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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
CTI BioPharma
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01636609
First received: July 6, 2012
Last updated: November 14, 2014
Last verified: November 2014
  Purpose

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.


Condition Intervention Phase
Leukemia
Drug: Cytarabine
Drug: 5-Azacytidine
Drug: Tosedostat
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Maximum tolerated daily oral dose defined as <33% of patients experiencing a dose limiting toxicity (DLT) during Cycle 1.


Secondary Outcome Measures:
  • Anti-Tumor Effects [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 96
Study Start Date: November 2012
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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: 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: 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.

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.


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 0-2.
  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 </= 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

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01636609

Locations
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
CTI BioPharma
Investigators
Principal Investigator: Jorge Cortes, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01636609     History of Changes
Other Study ID Numbers: 2011-0188, NCI-2012-01350
Study First Received: July 6, 2012
Last Updated: November 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
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

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Azacitidine
Cytarabine
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014