| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Relapsed and Refractory Multiple Myeloma (MM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Myeloma - cancer of white blood cells |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To evaluate Progression-Free Survival (PFS) according to International Myeloma Working Group (IMWG) response criteria (Rajkumar 2011) in subjects with relapsed or relapsed and refractory MM. |
|
| E.2.2 | Secondary objectives of the trial |
• Overall Response Rate (≥PR)
• PFS Rate at Landmark Points
• Duration of Response (DOR)
• Overall Survival (OS)
• Time to Progression (TTP)
• To evaluate the safety and tolerability of ibrutinib in combination with bortezomib and dexamethasone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects with MM who have received 1-3 prior lines of therapy and have demonstrated disease progression since the completion of the most recent treatment regimen.
2. Measurable disease defined by at least ONE of the following:
• Serum monoclonal protein (SPEP) ≥1 g/dL
• Urine monoclonal protein (UPEP) ≥200 mg by 24 hour urine electrophoresis
3. Adequate hematologic function
4. Adequate hepatic and renal function
5. Prothrombin time (PT)/ International normal ratio (INR) ≤1.5 x upper limit of normal (ULN)
and PTT (activated partial thromboplastin time [aPTT]) ≤1.5 x ULN
6. Male and female ≥18 years of age
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
8. Male and female subjects of reproductive potential who agree to use highly effective methods of birth control during the period of therapy and for 90 days after the last dose of study treatment. Female subjects who are of non-reproductive potential. Female subjects of reproductive potential must have a negative serum pregnancy test upon study entry.
Other protocol-defined inclusion criteria could apply |
|
| E.4 | Principal exclusion criteria |
1. Primary refractory disease defined as nonresponsive in patients who have never achieved a minimal response or better with any therapy.
2. History of plasma cell leukemia, primary amyloidosis, POEMS syndrome within 12 months prior to first administration of study treatment.
3. Recent prior chemotherapy
4. Prior exposure to BTK inhibitors
5. Refractory or non-responsive to prior PI therapy (bortezomib or carfilzomib)
6. History of hypersensitivity reactions to prior bortezomib, to boron, mannitol or nitrogen.
7. History of other malignancies
8. Peripheral neuropathy Grade ≥2 or Grade 1 with pain at Screening
9. Prior allogeneic stem cell transplant
10. Recent infection requiring systemic treatment that was completed <7 days before the first administration of study treatment and/or uncontrolled active
systemic infection.
11. Unresolved toxicities from prior anti-cancer therapy
12. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia)
13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
14. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV)
15. Major surgery within 4 weeks of first administration of study treatment.
16. Any life-threatening illness, medical condition, including uncontrolled Diabetes Mellitus, or organ system dysfunction
17. Currently active, clinically significant hepatic impairment
18. Currently active, clinically significant cardiovascular disease
19. Unable to swallow capsules or malabsorption syndrome
20. Subjects who received a strong cytochrome P (CYP) 450 3A inhibitor within 7 days prior to the first administration of study treatment or subjects who require continuous treatment with a strong CYP 3A
inhibitor
21. Lactating or pregnant
Other protocol-defined exclusion criteria could apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint of this study is mPFS. Progression free survival is defined as the time from the date of first dose of study treatment to confirmed disease progression or death from any cause, whichever occurs first. The mPFS is the time at which the percentage or probability of surviving and progression-free is 50%. The mPFS will be assessed according to the IMWG response criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis is planned to include data up to 12 months after the last subject is enrolled or 83 PFS events, whichever occur earlier. This is estimated to occur Q3 2019. |
|
| E.5.2 | Secondary end point(s) |
• ORR is the proportion of subjects who achieve a PR or better over the course of the study but prior to initiation of subsequent anti-cancer therapy.
• PFS rates at landmark points are the percentages or probabilities of surviving and progression-free at the landmark time points. The landmark time points will be described further in the SAP.
• The DOR is defined as the interval between the date of initial documentation of a response and the date of first documented evidence of progressive disease, death, or date of censoring if applicable, for responders only. Responders are subjects in the ITT population who achieve PR or better according to the IMWG response criteria. Non
responders (≤PR) will be excluded from the analysis for DOR.
• OS is defined as the time from the date of first dose of study treatment until date of death due to any cause.
• TTP is defined as the time from the start of treatment until date of disease progression. Subjects who die due to causes other than disease progression will be censored at the date of death. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The analysis of secondary endpoints will also occur at the time of the primary analysis. In addition, a final analysis will occur at the time of study closure and may include updates to the secondary endpoints as applicable for those subjects either continuing on treatment at the time of the primary analysis or those that have discontinued treatment but not yet experienced an event (progression or death). |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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.8.4.1 | 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 | 45 |
| 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 |
| Czech Republic |
| France |
| Germany |
| Greece |
| Italy |
| Poland |
| Spain |
| Turkey |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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