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The Role of Ruxolitinib in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm

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ClinicalTrials.gov Identifier: NCT03558607
Recruitment Status : Recruiting
First Posted : June 15, 2018
Last Update Posted : September 10, 2018
Sponsor:
Information provided by (Responsible Party):
Seoul National University Hospital

Brief Summary:
This trial aimed to investigate the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-myeloproliferative neoplasm secondary acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Disorder Drug: Ruxolitinib Phase 1 Phase 2

Detailed Description:

Acute myeloid leukemia (AML) is an uncommon, but often deadly complication of myeloproliferative neoplasms (MPN). Post-MPN AML is aggressive and resistant to conventional treatment with median survival of 3-5 months. Although allogeneic stem cell transplantation (alloSCT) have some prospective of promise in these patient, most of them are ineligible for alloSCT because of advanced age at diagnosis, comorbidities and scarcity of a compatible donor. Therefore, there is an urgent need for new therapeutic strategy for post-MPN AML.

Cytogenetic and/or molecular abnormalities associated with poor prognosis are quite common in patients with post-MPN AML. Although these findings likely contribute to the aggressive natural history and resistance to standard therapies, the genetic complexity of post-MPN AML may ultimately permit targeted therapy. Among these abnormalities, Janus kinase 2 (JAK2) has come to the fore recently. JAK2 V617F mutation, which is a hallmark of MPN, has been reported to be carried in approximately 35-50% of patients with post-MPN AML. We believe that this mutation be the most oncogenic driver in post-MPN AML.

In fact, BCR/ABL(+) acute leukemia (either blast crisis of CML or Ph+ ALL) is a similar disease model of the post-MPN AML. The clinical outcome of these disease has improved dramatically with ABL tyrosine kinase inhibitors (TKIs), such as imatinib, and nilotinib. It is a standard practice to give ABL TKI along with cytotoxic chemotherapy to BCR/ABL(+) acute leukemia. On the other hand, in BCR/ABL(+) acute leukemia, it is well known that single agent ABL TKI is not sufficient to control disease.

Likewise, ruxolitinib, which is a targeted agent for JAK2, have a great possibility to show efficacy for post-MPN AML when combined with cytotoxic agents. In a previous investigational study of ruxolitinib for refractory/relapsed leukemias, 2 of 3 AML patients evolving from MPN achieved complete remission with two cycles of ruxolitinib. In fact, many clinical trials are ongoing to investigate the therapeutic efficacy of ruxolitinib in post-MPN AML as a single agent.

However, considering a lesson from BCR/ABL(+) acute leukemia, ruxolitinib as a single agent may not be enough to cure these patients with post-MPN AML. Hence, for patients who are fit for intensive chemotherapy, it would easily conjectured that ruxolitinib in combination with cytotoxic chemotherapy would be better for these patients. Therefore, combination of ruxolitinib and cytotoxic chemotherapy would be an optimal treatment for post-MPN AML. From an epidemiologic perspective, it is true that post-MPN AML develops in elderly patients frequently. However, patients who fit for intensive chemotherapy are also encountered in the clinic for post-MPN AML not infrequently, justifying this study design. NCCN guideline also recommend intensive induction treatment for patients > 60 years when there performance and comorbidity allows intensive treatment.

In this study, the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-MPN AML will be investigated. Unlike other clinical trials induction and consolidation treatment should include cytotoxic chemotherapeutic agents in addition to ruxolitinib.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 17 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Concomitant Ruxolitinib Induction and Maintenance With Cytarabine Based Chemotherapy in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm
Estimated Study Start Date : February 1, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: Experimental arm Drug: Ruxolitinib

Induction chemotherapy include combination of cytarabine (200mg/m2) and idarubicin (12mg/m2). Both 7+3 and 5+2 regimen is allowed according to age and performance status (PS) as follows;

  • If Age < 55 years and ECOG PS < 2 : 7+3 regimen
  • If Age ≥ 55 years or ECOG PS = 2 : 5+2 regimen

Ruxolitinib is administered for 14 days during induction/consolidation phase. After complete remission after induction, ruxolitinib is administered for the first 14 days during consolidation chemotherapy. Maximum 3 cycles of consolidation is recommended. In case of allogeneic stem cell transplantation (alloSCT), ruxolitinib is discontinued at the time of transplantation. After completion of consolidation, 2 years of ruxolitinib maintenance is planned. The follow-up period is from the time of enrollment until 24 months.





Primary Outcome Measures :
  1. complete remission rate [ Time Frame: After 12 months from induction chemotherapy ]
  2. complete remission with incompletre recovery rate [ Time Frame: After 12 months from induction chemotherapy ]

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 3, 6, 12, 24 months after induction chemotherapy ]
    from the date of transplantation to death from any cause

  2. Progression-free survival [ Time Frame: 3, 6, 12, 24 months after induction chemotherapy ]
    from the date of transplantation to the date of disease progression or death from any cause

  3. Toxicity profile [ Time Frame: 3, 6, 12, 24 months after induction chemotherapy ]
    according to CTCAE version 4.03



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Cytologically confirmed AML following MPN
  • ECOG performance status 2 or better
  • Adequate physical condition that could tolerate cytotoxic induction chemotherapy judged by investigator
  • Age 18 years or older
  • Adequate cardiac function
  • Adequate hepatic, and renal function
  • Serum creatinine ≤ 2.5 mg/dl
  • ALT (SGOT) and/or AST (SGPT) equal to or than 1.5 x upper limit of normal
  • Life expectancy of ≥ 3 months
  • Signed and dated informed consent of document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment
  • For women of childbearing age, it should be confirmed that they are not pregnant and that they should be contraception during the study period and for up to 4 weeks after the end of the study
  • Male should agree to the barrier method during the study period and up to four weeks after the end of the study

Exclusion Criteria:

  • Diagnosis of any serious secondary malignancy within the last 2 years, except for adequately treated basal cell or squamous cell carcinoma of skin, or in situ carcinoma of cervix uteri
  • Pregnancy or breast feeding
  • Other severe acute or chronic medical or psychiatric condition
  • Prior treatment with ruxolitinib
  • Patients who received other chemotherapy within 2 weeks of the study enrollment
  • Patients participating in other clinical studies at the time of registration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03558607


Contacts
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Contact: Youngil Koh, Dr. +82-2-2072-3079 go01@snu.ac.kr
Contact: Ryul Kim, Dr. +82 10 9412 6108 chrono0707@icloud.com

Locations
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Korea, Republic of
Seoul National University Bundang Hospital Recruiting
Seongnam, Korea, Republic of, 13620
Contact: Ryul Kim, Dr    +82 10 9412 6108    chrono0707@icloud.com   
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 03080
Contact: Ryul Kim, MD    +82 10 9412 6108    chrono0707@icloud.com   
Principal Investigator: Youngil Koh, MD         
Sub-Investigator: Sung soo Yoon, MD, PhD         
Sub-Investigator: In ho Kim, MD         
Sub-Investigator: Ryul Kim, MD         
Sponsors and Collaborators
Seoul National University Hospital

Publications:

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Responsible Party: Seoul National University Hospital
ClinicalTrials.gov Identifier: NCT03558607     History of Changes
Other Study ID Numbers: H-1803-145-934
First Posted: June 15, 2018    Key Record Dates
Last Update Posted: September 10, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Neoplasms
Neoplasm Metastasis
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myeloproliferative Disorders
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Cytarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs