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Use of Ribavirin and Low Dose Ara-C to Treat Acute Myeloid Leukemia

Primary Purpose

Acute Myeloid Leukemia

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Ribavirin
Cytarabine arabinoside
Sponsored by
Jewish General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring AML

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • The following patients with acute myeloid leukemia (AML) are eligible:

    • De novo AML M4 or M5 FAB subtype or high eIF4E.
    • Secondary AML after a myelodysplastic syndrome (MDS) or a myeloproliferative disorder (not chronic myelogenous leukemia), if M4 or M5 FAB subtype or high eIF4E.
    • Therapy-related AML if M4 or M5 FAB subtype or high eIF4E.
    • CML blast crisis if they have failed imatinib and at least one other tyrosine kinase inhibitor.
  • All patients must have failed primary therapy (defined as two induction chemotherapies), have relapsed, or are not suitable candidates for intensive induction chemotherapy.
  • Patients who have a dry aspirate or extramedullary disease only are eligible for this study if they have a pre-treatment marrow or tissue biopsy demonstrating AML M4 or M5 subtype or high eIF4E expression.
  • ECOG performance status 0, 1, 2 or 3.
  • Life expectancy > 4 weeks.
  • Age is > 18 years.
  • Female patients of childbearing potential must have a negative serum (beta-HCG) pregnancy test within 14 days of starting protocol and must not be breastfeeding. Men and women of childbearing potential must agree to use an effective means of contraception throughout the study and for at least 30 days after completion of protocol.
  • Adequate renal and hepatic function: serum creatinine < 1.5 x ULN; AST or ALT < 2.5 x ULN (or < 5 x ULN if liver involvement with leukemia); serum bilirubin < 1.5 x ULN.
  • Provide written consent after the investigational nature, study design, risks and benefits of the study have been explained.
  • Accessible for treatment and follow up.

Exclusion Criteria:

  • Uncontrolled central nervous system involvement by AML.
  • Active cardiovascular disease as defined by New York Heart Association (NYHA) class III-IV categorization.
  • Intercurrent illness or medical condition precluding safe administration of the planned protocol treatment or required follow-up.
  • Received any previous therapy for AML within 28 days prior to the study entry. Hydrea is permitted for the treatment of leukocytosis but must be stopped within 7 days of starting low dose ara-C and ribavirin.
  • Female patients who are pregnant or breastfeeding.
  • Concurrent treatment with other anti-cancer therapy.
  • Known infection with HIV.
  • History of other malignancy. Subjects who have been disease-free for 2 year or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
  • FAB AML M1, 2, 6, 7 will be excluded if they do not have high eIF4E expression. AML M3 is always excluded.

Sites / Locations

  • Jewish General Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ribavirin-Cytarabine arabinoside

Arm Description

Ribavirin will be given orally bid according to a dose escalation scheme daily for 28 days of a 28 day cycle Cytarabine arabinoside will be given 20 mg sc bid days 1 to 10 of a 28 day cycle

Outcomes

Primary Outcome Measures

Recommended Phase II Dose (RP2D) of Ribavirin When Given in Combination With Low-dose Ara-C
This 3+3 designed aimed to determine recommended phase II dose (RP2D) based on pharmacokinetics (PK) and maximum tolerated dose (MTD). For the dose to be selected, a target steady state level of ribavirin 20 uM was needed for all patients and no more than 1 of 6 patients could have had dose limiting toxicity at that dose.

Secondary Outcome Measures

Overall Response Rate
Overall response rate comprises complete response (<5% blasts in the bone marrow, and in the peripheral blood Hgb more than or equal to 100 g/L, platelets more than or equal to 100x10-9/L, and neutrophils more than or equal to 1x10-9/L), partial response (5 to 25% blasts in the bone marrow and same peripheral blood parameters) and blast response (a greater than 50% decrease in bone marrow blast count and 2 log reduction in peripheral blood blast count, sustained for at least 28 days).
Complete Response Rate
Defined as <5% blasts in the bone marrow and a hgb 100 g/L, platelets 100,000/uL, neutrophils 1000/uL.
Partial Response
Partial response was defined as 5 to 25% blasts in the bone marrow and Hgb >100g/L, platelets >100,000/ul and neutrophils >1000/ul.
Blast Response
Blast response was defined as a greater than 50% decrease in bone marrow blast count and 2 log reduction in peripheral blood blast count, sustained for at least 28 days.

Full Information

First Posted
January 25, 2010
Last Updated
September 28, 2023
Sponsor
Jewish General Hospital
Collaborators
The Leukemia and Lymphoma Society
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1. Study Identification

Unique Protocol Identification Number
NCT01056523
Brief Title
Use of Ribavirin and Low Dose Ara-C to Treat Acute Myeloid Leukemia
Official Title
A Phase I/II Study of Ribavirin and Low-dose Cytarabine Arabinoside (Ara-C) in Acute Myeloid Leukemia (AML) M4 and M5 Subtypes, and AML With High eIF4E Expression
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
January 2010 (undefined)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Jewish General Hospital
Collaborators
The Leukemia and Lymphoma Society

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of the study is to determine the maximum tolerated dose of ribavirin, when given in combination with low-dose ara-C and to determine if it is safe and well-tolerated in patients with acute myeloid leukemia.
Detailed Description
Primary Objectives In the Phase I portion of this study, we will determine the maximum tolerated dose and recommended phase II dose (RP2D) of ribavirin and low-dose ara-C. The primary objective of the Phase II portion of the study is to determine the overall response rate, including the complete remission (CR), complete remission with incomplete blood count recovery (CRi), partial remission (PR) or blast response (BR), to therapy with ribavirin and low dose ara-C at the RP2D. STUDY DESIGN AND DURATION This is a multicentre, open-label, single arm Phase I/II study of oral ribavirin and low-dose ara-C for patients with AML M4/M5 or AML with high expression of eIF4E, who have relapsed or refractory disease, or who are not suitable candidates for induction chemotherapy. This study will determine the recommended phase II dose and will evaluate efficacy. Correlative studies will be included to assess relevant molecular targets.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
AML

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ribavirin-Cytarabine arabinoside
Arm Type
Experimental
Arm Description
Ribavirin will be given orally bid according to a dose escalation scheme daily for 28 days of a 28 day cycle Cytarabine arabinoside will be given 20 mg sc bid days 1 to 10 of a 28 day cycle
Intervention Type
Drug
Intervention Name(s)
Ribavirin
Intervention Description
Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Intervention Type
Drug
Intervention Name(s)
Cytarabine arabinoside
Other Intervention Name(s)
Ara-C
Intervention Description
Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle. Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
Primary Outcome Measure Information:
Title
Recommended Phase II Dose (RP2D) of Ribavirin When Given in Combination With Low-dose Ara-C
Description
This 3+3 designed aimed to determine recommended phase II dose (RP2D) based on pharmacokinetics (PK) and maximum tolerated dose (MTD). For the dose to be selected, a target steady state level of ribavirin 20 uM was needed for all patients and no more than 1 of 6 patients could have had dose limiting toxicity at that dose.
Time Frame
56 days
Secondary Outcome Measure Information:
Title
Overall Response Rate
Description
Overall response rate comprises complete response (<5% blasts in the bone marrow, and in the peripheral blood Hgb more than or equal to 100 g/L, platelets more than or equal to 100x10-9/L, and neutrophils more than or equal to 1x10-9/L), partial response (5 to 25% blasts in the bone marrow and same peripheral blood parameters) and blast response (a greater than 50% decrease in bone marrow blast count and 2 log reduction in peripheral blood blast count, sustained for at least 28 days).
Time Frame
2-3 years
Title
Complete Response Rate
Description
Defined as <5% blasts in the bone marrow and a hgb 100 g/L, platelets 100,000/uL, neutrophils 1000/uL.
Time Frame
2-3 years
Title
Partial Response
Description
Partial response was defined as 5 to 25% blasts in the bone marrow and Hgb >100g/L, platelets >100,000/ul and neutrophils >1000/ul.
Time Frame
2-3 years
Title
Blast Response
Description
Blast response was defined as a greater than 50% decrease in bone marrow blast count and 2 log reduction in peripheral blood blast count, sustained for at least 28 days.
Time Frame
2-3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The following patients with acute myeloid leukemia (AML) are eligible: De novo AML M4 or M5 FAB subtype or high eIF4E. Secondary AML after a myelodysplastic syndrome (MDS) or a myeloproliferative disorder (not chronic myelogenous leukemia), if M4 or M5 FAB subtype or high eIF4E. Therapy-related AML if M4 or M5 FAB subtype or high eIF4E. CML blast crisis if they have failed imatinib and at least one other tyrosine kinase inhibitor. All patients must have failed primary therapy (defined as two induction chemotherapies), have relapsed, or are not suitable candidates for intensive induction chemotherapy. Patients who have a dry aspirate or extramedullary disease only are eligible for this study if they have a pre-treatment marrow or tissue biopsy demonstrating AML M4 or M5 subtype or high eIF4E expression. ECOG performance status 0, 1, 2 or 3. Life expectancy > 4 weeks. Age is > 18 years. Female patients of childbearing potential must have a negative serum (beta-HCG) pregnancy test within 14 days of starting protocol and must not be breastfeeding. Men and women of childbearing potential must agree to use an effective means of contraception throughout the study and for at least 30 days after completion of protocol. Adequate renal and hepatic function: serum creatinine < 1.5 x ULN; AST or ALT < 2.5 x ULN (or < 5 x ULN if liver involvement with leukemia); serum bilirubin < 1.5 x ULN. Provide written consent after the investigational nature, study design, risks and benefits of the study have been explained. Accessible for treatment and follow up. Exclusion Criteria: Uncontrolled central nervous system involvement by AML. Active cardiovascular disease as defined by New York Heart Association (NYHA) class III-IV categorization. Intercurrent illness or medical condition precluding safe administration of the planned protocol treatment or required follow-up. Received any previous therapy for AML within 28 days prior to the study entry. Hydrea is permitted for the treatment of leukocytosis but must be stopped within 7 days of starting low dose ara-C and ribavirin. Female patients who are pregnant or breastfeeding. Concurrent treatment with other anti-cancer therapy. Known infection with HIV. History of other malignancy. Subjects who have been disease-free for 2 year or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. FAB AML M1, 2, 6, 7 will be excluded if they do not have high eIF4E expression. AML M3 is always excluded.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sarit Assouline, MD
Organizational Affiliation
Jewish General Hospital, McGill University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Katherine Borden, PhD
Organizational Affiliation
Université de Montréal
Official's Role
Study Director
Facility Information:
Facility Name
Jewish General Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
19433856
Citation
Assouline S, Culjkovic B, Cocolakis E, Rousseau C, Beslu N, Amri A, Caplan S, Leber B, Roy DC, Miller WH Jr, Borden KL. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood. 2009 Jul 9;114(2):257-60. doi: 10.1182/blood-2009-02-205153. Epub 2009 May 11.
Results Reference
background
PubMed Identifier
25425688
Citation
Assouline S, Culjkovic-Kraljacic B, Bergeron J, Caplan S, Cocolakis E, Lambert C, Lau CJ, Zahreddine HA, Miller WH Jr, Borden KL. A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E. Haematologica. 2015 Jan;100(1):e7-9. doi: 10.3324/haematol.2014.111245. Epub 2014 Nov 25. No abstract available.
Results Reference
result

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Use of Ribavirin and Low Dose Ara-C to Treat Acute Myeloid Leukemia

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