Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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)

This study has been completed.
Sponsor:
Information provided by:
Chroma Therapeutics
ClinicalTrials.gov Identifier:
NCT00689000
First received: May 29, 2008
Last updated: October 21, 2010
Last verified: October 2010
  Purpose

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.

Condition Intervention Phase
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Multiple Myeloma
Drug: CHR-2797 (tosedostat): Aminopeptidase inhibitor
Phase 1
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: A Phase I-II Study to Evaluate the Safety, Tolerability and Anti-Disease Activity of the Aminopeptidase Inhibitor, CHR-2797, in Elderly and/or Treatment Refractory Patients With Acute Myeloid Leukemia or Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Chroma Therapeutics:

Primary Outcome Measures:
  • Phase I: To determine the safety, tolerability, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of CHR-2797 when administered orally, once daily. [ Time Frame: first 28 days of treatment ] [ Designated as safety issue: Yes ]
  • Phase II: To evaluate the anti-leukaemia/myeloma effect of the recommended dose of single agent CHR-2797. [ Time Frame: End of study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Phase I and II: To determine trough levels of CHR-2797 when administered orally, once daily, at different dose levels. [ Time Frame: End of study ] [ Designated as safety issue: Yes ]
  • Phase II: To evaluate the safety and tolerability of the recommended dose of CHR-2797 when administered orally, once daily. [ Time Frame: End of study ] [ Designated as safety issue: Yes ]

Enrollment: 57
Study Start Date: May 2006
Study Completion Date: December 2007
Primary Completion Date: December 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CHR-2797 (tosedostat)
oral, once daily administration of CHR-2797 to determine safety & anti-disease activity.
Drug: CHR-2797 (tosedostat): Aminopeptidase inhibitor

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

Other Names:
  • tosedostat
  • CHR-2797
  • aminopeptidase inhibitor

Detailed Description:

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. Cohorts of 3-6 patients each will be treated with escalating, once daily, oral doses of CHR-2797 for 84 days (12 weeks), of which the first 28 days constitute the dose finding/ DLT phase. The starting dose will be 60 mg once daily. Doses will be increased in a stepwise fashion by around 40 percent per step until the MTD is reached. The proportion of patients with Multiple Myeloma will be limited to one third: one per cohort of 3 or 2 per cohort of 6. It is anticipated that 24-30 patients will be enrolled in the phase I portion of the trial. A decision will be made with regard to the disease indication to be tested in phase II (either AML/MDS or MM or both), after completion of phase I, or following definition of MTD.

Phase II: the recommended dose as determined in phase I, will be administered for 84 days to a maximum of 40 patients. The primary objective is to determine whether CHR-2797 has sufficient biological activity against the disease(s) under study. A multinomial stopping rule has been included in the design that incorporates objective responses and early progression into a decision to stop or continue this phase I/II trial. An interim assessment will be performed after 15 patients have received the maximum acceptable dose (MAD) dose of CHR-2797 with clearly defined early stopping rules.

There will be a clinical conference at the end of every cohort in the phase I portion of the study, between phase I and II and after the first 15 patients have completed therapy in phase II.

  Eligibility

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

Inclusion Criteria:

  • 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:

    1. 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).
    2. Total bilirubin ≤ 1.5 x upper normal limit.
    3. AST (SGOT), ALT (SGPT) ≤ 2.5 x upper normal limit.
    4. 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.

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00689000

Locations
United Kingdom
Nexus Oncology Ltd
Edinburgh, Scotland, United Kingdom, EH25 9PP
Sponsors and Collaborators
Chroma Therapeutics
Investigators
Principal Investigator: 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
  More Information

Publications:
Responsible Party: Dr Leon Hooftman, Chief Medical Officer, Chroma Therapeutics
ClinicalTrials.gov Identifier: NCT00689000     History of Changes
Other Study ID Numbers: CHR-2797-002
Study First Received: May 29, 2008
Last Updated: October 21, 2010
Health Authority: Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Germany: Federal Institute for Drugs and Medical Devices
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Chroma Therapeutics:
Leukemia
AML
MDS
MM
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Multiple Myeloma
Cancer
Hematological malignancies
Elderly
Refractory
Blood

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Multiple Myeloma
Myelodysplastic Syndromes
Neoplasms, Plasma Cell
Preleukemia
Syndrome
Blood Protein Disorders
Bone Marrow Diseases
Cardiovascular Diseases
Disease
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Pathologic Processes
Precancerous Conditions
Vascular Diseases

ClinicalTrials.gov processed this record on November 24, 2014