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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01056523
• Other study ID #: Ribavirin-002
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 2010
• Est. completion date: January 2015

Study information

• Verified date: September 2023
• Source: Jewish General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Ribavirin
Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
• Cytarabine arabinoside
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.

Locations

Country	Name	City	State
Canada	Jewish General Hospital	Montreal	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Jewish General Hospital	The Leukemia and Lymphoma Society

Country where clinical trial is conducted

Canada, 

References & Publications (2)

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. — View 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	56 days
Secondary	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).	2-3 years
Secondary	Complete Response Rate	Defined as <5% blasts in the bone marrow and a hgb 100 g/L, platelets 100,000/uL, neutrophils 1000/uL.	2-3 years
Secondary	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.	2-3 years
Secondary	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.	2-3 years