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 |
Cancer of plasma cells, a type of white blood cell normally responsible for producing antibodies |
|
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the progression-free survival (PFS) of once weekly
carfilzomib dosing in combination with dexamethasone to the PFS of
twice weekly carfilzomib dosing in combination with dexamethasone in
subjects with relapsed and refractory multiple myeloma who have
received prior treatment with a proteasome inhibitor and an IMiD
(immunomodulatory agent). |
|
E.2.2 | Secondary objectives of the trial |
Overall response rate (ORR)
Overall survival (OS)
Safety and tolerability
Pharmacokinetics (PK) of carfilzomib using sparse sampling |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
INTENSIVE PHARMACOKINETICS/PHARMACODYNAMICS SUBSTUDY
&
SPARSE PHARMACOKINETIC SAMPLING
|
|
E.3 | Principal inclusion criteria |
101. Age ≥ 18 years
102. Able to provide written informed consent in accordance with
federal, local,
and institutional guidelines
103. Relapsed multiple myeloma
104. Refractory multiple myeloma, defined as meeting 1 or more of the
following:
a. Nonresponsive to most recent therapy (stable disease or progressive
disease
[PD] while on treatment), or
b. Disease progression within 60 days of discontinuation from most
recent
therapy
105. At least 2, but no more than 3, prior lines of therapy for multiple
myeloma
106. Prior exposure to an IMiD
107. Prior exposure to a proteasome inhibitor (PI)
108. Documented response of at least partial response (PR) to at least 1
prior line of
therapy
109. Measurable disease, with at least 1 of the following assessed at a
central
laboratory within the 21 days prior to randomization:
a. Serum M-protein ≥ 0.5 g/dL
b. Urine M-protein ≥ 200 mg/24 hours
c. 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
110. Eastern Cooperative Oncology Group Performance Status (ECOG PS)
of 0 or 1
111. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days
prior to
randomization
112. Adequate organ and bone marrow function performed at a central
laboratory
within the 21 days prior to randomization, defined by:
a. Bilirubin < 1.5 times the upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT)
< 3 times the ULN
c. Absolute neutrophil count (ANC) ≥ 1 × 109/L (screening ANC must be
independent of growth factor support for ≥ 7 days)
d. Hemoglobin ≥ 8 g/dL (Use of erythropoietic stimulating factors and
red blood
cell [RBC] transfusions per institutional guidelines are allowed, however
the
most recent RBC transfusion may not have been done within 7 days prior
to
obtaining the screening hemoglobin.)
e. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma
involvement in the
bone marrow is > 50%. Subjects must not have received platelet
transfusions
for at least 7 days prior to obtaining the screening platelet count.)
f. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min.
Calculation must be based on the Cockcroft and Gault formula:
[(140 – Age) × Mass (kg) / (72 × Creatinine mg/dL)]; multiply result by
0.85
if female
113. Females of childbearing potential (FCBP) must have a confirmed
negative serum
pregnancy test performed at a central laboratory, within the 21 days
prior to
randomization, and must not be breastfeeding.
114. Females of childbearing potential must agree to use highly effective
method(s) of
contraception, during the study and for 30 days following the last study
drug
administration. (Refer to Appendix K for specific contraceptive
requirements).
115. Male subjects who are sexually active with an FCBP must agree to
use
condoms (unless they have had a vasectomy with medical confirmation
of surgical success), during treatment and for an additional 90 days
following
the last study drug administration.
116. Male subjects must agree to not donate sperm, during treatment
and for an
additional 90 days following the last study drug administration.
|
|
E.4 | Principal exclusion criteria |
201. Waldenström macroglobulinemia
202. Multiple myeloma of Immunoglobulin M (IgM) subtype
203. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,
monoclonal
protein, and skin changes)
204. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by
standard
differential)
205. Myelodysplastic syndrome
206. Second malignancy within the past 5 years except:
a. Adequately treated basal cell or squamous cell skin cancer
b. Carcinoma in situ of the cervix
c. Prostate cancer < Gleason score 6 with stable prostate-specific
antigen (PSA)
over 12 months
d. Ductal breast carcinoma in situ with full surgical resection (i.e.,
negative
margins)
e. Treated medullary or papillary thyroid cancer
f. Similar condition with an expectation of > 95% five-year disease-free
survival
207. History of or current amyloidosis
208. Cytotoxic chemotherapy or other antineoplastic therapy, aside from
immunotherapy or proteasome inhibitors, within the 28 days prior to
randomization
209. Immunotherapy, such as an IMiD, or a proteasome inhibitor, within
the
21 days prior to randomization
210. Glucocorticoid therapy exceeding a cumulative dose of 160 mg
dexamethasone or
equivalent, within the 14 days prior to randomization
211. Radiation therapy:
a. Focal therapy within the 7 days prior to randomization
b. Extended field therapy within the 21 days prior to randomization
212. Prior treatment with either carfilzomib or oprozomib
213. Known history of allergy to Captisol (a cyclodextrin derivative used
to solubilize
carfilzomib)
214. Contraindication to dexamethasone or any of the required
concomitant
medications or supportive treatments
215. Active congestive heart failure (New York Heart Association [NYHA]
Class III
or IV, refer to Appendix F), symptomatic ischemia, conduction
abnormalities
uncontrolled by conventional intervention, acute diffuse infiltrative
pulmonary
disease, pericardial disease, or myocardial infarction within 6 months
prior to
randomization
216. Active infection requiring systemic treatment within the 14 days
prior to
randomization
217. Pleural effusions requiring thoracentesis within the 14 days prior to
randomization
218. Ascites requiring paracentesis within the 14 days prior to
randomization
219. Ongoing graft-versus-host disease
220. Uncontrolled hypertension or diabetes mellitus
221. Significant neuropathy (≥ Grade 3) within the 14 days prior to
randomization
222. Known cirrhosis
223. Known human immunodeficiency virus (HIV) seropositivity,
hepatitis C
infection, or hepatitis B infection. Subjects with past hepatitis B virus
infection,
defined as having a negative HBsAg test and a positive antibody to
hepatitis B
core antigen (anti-HBc) antibody test, are eligible. Subjects positive for
hepatitis
C virus (HCV) antibody are eligible only if polymerase chain reaction
(PCR) is
negative for HCV RNA.
224. Participation in another interventional study within the 28 days
prior to
randomization
225. Major surgery (except kyphoplasty) within the 28 days prior to
randomization
227. Any other clinically significant medical disease or social condition
that, in the
investigator's opinion, may interfere with protocol adherence or a
subject's ability
to give informed consent, be compliant with study procedures, or
provide accurate
information.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is PFS, which is defined as the time in months from
randomization to the earlier of disease progression or death due to any
cause. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final PFS analysis will be conducted when approximately 350 PFS
events have occurred or by end of year 2018, whichever is earlier. A
total of 350 PFS events will provide 83% power to detect a significant
difference in PFS between the 2 treatment groups with 1 interim
analysis if the underlying HR is 0.73. The interim analysis will be
performed when approximately 75% of the total PFS events (i.e., 263
events) have occurred. |
|
E.5.2 | Secondary end point(s) |
The secondary endpoints of the study are as follows:
ORR, defined as the proportion of subjects who achieved a confirmed
PR, VGPR, CR, or sCR, according to the IMWG-URC.
OS defined as the time in months from randomization to death due to
any cause.
Safety and tolerability
Sparse PK |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR will be analyzed at the time of the PFS analysis (interim or final),
only if the PFS analysis crosses the boundary.
- The analysis of OS will be conducted at the time of the PFS analysis
(interim or final), only if both PFS and ORR analyses are positive |
|
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 | 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 | No |
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) | No |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Belgium |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Norway |
Poland |
Spain |
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 primary completion date is defined as the date when the last
subject is assessed or receives an intervention for the final collection of
data for the primary endpoint(s), for the purposes of conducting the
primary analysis, whether the study concluded as planned in the
protocol or was terminated early.
The end of study date is defined last subject last visit, following any
additional parts in the study (e.g., long-term follow-up), as applicable. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |