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Treatment of Elderly Patients With Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic (MD) Syndrome With Laromustine and Infusional Cytarabine

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ClinicalTrials.gov Identifier: NCT00655395
Recruitment Status : Unknown
Verified March 2010 by Weill Medical College of Cornell University.
Recruitment status was:  Active, not recruiting
First Posted : April 9, 2008
Last Update Posted : March 9, 2010
Sponsor:
Collaborator:
Information provided by:

Study Description
Brief Summary:
  • The purpose of the Phase I portion of this study is to evaluate the safety of this combination of medications and to determine the appropriate dose of VNP40101M to be used in combination with infusional cytarabine (araC) in elderly patients with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS).
  • The purpose of the Phase II portion of the study is to evaluate the effectiveness (overall response rate) for patients treated with VNP40101M and infusional cytarabine induction therapy.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS) Drug: Laromustine (VNP40101M) and Ara-C Phase 1 Phase 2

Detailed Description:

There is no known standard chemotherapy that is considered effective for older patients with AML or high risk MDS at this time, and with current treatment, tumor reduction can be difficult to achieve and is short-lived. We are, therefore, interested in developing new drugs that might have a longer-lasting effect against disease.

Laromustine is a new drug that has been shown to have anti-cancer activity in animal and human studies. It interacts with the DNA of a cancer cell and kills the cell. Cytarabine (AraC) is a commercially available chemotherapy drug that is active against leukemia and used routinely when the disease is first diagnosed. In previous studies, when higher doses of laromustine were given, laromustine and AraC achieved more responses than patients treated with AraC alone. However, this advantage was offset by the fact that more patients given laromustine/AraC died to due side effects. We wish to determine the effectiveness of laromustine in combination with infusional AraC in AML and high risk MDS patients who are 60 or more years of age.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/Phase II Evaluation of Laromustine (VNP40101M), A Sulfonylhydrazine Alkylating Agent, Combined With Infusional Cytarabine in Elderly Patients With Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome
Study Start Date : March 2008
Estimated Primary Completion Date : April 2010
Estimated Study Completion Date : October 2010


Arms and Interventions

Arm Intervention/treatment
Experimental: 1
  1. Laromustine 300 mg/m2 (cohort 1) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Drug: Laromustine (VNP40101M) and Ara-C
  1. Laromustine 300 mg/m2 (cohort 1), 400 mg/m2 (cohort 2), 500 mg/m2 (cohort 3) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Experimental: 2
  1. Laromustine 400 mg/m2 (cohort 2) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Drug: Laromustine (VNP40101M) and Ara-C
  1. Laromustine 300 mg/m2 (cohort 1), 400 mg/m2 (cohort 2), 500 mg/m2 (cohort 3) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Experimental: 3
  1. Laromustine 500 mg/m2 (cohort 3) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Drug: Laromustine (VNP40101M) and Ara-C
  1. Laromustine 300 mg/m2 (cohort 1), 400 mg/m2 (cohort 2), 500 mg/m2 (cohort 3) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Experimental: 5
  1. Laromustine will be administered at the recommended phase II dose on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Drug: Laromustine (VNP40101M) and Ara-C
  1. Laromustine 300 mg/m2 (cohort 1), 400 mg/m2 (cohort 2), 500 mg/m2 (cohort 3) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Experimental: 4
  1. Laromustine 600 mg/m2 (cohort 4) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.
Drug: Laromustine (VNP40101M) and Ara-C
  1. Laromustine 300 mg/m2 (cohort 1), 400 mg/m2 (cohort 2), 500 mg/m2 (cohort 3) IV on day 1 over 30 - 60 minutes. Laromustine will be administered approximately 3-4 hours following the start of infusional Ara C.
  2. Ara C at 100 mg/m2/day as a continuous infusion daily for 7 days. Appropriate antiemetics are given during the Ara C infusion.


Outcome Measures

Primary Outcome Measures :
  1. The objectives of this study are to evaluate the safety and efficacy of VNP40101M in combination with infusional Ara C as induction therapy in elderly patients with AML or high-risk MDS evolving to AML. [ Time Frame: Subjects will be closely monitored continuously throughout the study. ]

Secondary Outcome Measures :
  1. The secondary objective of this study is to evaluate this regimen for toxicities in this elderly population. [ Time Frame: Subjects will be closely monitored continuously throughout the study. ]

Eligibility Criteria

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Ages Eligible for Study:   60 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of AML based on WHO criteria (greater than 20% blasts in the bone marrow or blood) excluding AML M3, acute promyelocytic leukemia OR diagnosis of high-risk MDS defined as International Prognostic Scoring System INT-2.
  • ECOG performance status equal to 0, 1, 2.
  • No prior treatment for AML with myeloablative treatment. Patients may have prior treatment with a biologic therapy. Patients with MDS or AML that has evolved from MDS could have received prior low-dose cytotoxic therapy with agents such as azacytidine or low-dose Ara C.
  • Ability to sign an Informed Consent according to institutional guidelines.
  • Patients must have the following clinical laboratory values within 24 hours prior to beginning protocol treatment: a) serum creatinine less than or equal to 2.0mg/dl. b) total bilirubin less than or equal to 2.0 mg/dl c) ALT or AST less than or equal to 5 times the upper limit of normal.

Exclusion Criteria:

  • Uncontrolled active infection. Patients with infections who are under active treatment with antibiotics and whose infections are controlled may be entered into the study. Patients with chronic hepatitis are eligible.
  • Active heart disease including myocardial infarction, symptomatic coronary artery disease, arrhythmias not controlled by medication or uncontrolled congestive heart failure.
  • Severe pulmonary disease not controlled with medication.
  • Patients with serum creatinine > 2.0, serum bilirubin > 2.0. ALT or AST greater that 5 times the upper limit of normal. Patients with bilirubin or creatinine outside the acceptable levels will be considered eligible if this abnormality is clearly leukemia related and discussed with the principal's investigator prior to enrollment.
  • Patients concurrently receiving any other standard or investigational treatment for leukemia with the exception of hydroxyurea.
  • Since the formulation contains 30% ethanol, patients being treated with Antabuse (disulfiram) are excluded from the study.
  • Patients with APL t(15;17)
  • Patients with ECOG performance status of 3 or 4.
  • Patients should be off metronidazole (Flagyl) at least 24 hours before starting laromustine.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00655395


Locations
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10021
Sponsors and Collaborators
Weill Medical College of Cornell University
Vion Pharmaceuticals
More Information

Responsible Party: Ellen Ritchie, M.D. / Assistant Professor or Medicine, Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT00655395     History of Changes
Other Study ID Numbers: 0702009008
VNP40101M
First Posted: April 9, 2008    Key Record Dates
Last Update Posted: March 9, 2010
Last Verified: March 2010

Keywords provided by Weill Medical College of Cornell University:
Leukemia
MDS

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Antiemetics
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents