Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation

NCT ID: NCT00375219

Last Updated: 2021-11-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 103 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-09-20
• Study Completion Date: 2013-06-28

Brief Summary

To evaluate the safety and efficacy of subcutaneous administration of omacetaxine mepesuccinate (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed prior imatinib therapy and have the T315I kinase domain gene mutation.

Detailed Description

Point mutations within the ABL kinase domain of the BCR-ABL gene are emerging as the most frequent mechanism for resistance to imatinib and resultant reactivation of kinase activity. The risk of mutation development is particularly high in patients who are beyond chronic phase, as well as those with a long duration of disease prior to imatinib therapy.

The T315I kinase domain (KD) point mutation has merited particular attention, as T315I expressing CML cells are markedly resistant to imatinib. CML patients with the T315I KD mutation, therefore, do not respond to continued treatment with imatinib, and preliminary clinical data indicate that neither of two newer tyrosine kinase inhibitors will have activity in patients with T315I KD mutation either.

Omacetaxine mepesuccinate (HHT) is a potent inducer of apoptosis (programmed cell death) in myeloid cells and inhibits angiogenesis (blood vessel formation). In Phase 2 studies, HHT has demonstrated clinical activity in patients with CML, both as a single agent and in-combination with other chemotherapeutic drugs. HHT works via a different mechanism than imatinib or other tyrosine kinase inhibitors (TKI's), and HHT has been shown to inhibit in vitro CML cell lines which harbor the T315I KD mutation and are highly resistant to imatinib. Therefore, CML patients who have the T315I KD mutation may still respond to treatment with HHT. HHT may therefore be an attractive therapeutic option for patients with the T315I KD mutation.

On this basis, a multicenter clinical trial is being conducted of HHT therapy for CML patients who have failed prior imatinib therapy and have the T315I KD mutation.

Patients will be treated with an induction course consisting of subcutaneous (SC) HHT twice daily for 14 consecutive days every 28 days. Patients who demonstrate a response, may receive maintenance therapy for up to 24 months, consisting of subcutaneous (SC) HHT twice daily for 7 days every 28 days.

Conditions

Chronic Myeloid Leukemia

Keywords

Chronic Myeloid Leukemia; CML; HHT; Homoharringtonine; Omacetaxine; T315i; ChemGenex; ChemGenex Pharmaceuticals

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

omacetaxine

Treatment was the same for all cohorts: induction therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m\^2 twice a day (BID), administered for 14 consecutive days every 28 (±3) days for up to 6 cycles. Maintenance therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m\^2 twice a day (BID), administered for 7 consecutive days every 28 (±3) days for up to 3 years.

Group Type: EXPERIMENTAL

Omacetaxine mepesuccinate

Intervention Type: DRUG

Induction:

1.25 mg/m^2 subcutaneously, twice daily for 14 consecutive days every 28 days until response. Patients not demonstrating evidence of clinical response after 6 induction cycles will be considered for removal from the study.

Maintenance:

1.25 mg/m^2 subcutaneously, twice daily for 7 consecutive days in a 28-day cycle, for up to 3 years.

Interventions

Omacetaxine mepesuccinate

Induction:

1.25 mg/m^2 subcutaneously, twice daily for 14 consecutive days every 28 days until response. Patients not demonstrating evidence of clinical response after 6 induction cycles will be considered for removal from the study.

Maintenance:

1.25 mg/m^2 subcutaneously, twice daily for 7 consecutive days in a 28-day cycle, for up to 3 years.

Intervention Type: DRUG

Other Intervention Names

Homoharringtonine; OMA; Synribo; HHT; CGX-635

Eligibility Criteria

Inclusion Criteria

• Male or female patients, age 18 years or older
• Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase
• The patient will have the T315I BCR-ABL gene mutation
• Patients will have failed prior imatinib therapy
• ECOG performance status 0-2

Exclusion Criteria

• NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure
• Myocardial infarction in the previous 12 weeks
• Lymphoid Ph+ blast crisis

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cephalon

INDUSTRY

Sponsor Role: collaborator

ChemGenex Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Teva Branded Pharmaceutical Products R&D, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jorge Cortes, MD

Role: PRINCIPAL_INVESTIGATOR

Univ. of Texas M.D. Anderson Cancer Center

Andreas Hochhaus, MD Prof Dr

Role: PRINCIPAL_INVESTIGATOR

Mannheim der Universitat Heidelberg

Locations

Teva Investigational Site 003

Los Angeles, California, United States

Teva Investigational Site 007

Jacksonville, Florida, United States

Teva Investigational Site 006

Atlanta, Georgia, United States

Teva Investigational Site 008

Beech Grove, Indiana, United States

Teva Investigational Site 011

Baltimore, Maryland, United States

Teva Investigational Site 004

Boston, Massachusetts, United States

Teva Investigational Site 005

Buffalo, New York, United States

Teva Investigational Site 002

The Bronx, New York, United States

Teva Investigational Site 010

Philadelphia, Pennsylvania, United States

Teva Investigational Site 001

Houston, Texas, United States

Teva Investigational Site 013

Montreal, , Canada

Teva Investigational Site 009

Toronto, , Canada

Teva Investigational Site 029

Bordeaux, , France

Teva Investigational Site 021

Le Chesnay, , France

Teva Investigational Site 022

Lille, , France

Teva Investigational Site 020

Lyon, , France

Teva Investigational Site 024

Nice, , France

Teva Investigational Site 028

Paris, , France

Teva Investigational Site 023

Poitiers, , France

Teva Investigational Site 027

Strasbourg, , France

Teva Investigational Site 025

Toulouse, , France

Teva Investigational Site 026

Vandœuvre-lès-Nancy, , France

Teva Investigational Site 031

Berlin, , Germany

Teva Investigational Site 030

Mannheim, , Germany

Teva Investigational Site 050

Budapest, , Hungary

Teva Investigational Site 071

Hyderabad, , India

Teva Investigational Site 070

Mumbai, , India

Teva Investigational Site 090

Bologna, , Italy

Teva Investigational Site 060

Gdansk, , Poland

Teva Investigational Site 061

Warsaw, , Poland

Teva Investigational Site 080

Singapore, , Singapore

Teva Investigational Site 040

London, , United Kingdom

Countries

Australia; United States; Canada; France; Germany; Hungary; India; Italy; Poland; Singapore; United Kingdom

References

Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012 Sep 27;120(13):2573-80. doi: 10.1182/blood-2012-03-415307. Epub 2012 Aug 15.

Reference Type: DERIVED

PMID: 22896000 (View on PubMed)

Other Identifiers

2006-000176-32

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CGX-635-CML-202

Identifier Type: -

Identifier Source: org_study_id