E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory Multiple Myeloma |
|
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 | 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 |
|
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 |
|
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 |
|
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 is allowed if the patient achieved at least a PR to the most recent therapy with PI, did not relapse within 60 days of discontinuation, and PI was no removed due to toxicity
*Prior therapy with a lenalidomide and dexamethasone is allowed if the patient achieved at least a PR to the most recent therapy with lenalidomide and dexamethasone, did not progress within 3 months of a lenalidomide and dexamethasone-containing treatment, did not relapse within 60 days of discontinuation of treatment, and treatment was no removed due to toxicity
History of prior neuropathy is permitted if not exceeding grade 2 which has either resolved within 14 days of enrollment or if ongoing is ≤ grade 1
Patients are permitted to have received single agent lenalidomide as maintenance therapy during the 6-months prior to first study treatment.
*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). |
|
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 allowed). Tests to be performed if required per local country regulations.
*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 is greater than or equal to ≥ 160 mmHg - systolic or greater than or equal to ≥ 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)≥ 2.5x
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.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
overall response (OR, 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 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Over the duration of the study |
|
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 |
|
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 |
|
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
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 |
Canada |
Japan |
Russian Federation |
Turkey |
United States |
Austria |
Bulgaria |
Finland |
France |
Germany |
Lithuania |
Netherlands |
Romania |
Slovakia |
Spain |
Sweden |
Czechia |
Greece |
|
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
|
|
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 | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |