E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
relapsed or refractory multiple myeloma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
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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 |
The primary objective of Part I is to assess the safety of CNTO 328 when administered as an IV infusion in combination with bortezomib in subjects with relapsed or refractory multiple myeloma. The primary objective of Part II of the study is to compare the efficacy, in terms of progression-free survival (PFS) of CNTO 328 when administered as an IV infusion in combination with bortezomib alone in subjects with relapsed or refractory multiple myeloma. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to assess the other efficacy endpoints, safety, population pharmacokinetics, pharmacodynamics, and immune response of CNTO 328 in subjects with relapsed or refractory multiple myeloma. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for the study, subjects must meet all of the following criteria:
1. Male or female age ≥ 18 years
2. Signed informed consent obtained prior to any study-specific screening procedures
3. Confirmed diagnosis of multiple myeloma
4. Measurable secretory disease defined as either serum monoclonal paraprotein, (M-protein) ≥1 g/dL or urine monoclonal (light chain) protein (> 200 mg/24 hours)
5. Documented disease progression (according to EBMT criteria) after at least 1 prior line of therapy but no more than 3 or have had no response to previous treatment (primary refractory disease), or have undergone or are unsuitable for autologous hematopoietic stem cell transplantation a. A single line of therapy may consist of 1 or more drugs such as, melphalan plus prednisone; vincristine plus conventional doxorubicin (or Doxil/Caelyx) plus dexamethasone (VAD/DVd); lenalidomide; or high-dose pulse corticosteroid with or without thalidomide (rituximab alone or experimental agents alone should not be considered a line of therapy) b. A single line of therapy may include induction chemotherapy followed by autologous hematopoietic stem cell transplantation and maintenance therapy or progression of disease before a response during the initial line of therapy (primary refractory disease) with a regimen that may have contained an anthracycline, an alkylating agent, or high-dose corticosteroids (rituximab alone or experimental agents alone should not be considered a line of therapy
6. ECOG performance status score of ≤2
7. Subjects experiencing toxicities resulting from previous therapy must have fully recovered or stabilized to ≤ Grade 1
8. Subjects of childbearing potential must use adequate birth control measures. Female subjects of childbearing potential must have a negative serum pregnancy test at screening
9. Adequate bone marrow, liver, and renal function at first dose/randomization as described below: a. Hemoglobin ≥ 7.5 g/dL (4.7 mmol/L; 75 g/L) with or without transfusion dependency b. Platelets ≥ 50,000/mm3 without transfusion dependency c. Absolute neutrophil count (ANC) ≥ 1000 mm3 without hematopoietic cytokine support d. AST, ALT, and alkaline phosphatase ≤ 3 x ULN e. Bilirubin ≤ 2 x ULN f. Calculated creatinine clearance ≥ 20 mL/min g. Corrected serum calcium < 12 mg/dL (3.0 mmol/L) or ionized calcium < 6.5 mg/dL (1.6 mmol/L). This level may be achieved by treatment but it must be reached before the subject is randomized
10. Able to adhere to study visit schedule and all protocol requirements
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria may not be enrolled in the study:
1. Prior treatment with bortezomib
2. Hypersensitivity or allergic reactions to boron or mannitol, or compounds containing these components
3. Removed the criteria that excluded subjects with prior dexamethasone exposure
4. ≥ Grade 2 peripheral neuropathy (according to NCI CTCAE, Version 3.0)
5. Treatment with systemic cancer therapy (including clarithromycin) or radiotherapy within 30 days of randomization
6. Treatment with nitrosoureas within 42 days of first dose/randomization
7. Major surgery within 30 days of first dose/randomization or planning to have surgery (except for minor surgical procedures) during the study
8. Received any investigational drug/agent within 30 days or 5 half-lives (whichever is longer) of first dose/randomization
9. Received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant
10. Has clinically significant residual toxicities associated with prior autologous bone marrow or autologous peripheral blood stem cell transplant
11. Administered platelet transfusion or neutrophil growth factor within 2 weeks prior to the collection of screening hematology laboratory sample
12. Transplanted solid organ with the exception of a corneal transplant (≥ 3 months prior to first dose/randomization)
13. Received any mAb within 60 days of first dose/randomization
14. Serious concurrent illness (medical or psychiatric), uncontrolled infection (including acute, diffuse infiltrative pulmonary disease), or any uncontrolled medical condition (eg, uncontrolled diabetes), including the presence of laboratory abnormalities, that places the subject at unacceptable risk by participating in the study or confounds the ability to interpret data from the study
15. Myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class II or higher heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic, clinically significant conduction system abnormalities, baseline QTc interval >450 milliseconds, history of hypokalemia, or any cardiac condition that is ≥ Grade 3
16. Prior or concomitant malignancy (other than multiple myeloma) except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other cancer for which the subject has been disease-free for ≥ 3 years
17. Any other concomitant disease-related treatment such as, immunotherapy, biotherapy, radiotherapy, chemotherapy, investigative therapy, or immunosuppressive therapy/corticoid steroids (other than study specific treatments)
18. Vaccinated with live or attenuated vaccines within 4 weeks of the first administration of CNTO 328/placebo
19. Known to be seropositive for HIV, or active hepatitis A, B or C infection
20. Pregnant or lactating women
21. Known allergies or clinically significant reactions to murine, chimeric or human proteins |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints for the study are safety for Part I and progression-free survival (PFS) for Part 2. |
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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 | No |
E.6.10 | Pharmacogenetic | No |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Part 1 is open-label single-arm safety run-in |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |