Page 38 - 2018_12-Haematologica-web

E. Campo et al.
Table 3. Overview of clinical evidence from phase 2/3 trials for novel treatments in patients with TP53 aberrations.
Study/treatment Sponsors
RESONATE-17:
A phase 2, open-label, multicenter study
of ibrutinib in patients with R/R CLL/SLL
and del(17)p Ibrutinib 420 mg OD
NCT01744691
Pharmacyclics LLC. Janssen Research
& Development, LLC
RESONATE: a phase 3, open-label, multicenter study of ibrutinib versus
ofatumumab in patients with previously treated CLL/SLL
Ibrutinib 420 mg
OD versus ofatumumab
NCT01578707
Pharmacyclics LLC. Janssen Research & Development, LLC
Study 101-08: a phase 2 study of idelalisib plus rituximab in elderly patients with untreated CLL or SLL
Idelalisib 150 mg BD plus rituximab
NCT01203930 Gilead Sciences
Study 116: a randomized, double-blind, placebo- controlled study of idelalisib in combination with rituximab for previously treated CLL
Idelalisib 150 mg
BD plus rituximab versus placebo plus rituximab
NCT01539512 Gilead Sciences
Population
Adult patients with previously treated del(17p) CLL or SLL (n=144) Median age (range): 64 (57-72)
ECOG score: 0: 49 (34%) ≥1: 95 (66%)
Median prior regimens (IQR): 2 (1–3)
Adult patients with R/R CLL/SLL (n=391)
Ibrutinib arm. Median age (range): 67 (30–86)
ECOG score: 0: 79 (41%) 1: 116 (59%)
Median prior regimens: 3 (1–12) Ofatumumab arm. Median age (range): 67 (37–88)
ECOG score:
0: 80 (41%)
1:116 (59%)
Median prior regimens: 2 (1–13)
Older patients
(≥65 years) with previously untreated CLL or SLL (n=64) Median age (range): 71 (65–90)
ECOG score/Karnofsky status: not reported Median prior regimens: 0
Adult patients with R/R CLL not eligible
for cytotoxic
agents (n=220);
PD within 24 months of last treatment Idelalisib + rituximab Median age (range): 71 (48–90)
ECOG score/Karnofsky status: not reported Median prior regimens: 3 (1–12)
Placebo + rituximab arm. Median age (range):
71 (47–92)
ECOG score/Karnofsky
status: not reported Median prior regimens: 3 (1–9)
TP53 aberrations at baseline
del(17p) 144/144 (100%)
TP53 mutations 107/116 (92%)
del(17p) 127/391 (32%)
Overall response in del(17p)/TP53
mutated population
ORR in del(17p) patients was 64% by independent review and 83% by investigator assessment (prespecified primary analysis, median
11.5 months follow-up)
ORR in del(17p) patients treated with ibrutinib: 89%
ORR in del(17p) patients treated with ofatumumab: 20% (median follow-up 19 months)
PFS in del(17p)/ TP53 mutated
population
Median PFS (investigator- assessed) not reached
at a median follow-up
of 11.5 months (prespecified primary analysis)
Median PFS in del(17p) and/or TP53 patients not reached at
19 months follow-up
in patients treated with ibrutinib
Median PFS in del(17p) and/or TP53 patients
5.8 months in patients treated with ofatumumab
Patients with both del17p and TP53 mutation (n=38) had worse
PFS compared with patients with neither of these abnormalities (n=68) (P=0.0381)
at a median follow-up of 19 months
Median PFS in del(17p) and/or TP53 patients not reached after a median 22.4 months on treatment
Median PFS in del(17p) and/or TP53 patients treated with idelalisib plus rituximab:
not reached
Median PFS in del(17p)
and/or TP53 patients treated with rituximab: 4.0 months (second interim analysis)
OS in del(17p)/ TP53 mutated population
Median OS not reached at
11.5 months (prespecified primary analysis)
Median OS in del(17p) or TP53 patients not reached
at 19 months follow-up in patients treated with ibrutinib
Median OS not reported in del(17p) or TP53 patients treated with ofatumumab
Median OS in del(17p) and/or TP53 patients not reached after a median of
22.4 months on treatment
Not reported in del(17p) and/or TP53 patients
Safety Reference (experimental arm,
overall population)
Grade 3–5 AE occurring (21) in >5% of patients:
Neutropenia (18%)
Pneumonia (13%)
Hypertension (13%)
Anemia (10%) Thrombocytopenia (8%) Atrial fibrillation (6%) (24-month extended analysis)
Grade 3–5 AE occurred
in 56% of patients
treated with idelalisib
+ rituximab and 48% treated with placebo + rituximab Grade 3–5 AE occurred
in >5% of patients: Idelalisib + rituximab Neutropenia (34%) Thrombocytopenia (10%) Placebo + rituximab Neutropenia (22%) Thrombocytopenia (16%) Anemia (14%) (overall study population)
Grade 3–5 AE occurred (22) in 89.1% of patients.
Grade 3–5 AE occurred
in >5% of patients:
Diarrhea and/or
colitis (42%)
Pneumonia (19%) (overall study population)
Grade 3–5 AE occurred (19, 23) in 56% of patients
treated with idelalisib
+ R and 48% treated
with placebo + rituximab Grade 3–5 AE occurred
in >5% of patients: Idelalisib + rituximab arm: Neutropenia (34%) Thrombocytopenia (10%) Placebo + rituximab arm: Neutropenia (22%) Thrombocytopenia (16%) Anemia (14%)
(overall study population)
continued on the next page
del(17p) only: 2/64 (3.1%)
TP53 mutation only: 3/63 (4.7%)
Either del(17p) or TP53 mutation: 9/64 (14.1%)
Both del(17p) and TP53 mutation: 4/64 (6.3%)
del(17p) and/or TP53 mutations
Idelalisib + rituximab 46/110 (42%)
Rituximab: 50/110 (45%)
ORR in either del(17p) or TP53 mutation: 100%
ORR in del(17p) and/or TP53 patients treated with Idelalisib plus rituximab: 77%
ORR in del(17p) and/or TP53 patients treated with rituximab: 15% (second interim analysis, median exposure 5 months with idelalisib,
4 months with rituximab)
(18, 99)
1962
haematologica | 2018; 103(12)