Page 27 - 2018_09-Mondo

Cardiovascular safety in MM
continued from the previous page
Study
CYKLONE61
Jakubowiak 201251
Dytfeld 201452
CARTHADEX62
Bringhen 201453
Bringhen 201754
Korde63
Phase N° of patients
1-2 64
Regimen
CFZ was-escalated to 15/20, 20/27, 20/36 and
20/45 mg/m2 to determine the MTD (20/36 mg/m2). CFZond1,2,8,9,15,16
Cy300mg/m2 ond1,8,15 T100mgond1–28,D40mgond1,8,15,22
CFZ(20,27,36mg/m2, ond1,2,8,9,15,16+d 1, 2, 15, 16 after cycle 8)
R 25 mg/d, d 1-21, D weekly (40/20 mg cycles 1-4/5+) in 28-d cycles
Dose escalation:
CFZ20mg/m2 forcycle1ond1,2,8,9,15,16 of28d,andthenat20,27,or
36 mg/m2 for 7 cycles.
Maintenance CFZ-R-D (cycles 9-24): CFZ on d 1, 2, 15, 16. R25mgond1–21,Dond1,8,15,22
at 40 mg (cycles 1-4), and at 20 mg thereafter.
Dose escalation:
CFZ20mg/m2 ond1,2then27mg/m2 on d8,9,15,16ofcycle1andond1,2,8,9,15,16
of cycles 2 to 4. T200mgond1-28,D40mgond1,8,15,22.
CFZ was escalated to 20/36 mg/m2 in cohort 2,
to 20/45 mg/m2 in cohort 3 and to 20/56 mg/m2 in cohort 4.
Dose escalation:
CFZond1,2,8,9,15,16(20mg/m2 ond1+2
of cycle 1 and 36 mg/m2 thereafter).
Cy300mg/m2 ond1,8,15,D40mgond1,8,15,22 Maintenance:
1-2
1-2
2
2
1/2
53
23 (subset of elderly patients of Jakubowiak 2012(49)
111
58
54
Median prior lines (range)
4
12(1-25)
24 (1-24)
4
9
Notes
After cycle 4, ASCT-candidates underwent stem cell collection then continued treatment with option of ASCT. Max. planned dose (CFZ
36 mg/m2) was expanded in phase 2.
MTD was not established, but
based on efficacy and safety, in phase II
CFZ dose was 36 mg/m2.13 After 24 cycles, patients continued single-agent maintenance lenalidomide off protocol.
Median age: 72 years (range: 65-81).
14 patients received a median of 24 cycles (range: 1-24), 2 at a CFZ dose of 20 mg/m2, 4 at 27 mg/m2, and 17 at 36 mg/m2.
Induction was followed by stem cell harvest after Cy priming (2 to 4 mg/m2) and G-CSF. Hereafter patients received high-dose M (200 mg/m2) and ASCT followed by consolidation treatment with 4 cyclesofCFZ-T-Dinthesamescheduleexcepta lower dose of T (50 mg).
CFZ 36 mg/m2 on d 1, 2, 15, 16 until progression/ intolerance.
Dose escalation:
2 45
CFZ on d 1, 8, 15 (20 mg/m2 on cycle 1, d 1; subsequent
doses were escalated in a standard 3+3 dose-escalation 9 scheme at 45, 56, 70 mg/m2. In phase 2, CFZ 70 mg/m2,
with same schedule as in phase 1)
Cy300mg/m2 ond1,8,15,D40mgond1,8,15,22. Maintenance:
CFZ 70 mg/m2 on d 1, 15 until progression or intolerance.
CFZ on d 1, 2, 8, 9, 15, 16 (starting dose, 20 mg/m2
on d 1 + 2 of cycle 1; target dose, 36 mg/m2 thereafter).
R 25 mg on d 2- 21 of cycle 1 and on d 1- 21 of cycles 2 through 8. Dond1,2,8,9,15,16,22,23(20mgforcycles1-4and
10 mg for cycles 5-8; D was not administered on d 1 of cycle 1).
ASCT-eligible patients underwent stem cell collection after 4 cycles and continued with treatment. After 8 cycles, all patients with at least stable disease were to receive 2 years of extended dosing with R.
The first 4 cycles were followed by high-dose M and ASCT and consolidation with 4 CFZ-Cy-D cycles
The first 4 cycles were followed by high-dose M
and ASCT and consolidation with 4 CFZ-R-D
FORTE55 2
154 309
CFZ20/36mg/m2 ond1,2,8,9,15,16
Cy300mg/m2 ond1,8,15,D20mgond1,2,8,9,15,16
CFZ20/36mg/m2 ond1,2,8,9,15,16
D 20mg on d 1, 2, 8, 9, 15, 16, R 25 mg d 1-21 cycles
8
4 4
CFZ:carfilzomib;R:lenalidomide;D:dexamethasone;V:bortezomib;P:prednisone;Cy:cyclophosphamide;d:day (s),MTD:maximum tolerated dose;M:melphalan;T:thalidomide;ASCT:autologous stem cell transplantation; MM: multiple myeloma.
ASPIRE37 and ENDEAVOR,31 and after analysis of safety data derived from 526 patients enrolled in four phase 2 carfilzomib studies.38
In the ASPIRE study, the incidence of dyspnea was 19.4% considering all grades and 2.8% considering only grade ≥3 events, although the origin (cardiac, infectious,
pulmonary) remained unspecified.37 There was also increased hypertension, which was almost double in the carfilzomib-Rd (KRd) group as compared to the Rd group (14.3% versus 6.9% for all grades and 4% versus 2% for grade ≥3 in the KRd and Rd groups, respectively). However, cardiac death rates were similar in the two
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