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

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ClinicalTrials.gov Identifier: NCT01636609
Recruitment Status : Active, not recruiting
First Posted : July 10, 2012
Last Update Posted : April 12, 2018
Sponsor:
Collaborator:
CTI BioPharma
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

July 6, 2012
July 10, 2012
April 12, 2018
November 2012
November 2018   (Final data collection date for primary outcome measure)
Maximum Tolerated Dose (MTD) [ Time Frame: 28 days ]
Maximum tolerated daily oral dose defined as <33% of patients experiencing a dose limiting toxicity (DLT) during Cycle 1.
Same as current
Complete list of historical versions of study NCT01636609 on ClinicalTrials.gov Archive Site
Anti-Tumor Effects [ Time Frame: 28 days ]
Response rate estimated by Bayesian posterior estimates, along with the 95% credible intervals for the two treatment arms. Survival or times to failure and time to progression functions estimated using the Kaplan-Meier method. Toxicity reported by type, frequency and severity. Highest toxicity grades per patient per course tabulated for selected adverse events and laboratory measurements.
Same as current
Not Provided
Not Provided
 
Combination Study of Cytarabine and Tosedostat in Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndromes (MDS)
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)

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.

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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Leukemia
  • Drug: Cytarabine

    Phase I Arm A: Starting dose of Cytarabine 7.5 mg subcutaneous (SQ) twice daily (BID) for 10 days every 28 days. Dose escalation will proceed up to the Target dose level (dose level 0) 10 mg SQ BID for 10 days.

    Phase II (Randomized) Starting dose of Cytarabine: Maximum tolerated dose from Phase I.

    Other Names:
    • Ara-C
    • Cytosar
    • DepoCyt
    • Cytosine Arabinosine Hydrochloride
  • Drug: 5-Azacytidine

    Phase I Arm B: Starting dose of 5-azacytidine 50 mg/m2 by vein (IV) or subcutaneously (SQ) daily for 7 days, on days 1-7 every 28 days. Dose escalation will proceed up to the Target dose level (dose level 0) 75 mg/m2 IV (or SQ) daily for 7 days, on days 1-7.

    Phase II (Randomized) Starting dose of 5-azacytidine: Maximum tolerated dose from Phase I.

    Other Names:
    • Azacitidine
    • 5-aza
    • Vidaza
    • 5-AZC
    • AZA-CR
    • Ladakamycin
    • NSC-102816
  • Drug: Tosedostat

    Phase I: 120 mg by mouth daily. After the first 4 weeks of therapy, a dose escalation to 180 mg daily may be considered for patients not achieving a CR provided the patient has not experienced any grade >/= 3 toxicity. Such instances should be discussed with the principal investigator and the sponsor and assessed on a case-by-case basis.

    Phase II: 120 mg by mouth daily. 120 mg by mouth daily during induction (i.e., first 28 days of therapy). After the first 4 weeks of therapy, a dose escalation to 180 mg daily may be considered for patients not achieving a CR provided the patient has not experienced any grade >/= 3 toxicity. Such instances should be discussed with the principal investigator and the sponsor and assessed on a case-by-case basis.

  • Experimental: Cytarabine + Tosedostat

    Phase I Arm A: Starting dose of Cytarabine 7.5 mg subcutaneous (SQ) twice daily (BID) for 10 days every 28 days. Dose escalation will proceed up to the Target dose level (dose level 0) 10 mg SQ BID for 10 days.

    Phase II (Randomized) Starting dose of Cytarabine: Maximum tolerated dose from Phase I.

    Phase I and II Tosedostat: 120 mg by mouth daily. After the first 4 weeks of therapy, a dose escalation to 180 mg daily may be considered for patients not achieving a CR provided the patient has not experienced any grade >/= 3 toxicity. Such instances should be discussed with the principal investigator and the sponsor and assessed on a case-by-case basis.

    Interventions:
    • Drug: Cytarabine
    • Drug: Tosedostat
  • Experimental: 5-Azacytidine + Tosedostat

    Phase I Arm B: Starting dose of 5-azacytidine 50 mg/m2 by vein (IV) or subcutaneously (SQ) daily for 7 days, on days 1-7 every 28 days. Dose escalation will proceed up to the Target dose level (dose level 0) 75 mg/m2 IV (or SQ) daily for 7 days, on days 1-7.

    Phase II (Randomized) Starting dose of 5-azacytidine: Maximum tolerated dose from Phase I.

    Phase I and II Tosedostat: 120 mg by mouth daily. After the first 4 weeks of therapy, a dose escalation to 180 mg daily may be considered for patients not achieving a CR provided the patient has not experienced any grade >/= 3 toxicity. Such instances should be discussed with the principal investigator and the sponsor and assessed on a case-by-case basis.

    Interventions:
    • Drug: 5-Azacytidine
    • Drug: Tosedostat
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
96
Same as current
November 2019
November 2018   (Final data collection date for primary outcome measure)

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 4 weeks.
  8. Use of concomitant drugs that prolong QT/QTc interval are prohibited with the exception of antibiotics, antifungals, and other antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient, but only if clinically indicated and must be fully documented.
Sexes Eligible for Study: All
60 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01636609
2011-0188
NCI-2012-01350 ( Registry Identifier: NCI CTRP )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
M.D. Anderson Cancer Center
M.D. Anderson Cancer Center
CTI BioPharma
Principal Investigator: Jorge Cortes, MD M.D. Anderson Cancer Center
M.D. Anderson Cancer Center
April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP