Combination Study of Cytarabine and Tosedostat in Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndromes (MDS)

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase II, Phase ITreatment60 and over2011-0188
NCI-2012-01350, NCT01636609

Trial Description

Summary

The goal of the Phase 1 part of this clinical research study is to learn the highest

tolerable dose of cytarabine that can be given with tosedostat and the highest tolerable

dose of 5-azacitidine that can be given with tosedostat to patients with AML or MDS.

The goal of the Phase 2 part of the study is to learn if cytarabine with tosedostat and/or

5-azacitidine with tosedostat can help to control the disease. The safety of these

combinations will continue to be studied.

Tosedostat is designed to block the production of proteins that cancer cells need to grow.

Blocking these proteins may cause the cancer cells to die.

Cytarabine is designed to insert itself into DNA (genetic material) of cancer cells and stop

the DNA from repairing itself.

5-azacitidine is designed to block certain proteins in cancer cells whose job is to stop the

function of the tumor-fighting proteins. By blocking these proteins, the tumor-fighting

genes may be able to work better.

Further Study Information

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to receive

cytarabine with tosedostat (Group 1) or 5-azacitidine (Group 2). Your doctor will decide

which drugs you will receive.

You will be assigned to a study phase based on when you join this study. Up to 2 groups of

about 18 participants will be enrolled in the Phase I portion of the study, and up to 60

participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of cytarabine or 5-azacitidine you

receive will depend on when you joined this study. The first group of participants will

receive the lowest dose level of cytarabine or 5-azacitidine. The second group will receive

a higher dose of cytarabine or 5-azacitidine than the group before it, if no intolerable

side effects were seen.

If you are enrolled in the Phase II portion, you will receive cytarabine or 5-azacitidine at

the highest dose that was tolerated in the Phase I portion.

All participants will receive the same dose level of tosedostat.

Study Drug Administration:

In this study you receive induction therapy to try to control the disease and cause

remission (the point when tests and/or your doctor cannot find signs of the disease). If

the disease is in remission, you may receive more cycles (called Consolidation Cycles) to

help keep the disease under control.

Each study cycle is about 4 weeks long, but may be longer depending on your response to the

study drug(s).

Participants in both groups will take tosedostat by mouth 1 time every day. You should

take the pills at about the same time every day (about 24 hours between doses) during a meal

or just after a meal. You may take the drug with water.

You will be given a study drug diary, so you can record when you take each dose. You should

complete this diary every day and bring it with you to all study visits. You should also

bring any unused tosedostat to each study visit including all empty pots.

You should not take more than your assigned number of capsules within a 24-hour period. If

you accidentally take more on 1 day, you should tell your study doctor right away. If you

miss a dose in the morning then you can take the dose up until late afternoon (5pm). After

that time the dose should be omitted and you should continue your drug schedule as usual the

following day. Do not try to "make up" the missed dose after 5pm.

If you are in Group 1, you will also receive cytarabine by a needle under the skin 2 times

each day on Days 1-10.

If you are in Group 2, you will also receive 5-azacitidine by vein over 10-40 minutes or by

a needle under the skin each day on Days 1-7.

After induction, the amount of tosedostat you receive may be increased. Your doctor may

decide to stop the cytarabine or 5-azacitidine and continue with tosedostat alone.

Study Visits:

On Day 1 of Cycle 1:

You will have a physical exam, including measurement of your vital signs. vBlood (about

1 teaspoon) will be drawn for routine tests.

Blood (about 1 teaspoon) will be drawn for pharmacokinetic (PK) testing. PK testing

measures the amount of study drug in your body at different time points.

Your performance status will be recorded.

Your medical history will be recorded.

You will be asked about any drugs you may be taking.

On Days 8, 15, and 22 of Cycle 1 (+/- 2 days):

Your vital signs will be measured.

Blood (about 1 teaspoon) will be drawn for routine tests.

You will have an ECG.

You will be asked about any drugs you may be taking and side effects you may be having.

On Day 8 only, you will have a physical exam.

On Day 15 only, blood (about 1 teaspoon) will be drawn for PK testing.

On Day 28 of Cycle 1 (+/- 5 days) (this visit may be combined with the Day 1 of Cycle 2

visit):

You will have a physical exam, including measurement of your vital signs.

Blood (about 1 teaspoon) will be drawn for routine tests.

Blood (about 1 teaspoon) will be drawn for PK testing.

Your performance status will be recorded.

You will be asked about any drugs you may be taking and side effects you may be having.

You will have an ECG and an ECHO to check your heart function.

You will have a bone marrow biopsy/aspiration to check the status of the disease.

On Day 1 of Cycles 2 and beyond (+/- 5 days):

You will have a physical exam, including measurement of your vital signs.

Blood (about 1 teaspoon) will be drawn for routine tests.

Your performance status will be recorded.

You will be asked about any drugs you may be taking and side effects you may be having.

You will have an ECG and an ECHO to check your heart function.

During Cycles 2 and 3 only, blood (about 1 teaspoon) will be drawn for PK testing.

During odd-numbered cycles (3, 5, 7 and so on), you will have a bone marrow

biopsy/aspiration to check the status of the disease.

If your study doctor feels it is needed, you may have extra clinic visits, tests, or

procedures.

Participants Receiving Home Care:

If you will receive the first cycle at home, you will be called on Day 14 (+/- 5 days) of

Cycle 1 and asked about any side effects you may be having. This call will take about 15

minutes.

If you are receiving home care, you will return to MD Anderson before the start of each

cycle During Cycles 1-3, then every 3 cycles (+/- 1 cycle) until 1 year after the start of

therapy, and then every 6 months (+/- 1 month) after that.

Length of Study:

You may take the study drug for up to 1 year. You will be taken off study early if the

disease gets worse, if you have intolerable side effects, if you are not able to follow the

study directions, or if the study doctor thinks it is in your best interest.

Your participation on the study will be over once you have completed the follow-up.

Follow-Up:

About 28 days after your last dose of tosedostat:

You will have a physical exam, including measurement of your vital signs.

Your performance status will be recorded.

Blood (about 1 teaspoon) will be drawn for routine tests.

You will have an ECG and an ECHO to check your heart function.

You will be asked about any side effect that you may have had and any drugs you may be

taking.

Once you have completed the follow-up visit, the study staff may contact you by telephone

every 3-6 months to check the status of your health. Keeping in touch with you and checking

on your condition will help researchers look at the long-term effects of the study drug.

This is an investigational study. Tosedostat is not FDA approved or commercially available.

At this time, tosedostat is only being used in research. Cytarabine is FDA approved and

commercially available for certain types of MDS and AML. 5-azacitidine is FDA approved and

commercially available for certain types of MDS and AML.

Up to 96 patients will take part in this study. All patients will be enrolled at MD

Anderson.

Eligibility Criteria

Inclusion Criteria:

Inclusion Criteria:

1. Signed, informed consent must be obtained prior to any study specific procedures.

2. For the phase I portion of the study patients should have failed any number of prior

therapies, which should include at least the following: 1. Patients with MDS should

have failed prior therapy with a hypomethylating agent and/or with lenalidomide. 2.

Patients with AML should have failed any prior induction therapy or have relapsed

after prior therapy. 3. Patients with MDS who received therapy with a hypomethylating

agent and progress to AML are eligible at the time of diagnosis of AML regardless of

any prior therapy for AML. 4. Patients with any of the eligible diagnoses who have

received no prior therapy are eligible if not candidates to receive standard therapy

or if they refuse standard chemotherapy.

3. For the phase II Portion of the study, only patients who are previously untreated for

AML. 1. Patients with history of MDS who received therapy for MDS and progressed to

AML are eligible at the time of diagnosis of AML. Only induction chemotherapy

administered for AML will be considered for considerations of eligibility regarding

prior therapy. Patients who received therapy for MDS before transforming to AML

(e.g., with hypomethylating agents or lenalidomide) are eligible.

4. ECOG performance status of 0-1.

5. Women of child-bearing potential (i.e., women who are pre-menopausal or not

surgically sterile) must use acceptable contraceptive methods (abstinence,

intrauterine device [IUD], oral contraceptive or double barrier device) while on

study and must continue to do so for 3 months after stopping study drug, and must

have a negative urine or serum pregnancy test within 2 weeks prior to beginning

treatment on this trial. Sexually active men must also use acceptable contraceptive

methods for the duration of time on study. Pregnant and nursing patients are excluded

because the effects of tosedostat on a fetus or nursing child are unknown.

6. Patients must have been off chemotherapy for 2 weeks prior to entering this study,

unless there is evidence of rapidly progressive disease, and must have recovered from

the toxic effects of that therapy to at least grade 1. Use of hydroxyurea for

patients with rapidly proliferative disease is allowed before the start of study

therapy and for the first four weeks on therapy.

7. Patients must have the following clinical laboratory values unless considered due to

leukemic organ involvement: 1. Serum creatinine </= 2.0 mg/dl. 2. Total bilirubin </=

1.5x the upper limit of normal unless considered due to Gilbert's syndrome. 3.

Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) </= 3x the upper

limit of normal.

8. Age >/= 60 years

9. Left ventricular ejection fraction (LVEF) >/= 50% within 28 days prior to first dose

of study drug administration

10. Patient is able to comply with all study procedures including study drug

administration, visits and tests

11. For patients with history of anthracycline exposure or coronary artery disease

co-management by cardiology to optimize cardioprotective medications will be required

prior to Tosedostat initiation.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to uncontrolled

infection, symptomatic congestive heart failure (New York Heart Association Class III

or IV), or psychiatric illness/social situations that would limit compliance with

study requirements.

