Baseline assessment.
  • Hematopoietic growth factor receptor agonists (eg, erythropoietin (Epo), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag) must not be used as they may be associated with spleen size increases. Growth factors must not have been used for at least one month prior to receiving the first dose of study drug.

Trial locations and contacts

1 site in 1 country.

Canada1 site

  • Princess Margaret Hospital / University Health Network

    Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

Official title: A PHASE I/II, MULTI-CENTRE, TRIAL OF RUXOLITINIB THERAPY IN COMBINATION WITH NILOTINIB IN PATIENTS WITH PHILADELPHIA POSITIVE CHRONIC MYELOID LEUKEMIA OR ACUTE LYMPHOBLASTIC LEUKEMIA WHO HAVE FAILED TYROSINE KINASE INHIBITOR THERAPY

This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies with BCR-ABL kinase inhibition activity. Ruxolitinib is a tyrosine kinase inhibitor blocking alternative pathway independent of BCR-ABL mediated pathway, thus having a potential to overcome tyrosine kinase inhibitor resistance in Philadelphia positive CML or ALL patients. Phase I study will be conducted to define a recommended phase II dose (RPTD) and phase II study will examine the hypothesis that combinational approach will increase response rate of resistant CML/ALL patients, thus evaluating efficacy of the combination regimen.

Read the detailed description

The purpose of this study is to find out if multiple tyrosine kinase inhibitor resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) can be treated with combination approach of Nilotinib with Ruxolitinib which may block alternative pathway besides BCR-ABL kinase inhibition in Ph positive leukemia, esp against JAK2-STAT5 pathway. First step is to define the dose of Ruxolitinib with fixed dose of Nilotinib which had been approved at the dose of 400mg bid for imatinib failed CML.

During phase I part of the study,dose escalations will be decided on the basis of DLTs observed hence the exact sample size could not be predicted with certainty but will range between 9-12 patients. Three patients will be enrolled per dose level. Accordingly 9 patients are expected to be enrolled. If a DLT is observed, 3 more patients will be enrolled at the dose level in which the DLT occurred.

The study will be conducted at multiple sites across Canada and enrollment will be competitive. Once 3 patients are enrolled in a cohort, that dose level will be closed to enrollment until safety assessment of the 3 subjects is performed at the end of cycle 1. This procedure will be performed for each dosing cohort. Patients will be assigned to a dose level based on authorization from the sponsor in collaboration with Ozmosis Research Inc.

For the phase II part of the study, once the RPTD has been established in the phase I portion of this trial, the phase II will begin. The phase II portion will be a two-stage, single arm, unblinded study investigating the potential efficacy of the combination of Ruxolitinib and Nilotinib.

A maximum of 20 patients will be accrued in the phase II portion. Those patients treated in the phase I portion of this trial at the RPTD will be included in the analysis of the Phase II study.

Being tested
Nilotinib, Ruxolitinib
Keywords
tyrosine kinase inhibitor resistance, chronic myeloid leukemia, acute lymphoblastic leukemia, nilotinib, ruxolitinib
Medical subject headings
Leukemia, Myeloid, Chronic-Phase, Leukemia, Myeloid, Accelerated Phase, Blast Crisis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myelogenous, Chronic, BCR-ABL Positive

What participants receive

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

  • NilotinibDrug

    Also called Tasigna

    Nilotinib dose will remain fixed at 400mg bid throughout the cycles. BCR-ABL kinase inhibitor

  • RuxolitinibDrug

    Also called INCB018424, Jakavi

    In the phase I part of the study, dose escalation will follow a 3+3 study design at either of 3 fixed dose levels (10 mg bid, 15 mg bid or 20 mg bid).

    No intra-patient dose-escalation will occur. JAK inhibitor

Study groups in NCT01914484
Study groupRoleWhat they receive
Nilotinib with RuxolitinibExperimentalNilotinib: Given that recommended dose of Nilotinib for imatinib failed CML patients is 400mg twice daily, Nilotinib dose will remain fixed at 400mg bid throughout the cycles. Ruxolitinib: In the phase I part of the study, dose escalation will follow a 3+3 study design. Dose modifications will not occur, as the purpose of this study is to determine the maximum tolerated dose. Ruxolitinib will be given at one of 3 fixed dose levels for the duration of their treatment, either 10mg twice daily, 15mg twice daily or 20mg twice daily.
Receives: Drug: Nilotinib; Drug: Ruxolitinib

What is being measured

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

  1. Phase I: Maximum Tolerated Dose (MTD)

    Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).

    Measured: Average of 6 months

  2. Phase II: Major cytogenetic response

    Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients

    Measured: Average of 6 months

Secondary outcomes (4)

  1. Phase I: complete hematologic response

    Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in CML patients in AP or BP, and patients with Ph+ ALL.

    Measured: Average of 3 months

  2. Phase I: major cytogenetic response

    Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow taken at 6 months.

    Measured: Average of 6 months

  3. Phase I: Safety and tolerability

    It will be defined by NCI Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 for adverse event reporting.

    Measured: Average of 6 months

  4. Phase II: complete hematologic response

    Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in the CML patients in AP or BP and in patients with Ph+ ALL.

    Measured: Average of 3 months

Timeline

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

  1. First posted2 Aug 2013 (estimated)
  2. Study start1 Aug 2013
  3. Primary completion31 Dec 2018
  4. Study completion31 Dec 2018

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01914484
Sponsor's protocol ID
CAMN107ACA06T
Other IDs
OZM-051
Status last verified
Oct 2020
First submitted
28 Jul 2013
Last updated
2 Nov 2020
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Nilotinib and Ruxolitinib in people with Chronic Phase Chronic Myeloid Leukemia and Accelerated Phase Chronic Myeloid Leukemia, run by University Health Network, Toronto at 1 site 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 15 inclusion and 54 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: finished, as of the sponsor's last update on 2 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I: Maximum Tolerated Dose (MTD) (time frame: Average of 6 months). The study lists 2 primary outcomes in all. 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 NCT01914484.

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 2 Nov 2020.

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