Phase l/II Study of Ruxolitinib for Acute Leukemia

Study Overview
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Brief Summary
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The goal of this clinical research study is to find the highest tolerable dose of ruxolitinib that can be given to patients with acute leukemia and to learn if the study drug can help control the disease. The safety of the drug will also be studied.

Detailed Description
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The Study Drug: Ruxolitinib is designed to block a gene mutation that may be important in cancer cell growth and survival. By blocking the gene mutation, this may cause the cancer cells to die. Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 30 participants will be enrolled in the Phase I portion of the study, and up to 136 participants will be enrolled in Phase II. If you are enrolled in the Phase I portion, the dose of ruxolitinib you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of ruxolitinib. Each new group will receive a higher dose of ruxolitinib than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of ruxolitinib is found. If you are enrolled in the Phase II portion, you will receive ruxolitinib at the highest dose that was tolerated in the Phase I portion or at a lower dose. Study Drug Administration: You will take ruxolitinib tablet(s) by mouth 2 times a day on Days 1-28 of each 28-day study cycle. You will be asked to keep a diary to record the doses taken. You will be asked to bring your diary and any unused drug to your next visit. Study Visits: On Days 1, 7, 14, and 21 of Cycle 1: You will have a physical exam. Blood (about 2 teaspoons) will be drawn for routine tests. You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having. On Day 14 only, you will have a bone marrow aspiration performed to check the status of the disease. On Day 1 of Cycle 2: You will have a physical exam. You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having. Blood (about 2 teaspoons) will be drawn for routine tests. You will have a bone marrow aspiration performed to check the status of the disease. During Cycles 2 and beyond, blood (about 2 teaspoons) will be drawn for routine tests at least every 1-2 weeks. This blood may be drawn at a clinic close to your home. On Day 1 of Cycles 3, 6, 9, and beyond: You will have a physical exam. You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having. Blood (about 2 teaspoons) will be drawn for routine tests. You will have a bone marrow aspiration performed to check the status of the disease. On Day 1 of Cycle 3, this will only be done if your doctor thinks it is needed. Length of Study: You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse or intolerable side effects occur. Your participation on the study will be over once you have completed the end-of-study visit and the follow-up call. End-of-Study Visit: After your last dose of study drug, you will have an end-of-study visit. At this visit, the following tests and procedures will be performed: You will have a physical exam. You will be asked about any treatments you may have had, any other drugs you may be taking, and any side effects you may be having. Blood (about 2 teaspoons) will be drawn for routine tests. You will have a bone marrow aspiration performed to check the status of the disease. Follow-Up: About one month after your end-of-study visit, the study staff will call and ask about any side effects you may be having. This call should last about 5 minutes. This is an investigational study. Ruxolitinib is FDA approved and commercially available for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis and post-essential thrombocythemia (post-ET) myelofibrosis. Its use to treat acute leukemia is investigational. Up to 166 patients will take part in this study. All will be enrolled at MD Anderson.

Official Title
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A Phase I/II Study to Determine the Safety and Efficacy of Ruxolitinib, a JAK1/JAK2 Inhibitor, in Subjects With Relapsed or Refractory Acute Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be >14 years of age Must be diagnosed with refractory or relapsed AML or ALL. Must have adequate organ function as demonstrated by the following: o Alanine Aminotransferase (ALT) (SGOT) and/or Aspartate Aminotransferase (AST) (SGPT) equal to or less than 1.5x upper limit of normal o Serum creatinine equal to or less than 2.5 mg/dL Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 At least 2 weeks from prior leukemia-directed treatment to starting treatment drug (except for hydroxyurea, which is allowed if clinically indicated but should be stopped after 2 weeks of receiving study drug, and glucocorticoids, which are allowed but should be stopped upon starting treatment drug). Treatment-related toxicities from prior therapies must have resolved to Grade equal to or less than 1 (except for peripheral neuropathy, which should resolve to grade equal to or less than 2) No active malignancies with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. Females of childbearing potential (FCBP)(A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) must have negative pregnancy test. FCBP and males participating in the study must agree to use a reliable form of contraception or to practice complete abstinence from heterosexual intercourse while participating in the study and for at least 28 days after discontinuation from the study. If pregnancy or a positive pregnancy test does occur in a study subject, treatment with the study drug must be immediately discontinued. Exclusion Criteria: Known positive status for HIV, or known active hepatitis A, B, or C infection. Any serious medical condition or psychiatric illness that would prevent, (as judged by the treating physician) the subject from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Pregnant or lactating females. Acute promyelocytic leukemia Concurrent use of strong inducers or strong inhibitors of cytochrome P450 3A4 (CYP3A4). Strong inducers are rifampin and St. John's Worth. Strong inhibitors are HIV-antivirals, clarythromycin, itraconazole, ketoconazole, nefazodone, and telithromycin. Participating in any other research trial.

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Phase I is a standard 3+3 design and will be used to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and no formal evaluation of efficacy (response rate will be implemented. Patients in Phase I part who were treated at the MTD will be included toward patients assessed for response in the phase II stage.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib 50 mg BID<br>Phase I - Starting dose of Ruxolitinib 50 mg by mouth twice a day for 28 day cycle. | Drug: Ruxolitinib<br>* Phase I - Starting dose of 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I.<br>* Other names: INC424;|
| Experimental: Ruxolitinib 100 mg BID<br>Phase I dose of Ruxolitinib 100 mg by mouth twice a day for 28 day cycle. | Drug: Ruxolitinib<br>* Phase I - Starting dose of 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I.<br>* Other names: INC424;|
| Experimental: Ruxolitinib 200 mg BID<br>Phase I dose of Ruxolitinib 200 mg by mouth twice a day for 28 day cycle. | Drug: Ruxolitinib<br>* Phase I - Starting dose of 50 mg by mouth twice a day for 28 day cycle. Phase II - MTD reached in Phase I.<br>* Other names: INC424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | MTD defined as highest dose level at which no more than one out of six subject experiences dose limiting toxicity (DLT) during first cycle (28 days) of therapy. A non-hematologic DLT defined as a clinically significant grade 3 or 4 adverse event or abnormal laboratory value (according to Common Toxicity Criteria for Adverse Effects (CTCAE) criteria) assessed as related to study drug (and unrelated to disease progression, intercurrent illness, or concomitant medications) occurring during first 28 days on study. Participants who received at least 80% of the originally assigned doses in the first cycle were evaluable for DLT assessment of each cohort. | End of first 28 day cycle for toxicity | 
| Maximum Tolerated Dose (MTD) of Ruxolitinib | The MTD is defined as the highest dose level at which no more than one out of six subject experiences DLT during the first cycle (28 days) of therapy. | End of first 28 day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With a Response | Response is defined as complete remission (CR) + complete remission with incomplete blood count (CRi) + Hematologic improvement (HI). Response was to be assessed for participants who were evaluated for the Phase II portion of this study. CR is absolute neutrophil count (ANC) >/= 1x109/L and platelet count >/= 100x109/L, absence of leukemia blast cells, normal marrow differential, and complete resolution of extramedullary disease. CRi is CR but platelets are < 100x109/L or ANC is <1x109/L. HI is described by the number of individual, positively affected cell lines without the use of growth factors and/or transfusions (lasting at least 4 weeks). | Up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed Acute Leukemia, Acute myeloid leukemia, AML, Acute lymphocytic leukemia, ALL, Ruxolitinib, Jakafi, INC424, INCB018424