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Phase I/II Study of Cytarabine or 5-Azacitidine Combined With Tosedostat to Evaluate the Safety and Tolerability in Older Patients With Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndromes (MDS)


Phase 1/Phase 2
60 Years
N/A
Open (Enrolling)
Both
Leukemia

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Trial Information

Phase I/II Study of Cytarabine or 5-Azacitidine Combined With Tosedostat to Evaluate the Safety and Tolerability in Older Patients With Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndromes (MDS)


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.

- Blood (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.

- 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.

- 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.

- 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.


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 0-2.

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 1.5x the upper limit of normal unless considered due to Gilbert's syndrome. 3.
Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) 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

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 3 months,
symptomatic coronary artery disease, clinically significant arrhythmias not
controlled by medication, or uncontrolled congestive heart failure (New York Heart
Association Class III or IV).

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

4. Significant gastrointestinal disorders that may interfere with absorption of
tosedostat.

5. Patients who can receive an allogeneic stem cell transplant within 4 weeks.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

Maximum tolerated daily oral dose defined as <33% of patients experiencing a dose limiting toxicity (DLT) during Cycle 1.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Jorge Cortes, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2011-0188

NCT ID:

NCT01636609

Start Date:

November 2012

Completion Date:

Related Keywords:

  • Leukemia
  • Leukemia
  • Acute Myeloid Leukemia
  • AML
  • Myelodysplastic Syndromes
  • MDS
  • Relapsed
  • Refractory
  • Cytarabine
  • ARA-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine
  • 5-Azacytidine
  • Azacitidine
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816
  • Tosedostat
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030