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

Information source: Jewish General Hospital
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Acute Myeloid Leukemia

Intervention: Ribavirin (Drug); Cytarabine arabinoside (Drug)

Phase: Phase 1/Phase 2

Status: Completed

Sponsored by: Jewish General Hospital

Official(s) and/or principal investigator(s):
Sarit Assouline, MD, Principal Investigator, Affiliation: Jewish General Hospital, McGill University
Katherine Borden, PhD, Study Director, Affiliation: Université de Montréal

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.

Clinical Details

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

Primary outcome:

Recommended phase II dose of ribavirin when given in combination with low-dose ara-C

Maximum tolerated dose

Overall response rate (complete remission (CR), complete remission with incomplete blood count recovery (CRi), partial remission (PR) or blast response (BR))

Secondary outcome:

Time to response

Duration of response

Time to relapse

One year and overall survival

Hematological Improvement

Safety and tolerability of ribavirin and low dose ara-C

Correlation between expression and activity of eIF4E and response

Effect of ribavirin and low dose ara-C on the activity of eIF4E related pathways.

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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
Additional Information

Related publications:

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.

Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden KL. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18105-10. Epub 2004 Dec 15.

Starting date: January 2010
Last updated: April 1, 2015

Page last updated: August 23, 2015

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