E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients in relapse from prior treatment, with histologically and otherwise verified diagnosis of multiple myeloma. |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• In patients with advanced myeloma to assess the efficacy of PXD101 treatment (as measured by response rate (CR, PR, MR, NC/SD, PD) using the response criteria of Bladé et al Br.J.Haematol. 1998, 102: 1115-23)).
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E.2.2 | Secondary objectives of the trial |
Study part A • To examine time to response, duration of response, time to progression, and survival following single agent PXD101 therapy. • To examine safety following single agent PXD101 therapy
Secondary objectives Study Part B
• To examine the chemotherapy sensitizing effect of PXD101 by assessing the efficacy (response rate, duration of response, time to progression and survival) and safety of a combination of dexamethasone and PXD101. • To determine the pharmacokinetic parameters of the intravenous administration of PXD101 followed by oral dexamethasone on days 1 and 4. • To investigate the pharmacodynamic effects of PXD101 in blood mononuclear cells on days 1 and 4, and when possible in tumor biopsies (bone marrow), in patients receiving PXD101 in combination with dexamethasone.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
INCLUSION CRITERIA
1. Signed informed consent 2. A confirmed diagnosis of multiple myeloma, diagnostic criteria as follows, in patients who have failed at least two prior lines of therapy. Diagnostic criteria for multiple myeloma: A Monoclonal immunoglobulin (M-component) in serum of IgG-type > 30 g/l, of IgA type> 20 g/l, of IgD type or IgE type of any concentration and/or excretion of M-component in the urine of type k or l type > 1 g/24 hours. B M-component in serum and/or urine in lower concentration than indicated above in ‘A’. C 10% or more plasma cells in bone marrow aspirate or plasmocytosis in biopsy from bone marrow or soft tissue tumor D Osteolytic bone lesions.
The diagnosis of multiple myeloma demands one of the following combinations: A+C, A+D, or B+C+D.
3. Evaluable disease (as described above) 4. Adequate bone marrow and hepatic function including the following: WBC > 2.5 x 109/l, absolute neutrophil count ≥ 1.5 x 109/l, platelets ≥50x109/l Total bilirubin ≤1.5 x upper normal limit. AST (SGOT), ALT (SGPT) ≤2.5 x upper normal limit 5. Serum potassium within normal range. 6. Age ≥18 years 7. ECOG performance status (PS) ≤2 8. Estimated life expectancy greater than 3 months 9. Female patients with reproductive potential with a negative serum pregnancy test within the last 7 days before trial enrollment and use a safe contraceptive during and for a period of 60 days after the trial. Fertile female partners to male participants must likewise use contraceptive.
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E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA
1. Anticancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the last 4 weeks or a longer period depending on the defined characteristics of the agents used (e.g. 6 weeks for mitomycin or nitrosourea). Exception: bisphosphonates for bone disease caused by multiple myeloma. 2. Co-existing active infection or any co-existing medical condition likely to interfere with trial procedures. 3. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, congestive heart failure related to primary cardiac disease, a condition requiring anti-arrhythmic therapy, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry 4. A marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval >500; Long QT Syndrome; the required use of concomitant medication on PXD101 infusion days that may cause Torsade de Pointes. (See Appendix B for list). 5. Patients with renal insufficiency defined as a calculated creatinine clearance of <45 ml/min. 6. Clinically significant central nervous system disorders requiring neuroleptics or anti-convulsant medication 7. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies 8. Other malignant diseases requiring treatment 9. Non-secretory multiple myeloma or symptomatic amyloidosis 10. Pregnant or breast-feeding women 11. Women of childbearing age and potential, who do not use effective contraception 12. Known HIV positivity
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E.5 End points |
E.5.1 | Primary end point(s) |
10.3.1 The primary objective of the study is to determine the rates of OR and SD in multiple myeloma patients, refractory to prior therapy, after monotherapy with PXD101 and in combination with Dexamethasone. The primary target variable is therefore whether or not an individual patient shows confirmed CR, PR MR or SD. Descriptive statistics (incidence and confidence intervals) will be used to summarize the number of patients exhibiting an OR or SD in both parts of this study.
Secondary target variables include: • time to response, duration of response, time to progression, time to next therapy and survival following single agent PXD101 therapy and combination therapy with Dexamethasone. • safety parameters following single agent PXD101 therapy and combination therapy with Dexamethasone. • pharmacokinetic estimates of PXD101 monotherapy and in combination with Dexamethasone.
Time to event parameters will be estimated using the Kaplan-Meier method. All reported symptoms and adverse advents would be coded according to the NCI-CTC coding system and presented and summarized by dose. Crude incidence rates will be based on the maximum intensity grade for each patient. All patients who receive any amount of PXD101 will be included in these analyses. 95% confidence intervals will be calculated where appropriate.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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9. Independent response and review committee (IRC) An independent IRC will be formed (one statistician, 2 hematologists/ medical oncologists). They will perform an independent review of treatment response when the trial has been concluded.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |