Ruxolitinib for Chronic Myeloid Leukemia (CML) With Minimal Residual Disease (MRD)
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Purpose
This is a 2 part study. The goal of the first part of this clinical research study is to find the highest tolerable dose of ruxolitinib that can be given with a TKI that patient is already taking (such as gleevec, sprycel, or tasigna) as part of their standard of care treatment. The goal of the second part of this study is to learn if this drug combination can help to control CML. Although patient has a good response to therapy, the disease is still detectable at low levels (this is called "minimal residual disease"). Researchers believe that eliminating all detectable evidence of disease may decrease the chances that the leukemia will ever come back. The safety of the drug combination will also be studied in both parts.
Ruxolitinib is designed to block a protein called Jak2 that may help keep some leukemia cells alive even with TKI therapy. Blocking this protein may cause the cells to die.
| Condition | Intervention | Phase |
|---|---|---|
|
Leukemia |
Drug: Ruxolitinib Drug: TKI |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase I-II Study of Ruxolitinib (INCB18424) for Patients With Chronic Myeloid Leukemia (CML) With Minimal Residual Disease While on Therapy With Tyrosine Kinase Inhibitors |
- Maximum Tolerated Dose (MTD) for Ruxolitinib and Tyrosine Kinase Inhibitors (TKIs). [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]MTD is highest dose level at which 6 patients were treated and at most 1 patient experienced a dose limiting toxicity (DLT).
- Clinical Activity of Ruxolitinib and Tyrosine Kinase Inhibitor (TKI) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]Primary endpoint is to determine if residual disease as measured by PCR can decrease by at least 1 log or become undetectable within 12 months from the start of study therapy. Progression defined as a confirmed loss of complete cytogenetic response (CCyR) (i.e., >0% Ph+ metaphases among 20 metaphases counted by karyotype, or >10% positive by FISH) for patients who enter the study with this response. "Confirmed" is defined here as assessed in two consecutive cytogenetic analyses separated by at least a month. Survival endpoints (overall, event-free and free from blastic transformation) measured from the time of start of ruxolitinib therapy.
| Estimated Enrollment: | 48 |
| Study Start Date: | May 2013 |
| Estimated Primary Completion Date: | May 2019 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Ruxolitinib + TKI
Phase I Dose Escalation Group: Ruxolitinib starting dose level 10 mg orally, twice daily. Patients continue receiving commercially available TKIs (IM, NIL or DAS) at dose they had been receiving during the last 6 months. Phase II Dose Expansion Group: Ruxolitinib starting dose level MTD from Phase I Dose Escalation Group. Patients continue receiving commercially available TKIs (IM, NIL or DAS) at dose they had been receiving during the last 6 months. |
Drug: Ruxolitinib
Phase I Dose Escalation Group: Ruxolitinib starting dose level 10 mg orally, twice daily. Phase II Dose Expansion Group: Ruxolitinib starting dose level MTD from Phase I. Other Names:
Drug: TKI
Phase I Dose Escalation Group and Phase II Dose Expansion Group: Patients continue receiving commercially available TKIs (IM, NIL or DAS) at dose they had been receiving during the last 6 months.
Other Name: Tyrosine kinase inhibitor
|
Hide Detailed DescriptionDetailed Description:
Study Drug Administration:
If patient is found to be eligible to take part in this study, they will continue receiving the same TKI at the dose they had been receiving for the last 6 months.
Patient will also receive ruxolitinib by mouth 1 or 2 times daily. The dose level and how often patient takes the drug will depend on when they enter the study. The study staff will give patient more detailed instructions about how often they will take the drug and what they should do if they vomit or miss a dose of study drug.
In the first part of the study, patient will be assigned to a dose level of ruxolitinib based on when they join this study. Up to 3 dose levels of ruxolitinib will be tested. At least 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of ruxolitinib is found. This is called the Dose Escalation Group.
After the highest tolerated dose has been found, an extra 30 participants will receive ruxolitinib at that dose level. This is called the Dose Expansion Group.
Study Visits:
Each study cycle is 4 weeks.
At every visit, patient will be asked about any side effects they may have had and to list any drugs they may be taking.
Every 1-2 weeks for 8 weeks, then every 3 months, blood (about 1 teaspoon) will be drawn for routine tests.
Every 2-4 weeks for 8 weeks, then every 3 months, blood (about 1 teaspoon) will be drawn to test patient's kidney and liver function.
Before each cycle for the first 3 cycles, then every 3-6 cycles for the first year, then every 6-12 cycles after that, blood (about 1 tablespoon) drawn for molecular testing.
Every 3-6 months for the first year, then every 6-12 months after that patient will have a bone marrow aspirate to check the status of the disease.
Every 3 months (+/- 1 month) for the first 6 months, then every 6-12 months after that, patient will have a complete physical exam.
Length of Study:
Patient may continue taking the study drug for up to 2 years as long as the doctor thinks it is in their best interest. Patient will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if they are unable to follow study directions.
Patient's participation on the study will be over after they have completed both the end-of-treatment and follow-up visits.
End-of-Treatment Visits:
After patient's last dose of study drug, they will be called or they will come in to the clinic within 30 days and they will be asked about any side effects and/or symptoms they may be having. If patient is contacted by phone, the call should last about 2-3 minutes.
If patient ends their participation on this study because the disease has gotten worse, blood (about 1 tablespoon) will be drawn for molecular testing every 4 weeks for the first 6 months after they stop study treatment, then every 6 months for the next year, then every 6 weeks after that.
This is an investigational study. TKIs are approved for the treatment of CML and are given as part of their standard of care, even if they do not participate in this study. Ruxolitinib is FDA approved and commercially available for the treatment of patients with myelofibrosis. The combination of these drugs to treat CML is investigational.
Up to 48 patients will take part in this study. All will be enrolled at MD Anderson.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients 18 years or older with Philadelphia chromosome (Ph)-positive or BCR/ABL-positive CML (as determined by cytogenetics, FISH, or PCR).
- Patients must be on continuous TKI therapy for management of their CML. Any commercially available and FDA- approved TKI can be used, i.e., imatinib mesylate (IM), nilotinib (NIL) or dasatinib (DAS). Patients may be receiving TKI at entry in the frontline or salvage setting, including patients currently on imatinib after alpha-interferon failure or on dasatinib or nilotinib after failure to prior therapy including imatinib.
- Patients must have received the current TKI for at least 18 months and not have increased their dose in the last 6 months.
- Patients must be in complete cytogenetic remission (CCyR). For the phase I portion of the study, patients may be included without a CCyR provided they remain in chronic phase CML.
- Patients must have detectable BCR-ABL transcript levels meeting at least 1 of the following criteria: Patient has never achieved a major molecular response (MMR, as defined by a BCR-ABL/ABL </=0.1% in the international scale (currently equivalent to 0.28 in the MDACC molecular diagnostic laboratory), & transcript levels have shown in at least 2 consecutive measures separated by at least 1 month to have increased by any value; or achieved a major molecular response which has been lost, with an interim increase in transcript levels by at least one-log, confirmed in two consecutive analyses separated by at least 1 month; or patient has received therapy for at least 2 years & lacks a sustained major molecular response; or patient has received therapy for at least 5 years & lacks a sustained complete molecular response (CMR, defined as transcript levels still detectable in the MDACC molecular diagnostic laboratory).
- ***continued from above: Patients included in the phase I portion of the study are eligible regardless of their level of BCR-ABL transcripts.
- Patients must not have had a known interruption of TKI therapy of greater than 21 consecutive days or for a total of 6 weeks in the 6 months prior to enrollment.
- Patients must be able to understand and sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the institutional policies.
- Eastern Cooperative Oncology Group (ECOG) performance status </=2.
- Adequate organ function defined as: bilirubin <2x upper limit of normal (ULN) (unless associated with Gilbert's syndrome), and ALT or AST <2.5x ULN.
- Absolute neutrophil count (ANC) >/=1 x10(9)/L and platelets >/=100 x10(9)/L.
- Serum creatinine < 1.8 mg/dL or creatinine clearance greater or equal than 40 cc/min as defined by the Cockcroft-Gault Equation: Males(mL/min):(140-age)*IBW(kg) / 72*(serum creatinine (mg/dl)); Females (mL/min):0.85*(140-age)*IBW(kg) / 72*(serum creatinine (mg/dl)).
- Women of childbearing potential should be advised to avoid becoming pregnant while on therapy with Ruxolitinib and for 30 days after the last dose and practice effective methods of contraception. Men should be advised not to father a child while receiving treatment with Ruxolitinib and for 30 days after the last dose. Effective methods of contraception for this study include barrier methods (e.g., condoms, diaphragm); spermicidal jelly or foam; oral, depo provera, or injectable hormonal contraceptives; intrauterine devices; tubal ligation; and abstinence.
Exclusion Criteria:
- For the phase I portion of the study, patients in blast phase. For the phase II portion of the study, patients in accelerated or blast phase.
- Patients receiving any other investigational agents.
- Patients who are pregnant or breast-feeding.
- Patients with clinically significant heart disease (NYHA Class III or IV).
- Known or suspected hypersensitivity to ruxolitinib.
- Patients with advanced malignant hepatic tumors.
- Patients with known active hepatitis B or C, or HIV infection.
- Patients with other medical conditions or concomitant medications that in the opinion of the principal investigator may interfere with the therapeutic treatment.
Contacts and Locations| Contact: Jorge Cortes, MD | 713-794-5783 |
| United States, Texas | |
| UT MD Anderson Cancer Center | Not yet recruiting |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Jorge Cortes, MD | UT MD Anderson Cancer Center |
More Information
Additional Information:
No publications provided
| Responsible Party: | M.D. Anderson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT01751425 History of Changes |
| Other Study ID Numbers: | 2012-0697 |
| Study First Received: | December 14, 2012 |
| Last Updated: | December 17, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by M.D. Anderson Cancer Center:
|
Leukemia Chronic Myeloid Leukemia CML Minimal Residual Disease Philadelphia chromosome (Ph)-positive BCR/ABL-positive |
Ruxolitinib Jakafi INCB018424 INC424 TKI Tyrosine kinase inhibitor |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Neoplasm, Residual Neoplasms by Histologic Type Neoplasms |
Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Neoplastic Processes Pathologic Processes |
ClinicalTrials.gov processed this record on June 18, 2013