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Study to Assess the Safety, Tolerability, and Efficacy of Tipifarnib Plus Bortezomib in the Treatment of Acute Myeloid Leukemia (HEMOS AML 0106)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2009 by University of Bologna.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Janssen-Cilag Ltd.
Information provided by:
University of Bologna
ClinicalTrials.gov Identifier:
NCT00510939
First received: August 2, 2007
Last updated: August 13, 2009
Last verified: August 2009
History of Changes
  Purpose

This is one of the first studies of combination of Zarnestra plus Velcade in man. A primary objective of the study is therefore to assess the safety and tolerability of multiple doses of Zarnestra plus Velcade in patients with AML.

New treatments for patients that are untreatable with intensive chemotherapy aged de novo AML patients or post-relapse AML are urgently required since, at present, many of the drugs used for second line therapy are the same as those used for first induction and response rates are much lower.

  • The following evidence suggests that Velcade plus Zarnestra can be an attractive therapeutic combination for: AML patients.
  • Affymetrix gene profiling data showed expression of NFkB1 in all of 5 myeloid cell lines cell lines tested and 35% of over 250 patient samples ( data generated in collaboration with Sergio Ferrari and Pier Paolo Piccaluga unpublished results, our Institute and University of Modena,Italy)
  • Preclinical evidence showed that AML cells in suspension culture were prevented to develop de novo drug resistance and mediated drug resistance.

In Part B additional patients with AML will be treated to further characterize the tolerability,biological effects, and clinical efficacy of the combination Velcade plus Zarnestra. Patients on treatment for AML will undergo regular bone marrow aspirates and biopsies to assess responses to treatment. This will facilitate frequent assessment of biological endpoints (reduction in expression and phosphorylation of IKKb kinase, and downstream markers of signalling along with apoptosis, survival, proliferation and cellular size and ploidy) will be made in an attempt to confirm that the desired biological activity has been achieved at the maximum tolerated dose.


Condition Intervention Phase
Acute Myeloid Leukemia
 Drug: Tipifarnib plus Bortezomib
 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II, Open-Label, Multi-centre, 2-part Study to Assess the Safety, Tolerability, and Efficacy of Tipifarnib Plus Bortezomib in the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) Unfit for Conventional Chemotherapy ( >18 Years) or in Patients With Acute Myeloid Leukemia in First Relapse ( >60 Years)

Resource links provided by NLM:

Drug Information available for: Bortezomib
U.S. FDA Resources

Further study details as provided by University of Bologna:

Primary Outcome Measures:
  • PART A: Assess the safety and tolerability of combined use of Zarnestra plus multiple ascending doses of Velcade in patients with de novo AML unfit for conventional chemotherapy (age >18 years) or in first or subsequent relapse ( >60 years).(COMPLETED) [ Time Frame: August 2007 ] [ Designated as safety issue: No ]
  • Part B.1: Assess the effect of Tipifarnib plus the defined in part A dose of Velcade in patients with de novo AML unfit for conventional chemotherapy (age >18 years) or in Patients in first or subsequent relapse ( >60 years) (COMPLETED) [ Time Frame: December 2008 ] [ Designated as safety issue: No ]
  • Part B.2: Evaluate the overall response (CR, PR, HI) of patients with a RASGRP1/APTX gene expression ratio > 10, identified as predictive of a good clinical response to tipifarnib in patients with de novo AML unfit for conventional chemotherapy. [ Time Frame: June 2010 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To investigate the effect of Velcade on the expression of NFkB, and biomarkers of NFkB
  • Including phosphorylation of c-Rel on leukaemic blasts by flow cytometry, protein analysis,
  • Immunohistochemistry, and/or mRNA profiling using gene and SNPs DNA chip.

Estimated Enrollment: 72
Study Start Date: March 2007
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of written informed consent
  2. Male or female aged >18 years with newly diagnosed Acute Myeloid Leukemia (AML), de novo or secondary, unfit for conventional chemotherapy
  3. Male or female with Acute Myeloid Leukemia in first relapse ( > 60 years)
  4. WHO performance status ³ 2, or/and unwillingness to receive conventional chemotherapy
  5. Negative pregnancy test or evidence of post-menopausal status for female patients.
  6. RASGRP1/APTX gene expression ratio calculated at the screening >10 (part B.2 only)

Exclusion Criteria:

  1. Serum bilirubin 2 x> Upper Limit of Normal (ULN)
  2. Aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) >3.5 x ULN
  3. Serum creatinine ³ 2.5 x ULN or 24-hour creatinine clearance £ 60 mL/min (measured or calculated by Cockcroft-Gault)
  4. Patients with AML of FAB M3 classification (APL)
  5. Patients with a history of another primary malignancy within the previous 1 year other than basal cell carcinoma or carcinoma in situ, the patient is in remission
  6. Any clinically defined central nervous system AML.
  7. Participation in an investigational drug study within the 30 days prior to entry
  8. Evidence of uncontrolled infection or CNS-Hemorrhagic
  9. Patients with documented cases of human immunodeficiency virus (HIV)
  10. Peripheral Neuropathy or Neuropathic Pain grade > or = 2
  11. Has known or suspected hypersensitivity or intolerance to boron, mannitol, or heparin, if an indwelling catheter is used
  12. Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 7,NYHA Classification of Cardiac Disease), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
  13. RASGRP1/APTX gene expression ratio calculated at the screening <10 (part B.2 only)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00510939

Contacts
Contact: Giovanni Martinelli, MD +39 051 6363829 gmartino@alma.unibo.it
Contact: Barbara Lama, MD +39 051 6363827 barbara.lama@unibo.it

Locations
Italy
Istituto di Ematologia "L e A Seragnoli" Policlinico S.Orsola-Malpighi Recruiting
Bologna, Italy, 40138
Contact: Giovanni Martinelli, MD     +039 051 6363829     martg@tin.it    
Sponsors and Collaborators
University of Bologna
Janssen-Cilag Ltd.
Investigators
Principal Investigator: Giovanni Martinelli, MD Istituto di Ematologia ed Oncologia Medica "L.eA.Seràgnoli" Policlinico S.Orsola-Malpighi di Bologna
  More Information

No publications provided

Responsible Party: Giovanni Martinelli, Dipartimento di Ematologia "Seragnoli"- Policlinico Sant'Orsola Bologna
ClinicalTrials.gov Identifier: NCT00510939     History of Changes
Other Study ID Numbers: HEMOS AML 0106, EudraCT 2007-000273-35
Study First Received: August 2, 2007
Last Updated: August 13, 2009
Health Authority: Italy: The Italian Medicines Agency
Italy: Ethics Committee

Keywords provided by University of Bologna:
Acute myeloid leukemia
NFkB activity and leukemia
expression of NFkB

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Tipifarnib
Bortezomib
 Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 22, 2013