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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndrome, Multiple Myeloma

Intervention / Treatment
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* Drug: CHR-2797 (tosedostat): Aminopeptidase inhibitor


Participation Criteria
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Eligibility Criteria
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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: 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHR-2797 (tosedostat)<br>oral, once daily administration of CHR-2797 to determine safety & anti-disease activity. | Drug: CHR-2797 (tosedostat): Aminopeptidase inhibitor<br>* 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<br>* Other names: aminopeptidase inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, AML, MDS, MM, Acute Myeloid Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, Cancer, Hematological malignancies, Elderly, Refractory, Blood