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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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
compare efficacy of 56 mg/m2 carfilzomib administered once-weekly in combination with lenalidomide and dexamethasone (KRd 56 mg/m2) to 27 mg/m2 carfilzomib administered twice-weekly in combination with lenalidomide and dexamethasone (KRd 27 mg/m2) in subjects with RRMM with 1 to 3 prior lines of therapy |
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E.2.2 | Secondary objectives of the trial |
*compare progression-free survival (PFS) between treatment arms *compare patient-reported convenience with carfilzomib-dosing schedule between treatment arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
*Subject has provided informed consent prior to initiation of any study-specific activities or procedures or subject’s legally acceptable representative has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent. *Males or females ≥ 18 years of age. *Documented relapse or progressive multiple myeloma after last treatment (Subjects refractory to the most recent line of therapy are eligible, unless last treatment contained PI or lenalidomide and dexamethasone). *Subjects must have at least PR to at least 1 line of prior therapy. *Subjects must have received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation maintenance therapy will be considered as 1 line of therapy). See Section 12.8 for guidelines for documenting prior treatment. * Prior therapy with a PI or the combination of lenalidomide and dexamethasone are allowed if, • the patient had at least a PR to the most recent therapy with a PI or lenalidomide and dexamethasone, • neither PI or lenalidomide and dexamethasone in combination were ceased due to toxicity, (unless at the time of enrollment that toxicity was neuropathy not exceeding grade 2 which has either resolved or if ongoing is ≤ grade 1), • the patient has not received a PI and has not received lenalidomide and dexamethasone in combination in the 6 months prior to first study treatment. (Patients are permitted to have received single agent lenalidomide as maintenance therapy during the 6-months prior to first study treatment). *Previous treatment with a lenalidomide and dexamethasone containing regimen is allowed, as long as the subject did not progress during the first 3 months after initiating lenalidomide and dexamethasone containing therapy. Measurable disease with at least 1 of the following assessed within 28 days prior to randomization: • IgG multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL • IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL • urine M-protein ≥ 200 mg per 24 hours • in subjects without measurable serum or urine M-protein, serum-free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio *Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 2 (see Section 12.9).
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E.4 | Principal exclusion criteria |
Disease-related *Waldenström macroglobulinemia. *Multiple myeloma of IgM subtype. *POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). *Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential). *Primary amyloidosis (patients with multiple myeloma with asymptomatic deposition of amyloid plaques found on biopsy would be eligible if all other criteria are met). *Myelodysplastic syndrome. Other Medical Conditions *History of other malignancy within the past 5 years, with the following exceptions: • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease • Adequately treated cervical carcinoma in situ without evidence of disease • Adequately treated breast ductal carcinoma in situ without evidence of disease • Prostatic intraepithelial neoplasia without evidence of prostate cancer • Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ • Treated medullary or papillary thyroid cancer • Similar neoplastic conditions with an expectation of > 95% 5-year disease-free survival * Known HIV infection, hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response after antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen or core antibody that achieve sustained virologic response with antiviral therapy are permitted with a requirement for regular monitoring for reactivation for the duration of treatment on the study). *Ongoing graft-vs-host disease. *Acute active infection requiring systemic antibiotics, antifungal, antiviral (except antiviral therapy directed at hepatitis B) agents within 14 days prior to randomization. *Known cirrhosis. *Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior to randomization. *Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization. Cardiopulmonary Conditions * Uncontrolled hypertension, defined as subject whose blood pressure exceeds ≥ 160 mmHg - systolic or ≥ 100 mmHg diastolic when taken in accordance with the European Society of Hypertension/European Society of Cardiology 2018 guidelines. (Section 12.10; Williams et al, 2018). *Active congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization. *Intolerance to hydration due to pre-existing pulmonary or cardiac impairment. *History of interstitial lung disease or ongoing interstitial lung disease. Prior/Concomitant Therapy *Immunotherapy within 28 days prior to randomization. *Monoclonal antibody therapy within 28 days prior to randomization. *Chemotherapy with approved anticancer therapeutic within 28 days prior to randomization. *Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent dose of other corticosteroids. *Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 28 days prior to randomization (ie, prior radiation must have been to < 30% of the bone marrow). *Major surgery (except kyphoplasty) within 28 days prior to randomization. *Autologous or allogeneic stem cell transplant within 90 days prior to randomization. *Contraindication or intolerance to lenalidomide, dexamethasone, or carfilzomib. *Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib). *Subject has known hypersensitivity to any of the products or components to be administered during dosing, including hypersensitivity to antiviral drugs. Prior/Concurrent Clinical Study Experience *Currently receiving treatment in another investigational device or drug study, or < 28 days since ending treatment on another investigational device or drug study(ies). Organ Function Assessments * Hepatic dysfunction within 28 days prior to randomization: • direct bilirubin ≥ 1.5x the upper limit of normal (ULN) • aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2.5 x ULN *Left ventricular ejection fraction < 40% assessed by transthoracic echocardiogram (ECHO). *Absolute neutrophil count (ANC) < 1 x 109/L within 28 days prior to randomization. Screening ANC should be independent of growth factor support for ≥ 1 week.
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E.5 End points |
E.5.1 | Primary end point(s) |
overall response rate (ORR, defined as the proportion of best overall response of stringent complete response [sCR], complete response [CR], very good partial response [VGPR], and partial response [PR] per International Myeloma Working Group Uniform Response Criteria [IMWG-URC]) over the duration of the study |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Over the duration of the study |
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E.5.2 | Secondary end point(s) |
* PFS over the duration of the study *convenience as measured by the Patient-reported Convenience With Carfilzomib-dosing Schedule Question after cycle 4 of treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
*1-year PFS *convenience as measured by the Patient-reported Convenience With Carfilzomib-dosing Schedule Question after cycle 4 of treatment |
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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 | 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 | 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) | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 115 |
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 |
Bulgaria |
Canada |
Czechia |
Finland |
France |
Germany |
Greece |
Japan |
Lithuania |
Netherlands |
Romania |
Russian Federation |
Slovakia |
Spain |
Sweden |
Turkey |
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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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 | 0 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |