Page 124 - 2018_09-Mondo

J.F. San-Miguel et al.
Table 5. Safety profile with IMP induction and single-agent ixazomib maintenance (safety population).
Overall
New-onset AE during induction
New-onset AE during maintenance
n (%)
Grade ≥3 AE
Serious AE
AE leading to discontinuation of any study drug AE leading to dose reduction of any study drug
On-study death
Total (N=61)
54 (89)
31 (51) 15 (25) 32 (52)
3 (5)
RP2D 4.0 mg Arm B (N=26)
21 (81)
12 (46) 8 (31) 13 (50)
3 (12)
Total (N=61)
54 (89)
28 (46) 13 (21) 31 (51)
3 (5)*
RP2D 4.0 mg Arm B (N=26)
21 (81)
11 (42)
6 (23)
12 (46)
3 (12)*
Total (N=36)
18 (50)
8 (22) 2 (6) 3 (8) 0
RP2D 4.0 mg Arm B (N=13)
5 (38)
2 (15) 2 (15) 3 (23) 0
AE: adverse event; IMP: ixazomib-melphalan-prednisone; RP2D: recommended phase II dose. *On-study deaths: disease progression in 1 patient, and pneumonia and septic shock in 1 patient each (not considered drug related).
Table 6. Most common (≥30% incidence in either population) any-grade and grade ≥3 AEs (safety population).
Total (N=61)
47 (77)
38 (62) 38 (62) 33(54) 31 (51) 28 (46) 25 (41) 24(39) 23 (38) 22 (36) 22 (36) 20 (33) 19 (31) 18 (30)
17 (28)
Any-grade AE
4.0 mg Arm B (n=26)
16 (62)
17 (65)
12 (46)
11(42) 0 0
8 (31) 9 (35) 8 (31) 6 (23) 7 (27) 6 (23) 9 (35)
RP2D
Total (N=61)
30 (49)
RP2D
Grade ≥3 AE
4.0 mg Arm B (n=26)
n (%)
Thrombocytopenia
Diarrhea Neutropenia Nausea
Anemia
Vomiting Constipation PNNEC* Lymphopenia Asthenia Decreased appetite Pyrexia
Leukopenia
Rashes, eruptions and exanthems NEC*
Fatigue
7 (27)
7 (11) 27 (44)
4 (15) 6 (23)
9 (15)
2 (3)
1 (2)
11(42) 3(5) 1(4)
9 (35) 11 (42) 6 (23)
4 (15) 0
0
18 (30) 4 (7) 0
1 (2) 12 (20) 4 (7) 2 (3)
5 (19) 1 (4) 0
0
3 (12) 1 (4) 2 (8)
AE: adverse event; NEC: not elsewhere classified; PN: peripheral neuropathy; RP2D: recommended phase II dose. *Higher-level terms including multiple preferred terms: PN NEC includes peripheral sensory neuropathy,neuropathy peripheral and polyneuropathy;rashes eruptions and exanthems NEC includes rash macular,rash maculo-papular,rash,rash papular, rash generalized.
post-VMP induction was 20%,14 and in a matched-pairs analysis comparing the PETHEMA/GEM05 and VISTA regimens, the CR rate in PETHEMA/GEM05 patients improved from 19% post-induction to 30% overall, following maintenance.32 As shown by the improved responses in >30% of patients during extended treatment with single-agent ixazomib maintenance, patients continued to derive clinical benefit from long-term single-agent ixazomib maintenance, an observation consistent with results from other early-phase ixazomib studies.29,30
The overall safety profile was as expected based on previous studies of ixazomib regimens and MP,24,26,37-41 with most AEs being hematologic and gastrointestinal, which are among the common AEs reported with melphalan and proteasome inhibitors, including ixazomib.42 Dose reductions or discontinuations of any study drug were required in approximately half and a quarter of patients, respectively. The incidence of PN was comparable to that reported in studies of IRd in NDMM,25,30 and appeared lim- ited when compared with that reported with a VMP regi- men incorporating twice-weekly intravenous bortezomib (13% grade ≥3).43 Importantly, >80% of reported PN
events in the present study resolved or improved by study end. As suggested for IRd,26 the all-oral IMP regimen would be expected to be convenient for patients, and the number of planned visits to the clinic for administration of the regimen would be expected to be lower than with the VMP regimen, resulting in a lower patient burden. Our experience with regards to weekly and twice-weekly ixazomib dosing and dose level is in line with experience with IRd,44 which suggests that twice-weekly ixazomib may be associated with some additional toxicity, notably an increase in PN and rash.29,30
Importantly, the continued clinical benefit demonstrated with weekly single-agent ixazomib maintenance therapy was complemented by a favorable tolerability profile. The majority of AEs were observed during the induction period, only 6% of patients discontinued ixazomib maintenance because of AEs, and no on-study deaths occurred during maintenance. The number of patients who continued on long-term single-agent ixazomib maintenance therapy further emphasizes the tolerability of this regimen. Based on the efficacy and tolerability of single-agent maintenance seen in this and other trials, weekly ixazomib is under phase III
1524
haematologica | 2018; 103(9)