E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple Myeloma relapsing after one previous line therapy |
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E.1.1.1 | Medical condition in easily understood language |
Multiple Myeloma relapsing after one previous therapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective is to compare the efficacy and safety of masitinib 6 mg/kg/day in combination with bortezomib and dexamethazone to placebo in combination with bortezomib and dexamethazone in the treatment of patients with relapsing multiple myeloma who have received one previous therapy.
Primary endpoint: Overall Progression Free Survival (PFS) according to International Myeloma Working Group criteria 2009 (IMWG / revised Bladé criteria) |
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E.2.2 | Secondary objectives of the trial |
•Disease progression -Overall Time to Progression according to International Myeloma Working Group criteria 2009 (revised Bladé criteria) -Time To Next Treatment •Survival -Overall Survival •Response -Best Response rate during study according to International Myeloma Working Group criteria 2009 (revised Bladé criteria) •Quality of life assessment -Quality of Life according to the EORTC QLQ-C30 questionnaire at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 -ECOG Performance Status at week 0 (screening), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 -Bone pain Verbal Rating Score at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 -Analgesic (non-opioid) consumption at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 -Opioid consumption at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 •Safety assessments -Safety profile using the NCI CTC v4.02 classification |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient with confirmed multiple myeloma requiring systemic therapy. All three criteria must be met: • Clonal bone marrow plasma cells > 10% • Presence of serum and/or urinary monoclonal protein • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: - Hypercalcemia: serum calcium > 11.5 mg/100 ml or - Renal insufficiency: serum creatinine > 173 μmol/l - Anemia: normochromic, normocytic with a hemoglobin value of > 2g/100 ml below the lower limit of normal or a hemoglobin value < 10g/100 ml - Bone lesions: lytic lesions, severe osteopenia or pathologic fractures 2. Patient with multiple myeloma relapsing according to the International uniform response criteria for multiple myeloma (IMWG 2009/ revised Bladé criteria) (defined in Table 5) to one previous line of treatment (defined in Table 6). Patients previously treated, with Bortezomib, for multiple myeloma can be included if and only if : - they have shown minimal, partial or complete response to this treatment - they have not been refractory to this treatment (to be considered as bortezomib refractory patient, any patient who didn't show any response to previous bortezomib treatment or whose disease progressed during or within 60 days of bortezomib treatment) 3. Patient candidate for receiving the standard therapy (bortezomib and dexamethazone) 4. Patient with measurable progressive disease defined by at least one of the following two measurements: • Serum M-protein ≥ 1 g/dL • Urine M-protein ≥ 200 mg/24h 5. Patient with ECOG ≤ 2 6. Patients with adequate organ function : • Absolute neutrophils count (ANC) ≥ 1.5 x 109/L • Haemoglobin ≥ 10 g/dL • Platelets (PTL) ≥ 75 x 109/L • AST/ALT ≤ 3x ULN (≤ 5 x ULN in case of liver metastases) • Gamma GT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases) • Bilirubin ≤ 1.5x ULN (≤ 3 x ULN in case of liver metastases) • Creatinine clearance ≥ 30 mL/min (Cockcroft and Gault formula) • Albuminaemia ≥ 1 LLN • Urea ≤ 2 ULN • Albuminuria ≤ 300 mg/24 hours 7. Patient with life expectancy > 6 months 8. Man or non-pregnant non-lactating woman, age ≥18 years and weight >40 Kg and BMI > 18 kg/m² 9. Man and woman of childbearing potential, (entering the study after a menstrual period and who have a negative pregnancy test) must agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. 10. Patient able and willing to comply with study procedures as per protocol 11. Patient able to understand, sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures are performed. If the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable, the designated legal guardian must sign the informed consent. 12. Patient able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, during the first 2 months. |
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E.4 | Principal exclusion criteria |
1. Patient with peripheral neuropathy Grade >2 2. Patient with hypersensitivity to bortezomib, boron or dexamethazone 3. Patient whose disease progressed during or within 60 days of bortezomib treatment or of any other Multiple Myeloma therapy 4. Patient who received bortezomib within 6 months of randomization to this study 5. Past discontinuation of bortezomib due to associated grade 3 or higher adverse event 6. Patient with contra-indication to high dose of steroids (including ongoing active infection, use of live vaccines, virosis such as hepatitis, herpes, varicella, herpes zoster) 7. Patient with acute diffuse infiltrative pulmonary and pericardial disease 8. Patient treated for a cancer other than multiple myeloma within five years before enrolment, with the exception of basal cell carcinoma and cervical cancer in situ 9. Patient with central nervous system (CNS) metastasis or with history of CNS metastasis 10. Patient with one of the following cardiac conditions: • Patient with recent cardiac history (within 6 months) of: - Acute coronary syndrome - Acute heart failure (class III or IV of the NYHA classification) - Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death) • Patient with cardiac failure class III or IV of the NYHA classification • Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block) • Syncope without known aetiology within 3 months • Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension 11. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
Previous treatments 1. High dose of corticosteroids and/or local irradiation should be stopped at least 2 weeks prior to Baseline 2. Administration of any other treatment for multiple myeloma should be stopped at least 4 weeks prior to Baseline. Patients who received bortezomib within 6 months prior to Baseline are excluded 3. Treatment with any investigational agent should be stopped at least 4 weeks prior to Baseline 4. Patient eligible for bone-marrow transplantation as second line therapy |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Progression Free Survival (PFS) according to International Myeloma Working Group criteria 2009 (IMWG / revised Bladé criteria) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
date of documented progression or death during the study |
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E.5.2 | Secondary end point(s) |
Secondary endpoints • Disease progression: - Overall Time to Progression (TTP) according to International Myeloma Working Group criteria 2009 (IMWG / revised Bladé criteria) - Time To Next Treatment (TTNT) • Survival: - Overall Survival (OS) • Response: - Best Response rate during study according to International Myeloma Working Group criteria 2009 (IMWG / revised Bladé criteria) • Quality of life assessment: - Quality of Life according to the EORTC QLQ-C30 questionnaire at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 - ECOG Performance Status at week 0 (screening), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 - Bone pain Verbal Rating Score (VRS) at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 - Analgesic (non-opioid) consumption at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 - Opioid consumption at week 0 (baseline), 3, 6, 9, 12, 15, 18, 21, 24, 32, 40, 48, 56, 64 and 72 • Safety assessments: - Safety profile using the NCI CTC v4.02 classification (including adverse events, laboratory values, vital signs, and physical examination including ECG). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
TTP: date of documented progression; TTNT: date of initiation of a new line of treatment due to progression; OS: documented death; QOL: see paragraph above |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 | No |
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 |
Belgium |
Canada |
France |
Greece |
Austria |
Germany |
Hungary |
Korea, Republic of |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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week 72 of the last patient |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 31 |