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Myeloid Leukemia

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Imatinib Mesylate

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Tyrosine

Ph+ CP CML patients who were treated with IM for more than 3 years in sustained MR4.5 or undetectable transcript for at least 2 years are enrolled

Imatinib treatment discontinuing

Sahee Park, MS

Dong-Wook Kim, Professor

This prospective study is performed to identify safer and more concrete indicators of successful discontinuation and explore contributing factors for sustained undetectable transcript

Imatinib (IM) treatment has been the standard of care for chronic phase (CP) chronic myeloid leukemia (CML) and approximately 50% of CP CML patients who received IM treatment achieve complete molecular response (CMR) at 6-7 years.(Hochhaus A et al. Leukemia 2009;23:1054-1061, Hughes et al. Blood 2008;112:334) The recent data from a study aimed to assess whether IM can be discontinued in patients with a CMR lasting at least 2 years showed the probability of persistent CMR at 12 months was 41%, and suggested IM can be safely discontinued, at least in some patients with sustained CMR. (Mahon et al. Lancet Oncol 2010;11:1029-1035) However, to define whether discontinuation of IM treatment can be safely employed, further validation and much longer follow-up are needed.

Aims This prospective study is performed to identify safer and more concrete indicators of successful discontinuation and explore contributing factors for sustained undetectable transcript.

Primary Objective:

* To evaluate the probability of persistent undetectable molecular residual disease (UMRD) and MR4.5 at 12 months after discontinuation
* To measure the duration of persistent UMRD and MR4.5 after discontinuation
* To identify contributing factors for sustained undetectable transcript

Secondary Objective:

* To evaluate the probability of major molecular response (MMR) loss
* To evaluate the time taken to lose MMR at 12 months after discontinuation
* In patients with loss of MMR, the probability of re-achieving MMR/MR4.5
* To measure the time taken to re-achieve MMR/MR4.5 after IM resumption
* To identify contributing factors for sustained re-achieve MMR/MR4.5

Trial Design This is a prospective, multicenter, non-randomised IM discontinuation study.

Response Evaluation After discontinuation, molecular response was monitored using RQ-PCR assay every month up to 6 month follow-up, every 2 months up to 12 month follow-up, and every 3 months thereafter. The loss of MMR, MR4.5, and UMRD were defined on 2 consecutive assessments.

If loss of MMR occurred, IM treatment was re-introduced. Written informed consents were obtained for all patients

Discontinuation Study of Imatinib in Adult CP CML Patients Who Have a Complete Molecular Response to Imatinib

A Multi-center Study of the Discontinuation of Imatinib in Adult Patients With Ph+ CML in CP Who Have a Complete Molecular Response to Imatinib

Our primary objectives were to evaluate the probability of persistent undetectable molecular residual disease (UMRD) and MR4.5 at 12 months after discontinuation, to measure the duration of persistent UMRD and MR4.5 after discontinuation, and to identify contributing factors for sustained undetectable transcript.

Ministry of Health & Welfare, Korea

Seoul St. Mary's Hospital

Professor

Ponatinib

Ponatinib at a dose of 45 mg orally, once daily. If a dose is missed or vomited, the next dose should not be increased to account for missing a dose. Total duration of therapy 3 to 5 years.

Ponatinib at a dose of 30 mg orally, once daily. If a dose is missed or vomited, the next dose should not be increased to account for missing a dose. Total duration of therapy 3 to 5 years.

Starting dose: 45 mg by mouth once daily.

Jorge Cortes, MD

The goal of this clinical research study is to learn if ponatinib can help to control Chronic Myeloid Leukemia (CML) in accelerated phase. The safety of this drug will also be studied.

Ponatinib is designed to block the function of BCR-ABL, which is the abnormal protein responsible for causing leukemia in certain cells.

Ponatinib may cause a blood clot to form in an artery or in a vein. Depending on the location of the clot, this could cause a heart attack, a stroke, severe damage to other tissue, or death. A blood clot may occur within 2 weeks after you start taking the drug. About 25% (1 in 4) of patients taking the drug form an abnormal clot. Blood clots can occur in patients that do not have other known risk factors for forming clots. If you develop a blood clot, you will need to stop taking ponatinib. In some cases, emergency surgery could be needed to remove the clot and restore blood flow.

Study Drug Administration:

You will take ponatinib by mouth 1 time every day while you are on study with about a cup (8 ounces) of water. You should not eat within 2 hours before or after taking the drug. You will complete a study diary in which you will record the date and time that you take the study drug each time. If you miss any doses, you will also note this in the study diary. Bring this diary to every study visit, as described below.

Study Visits:

The tests and procedures for this study have a wide range of time in which they can be done. In general, your schedule of study visits will be as follows:

* Weekly in Month 1
* Monthly in Year 1
* Three (3) to 4 times in Year 2
* Two (2) to 3 times in every year after that

The study staff will help you schedule your study visits. The following tests and procedures will be performed:

* Every 1-2 weeks for the first 4 weeks, then every 4-6 weeks for the first year, then every 3-4 months for the next year, then every 4-6 months after that, blood (about 1/2 tablespoon) will be drawn for routine tests.
* Every 3 months for the first year, you will have an ECG.
* Every 3 months for the first year, then every 6-12 months after that, you will have a physical exam.
* Every 3-4 months for the first year, then every 6-12 months after that, blood (about 2 teaspoons) will be drawn to measure levels of leukemia cells in your body.
* Every 3-4 months for the first year, then every 6-12 months for the next 2 years, then every 2-3 years after that, you will have a bone marrow aspirate for genetic testing and to check the status of the disease.

Length of Participation:

You may continue taking the study drug for up to 5 years. You will be taken off study early if intolerable side effects occur, if the disease gets worse, or if you are unable to follow study directions.

Your participation on the study will be over when you have completed the follow-up visit/call.

Follow-Up:

If you leave the study, you will be called or you will come to the clinic within 30 days to learn about any side effects or symptoms you may be having. If you are called, this call will last about 2-3 minutes.

This is an investigational study. Ponatinib is FDA approved to treat patients with certain types of leukemia. Its use in this study is investigational.

Up to 80 patients will take part in this study. All will be enrolled at MD Anderson.

Participants enrolled before July 25, 2013 were given a starting dose of 45 mg per day. The study was amended and the dose was lowered due to tolerability. Participants enrolled after this date were given a starting dose of 30 mg per day.

Ponatinib - Frontline for Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP)

Ponatinib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Accelerated Phase

Proportion of participants with previously-untreated accelerated phase CML attaining complete cytogenetic response (CCyR) at 6 months of treatment with Ponatinib classified according to suppression of the Philadelphia chromosome (Ph) by cytogenetics (FISH if cytogenetic analysis not informative, e.g., insufficient metaphases). CCyR defined as Ph positive 0%.

Proportion of participants with previously-untreated accelerated phase CML receiving treatment of Ponatinib achieving a Complete cytogenetic response (CCyR). Classified according to suppression of the Philadelphia chromosome (Ph) by cytogenetics (FISH if cytogenetic analysis not informative, e.g., insufficient metaphases. CCyR is defined as Ph positive 0%.

Time to toxicity monitoring defined as any grade 3 or 4 drug-related non-hematologic adverse event that has not resolved to grade 2 or less after 6 weeks of optimal therapeutic management, or drug-related toxicity of any grade that in the opinion of the investigator prevents further therapy with ponatinib. Time to toxicity monitored using the Bayesian method of Thall, et al.

Ariad Pharmaceuticals

M.D. Anderson Cancer Center

Ponatinib 45 mg

Ponatinib 30 mg

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Jorge Cortes, MD/Professor, Leukemia

Ponatinib 45 mg orally, once daily. Dose escalation to 30 mg possible for participants with adverse events.

Ponatinib 30mg orally, once daily. Dose escalation to 30 mg possible for participants with adverse events.

Number of Participants With Complete Cytogenetic Response (CCyR)

Elevated Amylase

Lipase Elevation

Pancreatitis

Abdominal Pain

Hypertension

Elevated alanine aminotransferase (ALT)

One participant was not included in analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Discontinuation Study of Imatinib in Adult CP CML Patients Who Have a Complete Molecular Response to Imatinib	NCT01564836	Chronic Myeloid... Imatinib Complete Molecu...	Imatinib treatm...	18 Years -	Seoul St. Mary's Hospital
Ponatinib - Frontline for Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP)	NCT01570868	Leukemia	Ponatinib	18 Years -	M.D. Anderson Cancer Center
Ponatinib - Frontline for Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP)	NCT01570868	Leukemia	Ponatinib	18 Years -	M.D. Anderson Cancer Center
Ponatinib - Frontline for Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP)	NCT01570868	Leukemia	Ponatinib	18 Years -	M.D. Anderson Cancer Center
Discontinuation Study of Imatinib in Adult CP CML Patients Who Have a Complete Molecular Response to Imatinib	NCT01564836	Chronic Myeloid... Imatinib Complete Molecu...	Imatinib treatm...	18 Years -	Seoul St. Mary's Hospital

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