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J.F. San-Miguel et al.
Figure 1. Phase I study design. PD: progressive disease.
analysis techniques based on Kaplan-Meier estimates. All data
were summarized using descriptive statistics.
Results
Patient disposition and baseline characteristics
A total of 61 patients were enrolled: 11, 34, 10, and 6 to Arms A, B, C, and D, respectively (Tables 1 and 2). All patients received ≥1 dose of any study drug and were included in the safety population; 26 of these patients received ixazomib at the RP2D (Tables 1 and 2). The baseline demographics and disease characteristics of the safety population are shown in Table 1. Seven patients had high-risk cytogenetics; all were enrolled in Arm B.
Dose-limiting toxicities and recommended phase II dose
During phase I, 38 patients (9, 14, 9, and 6 in Arms A, B, C, and D, respectively) were evaluable for assessment of DLTs. Among these patients, 10 (26%) experienced a total of 16 DLTs in cycle 1. All DLTs were grade 3 or grade 4 in intensity.
The RP2D was determined as weekly ixazomib 4.0 mg (days 1, 8, and 15 of 28-day cycles) based on the Arm B MTD, ORR (Online Supplementary Table S4), and observed rates of toxicity across multiple cycles. Baseline characteristics for this RP2D cohort were similar to those for the total study population (Table 1). Detailed descriptions of DLTs and determination of the RP2D can be found in the Online Supplementary Material.
Treatment exposure
At final analysis, 4 patients remained on treatment. Primary reasons for discontinuation were progressive disease, patient withdrawal, and completion of protocol-specified treatment (Table 2). After a median fol-
Table 1. Patient demographics and disease characteristics at baseline (safety population).
Characteristic
Median age, years (range)
Male, n (%) Race, n (%)
White
Black / African American Asian
Other
ECOG performance status, n (%)
0 1 2
ISS stage, n (%) I
II
III
Type of myeloma at initial diagnosis, n (%)
IgG
IgA myeloma
Light-chain disease
Extramedullary disease, n (%)
Total (N=61)
74 (63-90)
23 (38)
57 (93)
1 (2)
1(2) 0
RP2D 4.0 mg Arm B (N=26)
74 (67-84)
10 (38)
High-risk cytogenetics, n (%)†
2 (3)
17 (28) 33 (54) 11 (18)
13 (21)
31 (51) 17 (28)*
36 (59)
20 (33)
5 (8)
6 (10)
7 (12)
4.3 (2.1-14.0)
34 (56)
1 (4)
7 (27) 13 (50) 6 (23)
5 (19) 14 (54) 7 (27)
20 (77)
5 (19)
1 (4)
2 (8)
5 (21)
4.6 (2.4-14.0)
13 (50)
Median β M, mg/L (range) 2
24 (92) 1 (4)
CrCl ≤60 mL/min, n (%)
β2M: beta-2 microglobulin; CrCl: creatinine clearance; ECOG: Eastern Cooperative Oncology Group; Ig: immunoglobulin; ISS: International Staging System; RP2D: recommended phase II dose.The safety population was defined as all patients receiving ≥1 dose of any study drug. *Unknown for two patients; †High-risk cytogenetics includes del17p, t(4:14), and t(14:16) abnormalities.
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haematologica | 2018; 103(9)