2. Active heart disease including myocardial infarction within previous 6 months,

symptomatic coronary artery disease, clinically significant arrhythmias not

controlled by medication, atrial fibrillation (whether active or known past history),

uncontrolled angina, or uncontrolled congestive heart failure (New York Heart

Association Class III or IV).

3. Recent exposure to cardiotoxic agents (including anthracyclines) within 3 months of

enrollment. Subjects with troponin-I and BNP levels above ULN are excluded.

4. Patients with APL (FAB type M3) or CML in blast crisis.

5. Significant gastrointestinal disorders that may interfere with absorption of

tosedostat.

6. Patients who have received a stem cell transplant in the past.

7. Patients who can receive an allogeneic stem cell transplant within

Exclusion Criteria:

Inclusion Criteria:

1. Signed, informed consent must be obtained prior to any study specific procedures.

2. For the phase I portion of the study patients should have failed any number of prior

therapies, which should include at least the following: 1. Patients with MDS should

have failed prior therapy with a hypomethylating agent and/or with lenalidomide. 2.

Patients with AML should have failed any prior induction therapy or have relapsed

after prior therapy. 3. Patients with MDS who received therapy with a hypomethylating

agent and progress to AML are eligible at the time of diagnosis of AML regardless of

any prior therapy for AML. 4. Patients with any of the eligible diagnoses who have

received no prior therapy are eligible if not candidates to receive standard therapy

or if they refuse standard chemotherapy.

3. For the phase II Portion of the study, only patients who are previously untreated for

AML. 1. Patients with history of MDS who received therapy for MDS and progressed to

AML are eligible at the time of diagnosis of AML. Only induction chemotherapy

administered for AML will be considered for considerations of eligibility regarding

prior therapy. Patients who received therapy for MDS before transforming to AML

(e.g., with hypomethylating agents or lenalidomide) are eligible.

4. ECOG performance status of 0-1.

5. Women of child-bearing potential (i.e., women who are pre-menopausal or not

surgically sterile) must use acceptable contraceptive methods (abstinence,

intrauterine device [IUD], oral contraceptive or double barrier device) while on

study and must continue to do so for 3 months after stopping study drug, and must

have a negative urine or serum pregnancy test within 2 weeks prior to beginning

treatment on this trial. Sexually active men must also use acceptable contraceptive

methods for the duration of time on study. Pregnant and nursing patients are excluded

because the effects of tosedostat on a fetus or nursing child are unknown.

6. Patients must have been off chemotherapy for 2 weeks prior to entering this study,

unless there is evidence of rapidly progressive disease, and must have recovered from

the toxic effects of that therapy to at least grade 1. Use of hydroxyurea for

patients with rapidly proliferative disease is allowed before the start of study

therapy and for the first four weeks on therapy.

7. Patients must have the following clinical laboratory values unless considered due to

leukemic organ involvement: 1. Serum creatinine </= 2.0 mg/dl. 2. Total bilirubin </=

1.5x the upper limit of normal unless considered due to Gilbert's syndrome. 3.

Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) </= 3x the upper

limit of normal.

8. Age >/= 60 years

9. Left ventricular ejection fraction (LVEF) >/= 50% within 28 days prior to first dose

of study drug administration

10. Patient is able to comply with all study procedures including study drug

administration, visits and tests

11. For patients with history of anthracycline exposure or coronary artery disease

co-management by cardiology to optimize cardioprotective medications will be required

prior to Tosedostat initiation.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to uncontrolled

infection, symptomatic congestive heart failure (New York Heart Association Class III

or IV), or psychiatric illness/social situations that would limit compliance with

study requirements.

2. Active heart disease including myocardial infarction within previous 6 months,

symptomatic coronary artery disease, clinically significant arrhythmias not

controlled by medication, atrial fibrillation (whether active or known past history),

uncontrolled angina, or uncontrolled congestive heart failure (New York Heart

Association Class III or IV).

3. Recent exposure to cardiotoxic agents (including anthracyclines) within 3 months of

enrollment. Subjects with troponin-I and BNP levels above ULN are excluded.

4. Patients with APL (FAB type M3) or CML in blast crisis.

5. Significant gastrointestinal disorders that may interfere with absorption of

tosedostat.

6. Patients who have received a stem cell transplant in the past.

7. Patients who can receive an allogeneic stem cell transplant within

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

M D Anderson Cancer Center

  • CTI BioPharma

Trial Sites

U.S.A.

Texas
Houston

M D Anderson Cancer Center

Jorge Eduardo Cortes
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01636609

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.