| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 this study is to compare Progression Free Survival (PFS) in subjects with relapsed multiple myeloma who are receiving CRd vs PFS in subjects receiving Rd alone in a randomized multicenter setting. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives include investigating the effect of carfilzomib given with lenalidomide and dexamethasone on other standard efficacy variables including overall survival (OS), overall response rate (ORR [sCR + CR + VGPR + PR]), disease control rate (DCR [overall responses + minimal response (MR) + stable disease lasting at least 8 weeks]), duration of response (DOR), change from baseline in quality of life (QOL) assessment measured by European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-MY20, time to progression (exploratory), QOL subscales of EORTC QLQ-C30 and QLQ-MY20 (exploratory), time to next treatment (exploratory), and clinical benefit response (CBR = [ORR + MR], exploratory).
Additionally, this study will examine the safety profile of CRd compared with Rd alone based on the incidence and severity of AEs and laboratory changes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease-related
1. Symptomatic multiple myeloma
2. Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):
- Serum M-protein ≥ 0.5 g/dL
- Urine Bence-Jones protein ≥ 200 mg/24 hours
- For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL)
3. Prior treatment with at least one, but no more than three, regimens for multiple myeloma
4. Documented relapse or progressive disease on or after any regimen (subjects refractory to the most recent line of therapy are eligible)
5. Achieved a response to at least one prior regimen (defined as ≥ 25% decrease in M protein [or total protein in countries in which electrophoresis is not routinely available])
Demographic
6. Age ≥ 18 years
7. Life expectancy ≥ 3 months
8. Eastern Cooperative Oncology Group (ECOG) performance status 0–2
Laboratory
9. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 21 days prior to randomization
10. Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L within 21 days prior to randomization
11. Hemoglobin ≥ 8 g/dL (80 g/L) within 21 days prior to randomization (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)
12. Platelet count ≥ 50 × 10^9/L (≥ 30 × 10^9/L if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization
13. Creatinine clearance (CrCl) ≥ 50 mL/minute (either measured or calculated using a standard formula such as Cockcroft and Gault) within 21 days prior to randomization
Ethical/Other
14. Written informed consent in accordance with federal, local, and institutional guidelines.
15. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception according to, and for the timeframe outlined in the RevAssist program (US participants), RevAid program (Canadian participants) or Appendix F (all other participants)
16. Male subjects must agree to practice contraception according to, and for the timeframe outlined in the RevAssist program (US participants), RevAid program (Canadian participants) or Appendix F (all other participants) |
|
| E.4 | Principal exclusion criteria |
Disease-related
1. If previously treated with bortezomib (alone or in combination), progression during treatment
2. If previously treated with a lenalidomide and dexamethasone (len/dex) combination:
- Progression during the first 3 months of initiating treatment
- Any progression during treatment if the lenalidomide/dexamethasone combination was the subject’s most recent line of therapy
3. Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded
4. Prior carfilzomib treatment
5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
6. Waldenström’s macroglobulinemia or IgM myeloma
7. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
Concurrent Treatments
8. Chemotherapy or investigational agent within 3 weeks prior to randomization or antibody therapy within 6 weeks prior to randomization
9. Radiotherapy to multiple sites or immunotherapy/antibody therapy within 28 days prior to randomization; localized radiotherapy to a single site within 7 days prior to randomization
10. Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 21 days prior to randomization
Concurrent Conditions
11. Pregnant or lactating females
12. Major surgery within 21 days prior to randomization
13. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
14. Known human immunodeficiency virus infection
15. Active hepatitis B or C infection
16. Myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
17. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization
18. Other malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Score 6 or less with stable prostate specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
19. Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to randomization
20. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
21. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
22. Ongoing graft-vs-host disease
23. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization
24. Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression free survival |
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Overall response rate (ORR): stringent complete response (sCR) + complete response (CR) + very good partial response (VGPR) + partial response (PR)
- Disease control rate (DCR): overall response rate + minimal response (MR) + stable disease (SD) lasting at least 8 weeks
- Duration of response (DOR) (for ORR + DCR separately)
- Change from baseline in quality of life assessments (EORTC QLQ-C30 and QLQ-MY20)
- Safety
- Time to progression (exploratory)
- QOL subscales of EORTC QLQ-C30 and QLQ-MY20 (exploratory)
- Time to next treatment (exploratory)
- Clinical benefit resonse (ORR + MR) (exploratory) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All the secondary endpoints will be evaluated at the same time as the primary endpoint, progression free survival, except for overall survival. For overall survival, the final analysis will be performed after approximately 510 deaths have occurred, which is anticipated to be approximately 72 months after the first subject is randomized. |
|
| 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 | 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 92 |
| 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 |
| Austria |
| Belgium |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| The end of the study will be defined as the last visit of the last subject enrolled in the study |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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