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 | 20.0 |
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 on or after any 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 lenalidomide and dexamethasone is allowed, as long
as the patient had at least a PR to most recent therapy with PI or lenalidomide
and dexamethasone, was not removed due to toxicity, and will have at least a
6-month PI or lenalidomide and dexamethasone treatment-free interval from last
dose received until first study treatment. (Patients may receive maintenance
therapy with lenalidomide during this 6-month PI or lenalidomide and
dexamethasone treatment-free interval).
*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 21 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 an average systolic blood pressure
≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment (measured
following European Society of Hypertension/European Society of Cardiology
2013 guidelines; Section 12.10).
*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 21 days prior to randomization.
*Monoclonal antibody therapy within 21 days prior to randomization.
*Chemotherapy with approved anticancer therapeutic within 21 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 21 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 21 days prior to randomization:
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 21 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 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 |
|
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) |
*1-year PFS
*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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 |
Bulgaria |
Canada |
Czech Republic |
France |
Germany |
Greece |
Japan |
Korea, Republic of |
Netherlands |
Romania |
Russian Federation |
Spain |
Sweden |
Turkey |
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
|
|
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |