Page 121 - 2018_09-Mondo

IMP phase I/II study in transplant-ineligible NDMM
Table 2. Ixazomib dose received and primary reason for discontinuation by study arm (safety population).
Arm A Arm B Arm C Arm D Total*
Ixazomib dose received, mg
Patients,N
Primary reason for discontinuation, n (%)
PD
AEs
Patientwithdrawal
Completion of protocol-specified treatment Unsatisfactory therapeutic response Preference for immunomodulatory
therapy given the PR
Studyterminatedbysponsor
3.0
3.7 3.0 4.0 5.5 3.0 4.0 4.0 (RP2D)
7 4 3 26 5 6 4 6 61
5(71) 2(50) 2(67) 11(42) 3(60) 3(50) 1(25) 2(33) 29(48) 0 0 0 8(31) 2(40) 0 1(25) 2(33) 13(21)
1(14) 2(50) 0
2(8) 2 (8) 1 (4) 1 (4)
1(4)
0 0 1(25) 0 6(10) 0 0 1(25) 1(17) 6(10) 01(17)002(3) 00001(2)
0 2(33) 0 1(17) 4(7)
1 (14) 0 0 0 0 0
1 (33) 0
0
0 0 0
AE: adverse event; PD: progressive disease; PR: partial response; RP2D: recommended phase II dose. *Discontinuation due to – PD: 8 during induction, 21 during maintenance; AEs: 11 during induction, 2 during maintenance; patient withdrawal: 3 during induction, 3 during maintenance; completion of protocol-specified treatment: all 6 during induction; unsatisfactory therapeutic response: both during induction; preference for immunomodulatory therapy: during induction; study terminated: all 4 during maintenance.
low up for OS of 43.6 months, patients had received a median of 16 cycles of ixazomib (12.5 cycles in the RP2D cohort; Online Supplementary Table S2). A total of 36 patients entered the maintenance phase (n=13 at the RP2D), and received a median number of maintenance cycles of 12, with a maximum duration of ixazomib treat- ment of 58 months (Online Supplementary Table S2). Thirteen patients (36%) remained on maintenance thera- py for ≥13 cycles (≥1 year), and 5 patients (14%) remained on maintenance for ≥25 cycles (≥2 years). Mean relative dose intensity over the whole study for ixazomib was 82.8% (87.1% at the RP2D), and ≥90% for both melpha- lan and prednisone (Online Supplementary Table S2).
Pharmacokinetic analyses are shown in Online Supplementary Table S3.
Efficacy
Fifty-three patients were evaluable for response, including 23 at the RP2D. Among response-evaluable patients, the confirmed CR+VGPR rate at the end of study was 48%, including 28% ≥CR (Table 3). The confirmed ORR at end of study was 66%, with 86% of patients achieving a ≥50% reduction in serum M-protein. In both the total population and at the RP2D, 48% of patients demonstrated a 100% reduction in their serum M-protein (Table 3). Median time to ≥VGPR and CR was 3.7 and 11.6 months, respectively (Table 4). Of the 7 high-risk patients, 1 patient achieved a CR and 3 patients achieved a PR; 2 patients were not evaluable for response.
Responses deepened during maintenance with single-agent ixazomib: in 11/32 (34%) response-evaluable patients overall (CR to sCR in 2 patients; VGPR to sCR in 5 patients; VGPR to CR in 3 patients; and PR to VGPR in 1 patient); and in 4/12 (33%) response-evaluable patients who received the RP2D (CR to sCR in 1 patient; VGPR to sCR in 2 patients; and PR to VGPR in 1 patient). The confirmed CR rate was 13% after induction, rising to 28% at the end of treatment (Table 3).
Thirteen of 53 (24%) response-evaluable patients were assessed for minimal residual disease (MRD) by flow cytometry, 5 of whom were in the RP2D cohort. Of these 13 patients, 12 had a best confirmed response of ≥CR and one had a best confirmed response of VGPR. MRD results
in 9 of the 12 patients with ≥CR (75%) (3 at the RP2D) were found to be negative. Therefore, in the total study population, 9 of 53 response-evaluable patients (17%; 3 of 23 [13%] in the RP2D cohort) were MRD-negative.
Evaluation of time-to-event data demonstrated the durability of responses (Table 4). Median time to best response (≥PR) was 4.6 months in the total study population and at the RP2D. Median duration of response was 22.6 months overall and 25.4 months in patients achieving ≥VGPR (Table 4). Median PFS was 22.1 months overall and 18.4 months at the RP2D after median follow up for PFS of 18.0 and 10.2 months, respectively (Figure 2A and Table 4). For patients who entered the maintenance phase, median PFS was 27.5 months (38.7 months at the RP2D) (Figure 2A and Table 4); median PFS for standard-risk patients who entered the maintenance phase was similar, at 28.8 months (38.7 months at the RP2D). Median OS was 54.4 months overall and not reached at the RP2D after median follow up of 43.6 months in the total population and 48.6 months in Arm B, respectively (Figure 2B and Table 4).
Safety
Safety profiles during induction and maintenance are shown in Table 5, and the most common toxicities are shown in Table 6. The most common grade ≥3 AEs (≥10% incidence) were thrombocytopenia, neutropenia, lymphopenia, leukopenia, anemia, and diarrhea (Table 6). Hematologic toxicities were less common at the RP2D than in the total population. The most common SAE was pneumonia (n=6 [10%]; n=2 [8%] at the RP2D). The only AE to result in discontinuation of study treatment in more than one patient was thrombocytopenia (n=3, 5%). None of the 3 on-study deaths (all in the RP2D cohort; attributed to pneumonia, septic shock, and worsening of end-stage MM, respectively) were considered by investigators to be related to study treatment.
There was a limited incidence of new-onset toxicities during single-agent ixazomib maintenance compared with IMP induction. Any-grade AEs with a ≥15% difference between patients who entered the maintenance period and those who did not were thrombocytopenia (64% for
haematologica | 2018; 103(9)
1521