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)

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

Sponsors

Lead Sponsor: Chroma Therapeutics

Source Chroma Therapeutics
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.

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.

Overall Status Completed
Start Date 2006-05-01
Completion Date 2007-12-01
Primary Completion Date 2007-12-01
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
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 Outcome
Measure Time Frame
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
Enrollment 57
Condition
Intervention

Intervention Type: Drug

Intervention Name: CHR-2797 (tosedostat): Aminopeptidase inhibitor

Description: 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

Arm Group Label: CHR-2797 (tosedostat)

Eligibility

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.

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Location
Facility: Nexus Oncology Ltd
Location Countries

United Kingdom

Verification Date

2010-10-01

Responsible Party

Name Title: Dr Leon Hooftman, Chief Medical Officer

Organization: Chroma Therapeutics

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: CHR-2797 (tosedostat)

Type: Experimental

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

Study Design Info

Allocation: Non-Randomized

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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