Safety and Anti-Disease Activity of CHR-2797 (Tosedostat) in Elderly and/or Treatment Refractory Patients With Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM)

NCT00689000 | Completed Phase 1 DMC

• 1 other identifier: CHR-2797-002
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, non-randomised, multi-centre phase I-II study of CHR-2797 administered orally once a day. The study involves two distinct phases:

• Phase I: an open-label, dose-escalating phase of the study to explore the safety, tolerability, and pharmacokinetics (PK) of CHR-2797.
• Phase II: the recommended dose level of CHR-2797, as determined in phase I, will be administered to a further cohort of approximately 40 patients to determine whether CHR-2797 has sufficient biological activity against the disease(s) under study.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome; Multiple Myeloma

Keywords

Leukemia; AML; MDS; MM; Acute Myeloid Leukemia; Myelodysplastic Syndrome; Multiple Myeloma; Cancer; Hematological malignancies; Elderly; Refractory; Blood

Outcome Measures

Primary Outcomes (2)

• Phase I: To determine the safety, tolerability, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of CHR-2797 when administered orally, once daily.

  first 28 days of treatment

• Phase II: To evaluate the anti-leukaemia/myeloma effect of the recommended dose of single agent CHR-2797.

  End of study

Secondary Outcomes (2)

• Phase I and II: To determine trough levels of CHR-2797 when administered orally, once daily, at different dose levels.

  End of study

• Phase II: To evaluate the safety and tolerability of the recommended dose of CHR-2797 when administered orally, once daily.

  End of study

Study Arms (1)

CHR-2797 (tosedostat)

EXPERIMENTAL

oral, once daily administration of CHR-2797 to determine safety \& anti-disease activity.

Drug: CHR-2797 (tosedostat): Aminopeptidase inhibitor

Interventions

CHR-2797 (tosedostat): Aminopeptidase inhibitor DRUG

Phase I: Once daily, oral ingestion of CHR-2797 capsules (60mg, 90mg, 130mg or 180mg) depending on cohort Phase II: Once daily, oral ingestion of 130mg CHR-2797 (recommended dose from Phase I) until progressive disease or withdrawal from the study

Also known as: tosedostat, CHR-2797, aminopeptidase inhibitor

CHR-2797 (tosedostat)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed, informed consent.
• Patients with AML, MDS (subtype RAEB-1 or RAEB-2), or MM whose disease has relapsed or is refractory to front line and/ or salvage therapy; elderly patients (≥ 60 years) with AML, MDS, MM who are not candidates for chemotherapy and for whom other therapy is inappropriate.
• Patients should have recovered from the acute adverse effects of prior therapies (excluding alopecia and grade II neuropathy).
• AML, MDS and MM are diseases of the haematopoietic system and can cause myelosuppression. Consequently supportive therapy should be given to ensure adequate values, according to local guidelines.
• A bone marrow aspirate/ biopsy performed within four weeks prior to study entry.
• Adequate bone marrow, hepatic and renal function including the following:
• Patients with high blast counts can be included in the trial, if they can be controlled by the use of hydroxyurea (500-3000 mg daily).
• Total bilirubin ≤ 1.5 x upper normal limit.
• AST (SGOT), ALT (SGPT) ≤ 2.5 x upper normal limit.
• Creatinine ≤1.5 x upper normal limit.
• Age ≥ 18 years
• Performance status (PS) ≤ 2 (ECOG scale).
• Estimated life-expectancy greater than 3 months.
• Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of the trial. A woman with reproductive potential is defined as one who is biologically capable of becoming pregnant. Patients who are not surgically sterile or postmenopausal must agree to use a medically acceptable and highly effective method of birth control for the duration of the study and to continue after the end of CHR-2797 treatment for a further 3 months (female patients) or for a further 6 months (for male patients and their partners). A highly effective method of birth control is defined as any method that results in a low failure rate, including implants, injectables, some intra-uterine devices (IUD's), sexual abstinence, and vasectomy/ sterilization. Sexually active males and females using oral contraceptive pills should also use barrier contraception. Although there is no reason to believe that the use of CHR-2797 has an effect on the pharmacokinetics of hormonal contraceptives, this has not yet been proven.

You may not qualify if:

• Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 4 weeks prior to trial entry- except for hydroxyurea (maximum daily dose is 3 g).
• Indolent, smouldering myeloma, monoclonal gammopathy with unknown significance.
• Patients who need a daily dose of hydroxyurea greater than 3 g to control leukocytosis.
• Co-existing active infection or serious concurrent illness.
• Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study
• Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies.
• Gastrointestinal disorders that may interfere with absorption of the study drug.
• Patients with platelet count(s) \< 20,000.
• Patients who have had a blood transfusion (platelet support or packed cells) within 7 days prior to study entry.
• Persistent grade II or greater toxicity from any cause (except haematological toxicities and peripheral neuropathy).
• Patients with grade III-IV peripheral neuropathy.
• Pregnant or breast-feeding women.

Sponsors & Collaborators

• Chroma Therapeutics: lead

Study Sites (1)

Nexus Oncology Ltd

Edinburgh, Scotland, EH25 9PP, United Kingdom

Location

Related Publications (1)

• Lowenberg B, Morgan G, Ossenkoppele GJ, Burnett AK, Zachee P, Duhrsen U, Dierickx D, Muller-Tidow C, Sonneveld P, Krug U, Bone E, Flores N, Richardson AF, Hooftman L, Jenkins C, Zweegman S, Davies F. Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia. J Clin Oncol. 2010 Oct 1;28(28):4333-8. doi: 10.1200/JCO.2009.27.6295. Epub 2010 Aug 23.

  PMID: 20733120 RESULT

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Multiple Myeloma; Leukemia; Neoplasms; Hematologic Neoplasms

Interventions

tosedostat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site

Study Officials

• Gareth Morgan, MD

  Royal Marsden Hospital, UK

  PRINCIPAL INVESTIGATOR

• Gert Ossenkoppele, MD

  Vrije Universiteit MC, Amsterdam

  PRINCIPAL INVESTIGATOR

• Pierre Zachée, MD

  ZNA Antwerpen, Belgium

  PRINCIPAL INVESTIGATOR

• Alan Burnett, MD

  University Hospital, Cardiff, United Kingdom

  PRINCIPAL INVESTIGATOR

• Michel Delforge, MD

  UZ Gasthuisberg, Leuven, Belgium

  PRINCIPAL INVESTIGATOR

• Bob Lowenberg, MD

  Erasmus MC, Rotterdam

  PRINCIPAL INVESTIGATOR

• Ulrich Dührsen, MD

  Universitätsklinikum, Essen, Germany

  PRINCIPAL INVESTIGATOR

• Carsten Müller-Tidow, MD

  Universitätsklinikum, Münster, Germany

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: May 29, 2008
• First Posted: June 3, 2008
• Study Start: May 1, 2006
• Primary Completion: December 1, 2007
• Study Completion: December 1, 2007
• Last Updated: October 22, 2010

Record last verified: 2010-10

Locations

GB (1)