Introduction
Materials and methods
Study design and conduct
Primary objectives
Assessments
Results
Patient characteristics
Patient demographics and baseline characteristics
Characteristic | Phase Ib INC280 + buparlisib (all patients) | Phase II INC280 400 mg BID Tab |
---|---|---|
N | 33 | 10 |
Median age, years (range) | 59.0 (27–75) | 48.0 (32–63) |
Sex: male, n (%) | 24 (72.7) | 3 (30.0) |
Race, n (%) | ||
Black | 1 (3.0) | 0 |
Caucasian | 29 (87.9) | 9 (90.0) |
Other | 3 (9.1) | 0 |
Unknown | 0 | 1 (10.0) |
ECOG PS, n (%) | ||
0 | 13 (39.4) | 3 (30.0) |
1 | 18 (54.5) | 5 (50.0) |
2 | 2 (6.1) | 2 (20.0) |
Type of last antineoplastic therapy, n (%) | ||
Medication | 27 (81.8) | 7 (70.0) |
Radiotherapy | 1 (3.0) | 1 (10.0) |
Surgery | 5 (15.2) | 2 (20.0) |
Biomarkers
Patient ID | Best overall response | IHC | FISH | FM NGS | Sequencing data with potential (known or likely) functional significance | ||||
---|---|---|---|---|---|---|---|---|---|
MET copy number | Ratiob | MET Copy Number | Ratioc | Copy number variant (copy number) | Short variant | rearrangement | |||
001 | PD | 32 | 5.59 | 1.19 | 5 | 612.1 | KDR(13), KIT(13), PDGFRA(13) | ATRX, EPHA6, H3F3A, HSP90AA1, TP53 | N/F |
002 | SD | 40 | 11.63 | 4.86 | 9 | 1.0 | CDK4(95), IGF1R(10), MET(9) | ATRX, IDH1, TP53 | N/F |
14d | 0.4d | ||||||||
003 | PD | 117 | 6.56 | 2.51 | 5 | 154.1 | CDK4(63),GLI1(22), MYCN(35), TP53(0) | ATRX, IDH1 | N/F |
004 | PD | 100 | 12.62 | 5.21 | 16 | 1.5 | CDKN2A(0), CDKN2B(0), MET(18) | AR, NF1, NPM1, PIK3R1, PRDM1 | N/F |
005 | PD | 5 | 5.12 | 1.26 | 3 | 1258.1 | PTEN, TERT, TP53 | KEAP1 | |
006 | PD | 112 | 6.38 | 1.85 | 6 | 63.5 | KDR(10), KIT(11), PDGFRA(40), TP53(0) | CDKN2A, FANCL, LZTR1, PIK3CA, TERT | PDGFRA |
6d | 29.4d | ||||||||
007 | SD | 0 | 8 | 1.41 | 4 | 396.3 | EGFR(107) | ARAF, BCL2, CDKN2A | EGFR |
008 | UNKa | 3 | 7.84 | 3.27 | N/A | N/A | EGFR, NF1, PTEN | N/F | |
009 | SD | 0 | 5.12 | 1.08 | 6 | 1258.1 | CDK4(29) | KMT2C, NF1, TERT, TP53 | N/F |
010 | PD | 33 | 20e | 2.5 | 4 | 1205.6 | N/F | APC, ATRX, NF1, PTEN, RB1, TP53 | FAT1 |
Patient ID | Best overall response | IHC | Sequencing data with potential (known or likely) functional significance | ||
---|---|---|---|---|---|
Copy number variant (copy number) | Short variant | Rearrangement | |||
101 | PD | 0 | |||
102 | PD | 50 | CDK4 (78), GLI1 (18), MDM2 (70), SOX2 (7) | PTEN, TERT | |
103 | PD | CDK4 (36), MDM2 (65) | PTEN, TERT | ||
104 | PD | 80 | CDKN2A (0), CDKN2B (0), EGFR (128) | AXL, EGFR, FLT4, KDM5A, TERT | |
105 | PD | 90 | EGFR (61), ERRFI1 (0) | EGFR, PTEN, TERT | CDKN2A, EGFR |
106 | PD | 100 | |||
107 | PD | ARID1A, FGFR2, PTEN, STAG2 | |||
108 | PD | CDKN2A (0), CDKN2B (0), EGFR (110) | EGFR, FAT1, NOTCH1, PTEN, SPTA1, TERT | EGFR | |
109 | PD | 101 | CDKN2A (0), CDKN2B (0) | FGFR4, NF1, PTEN, RB1, TERT, TP53 | NF1 |
110 | PD | 100 | CDKN2A (0), CDKN2B (0), EGFR (59) | EGFR, PTEN, TERT | |
111 | PD | CDKN2A (0), CDKN2B (0), EGFR (46), MDM4 (28), PIK3C2B (30) | EGFR, PTEN, TERT | EGFR | |
112 | PD | 90 | RB1 (0) | NF1, PTEN, TERT | |
113 | PD | 50 | CDKN2A (0), CDKN2B (0), MDM4 (53), PIK3C2B (54) | BRCA2, PTEN, STAG2, TERT | EGFR |
114 | UNK | 80 | CDKN2A (0), CDKN2B (0), EGFR (40) | PTEN, TERT | |
115 | PD | CDKN2A (0) | PTEN | ||
116 | PD | 100 | CDKN2A (0), CDKN2C (0), KDR (6), KIT (6), PDGFRA (6), PTEN (0) | TERT, TP53 | |
117 | PD | 110 | NF1, PIK3CA, PTEN, RB1, TP53 | ||
118 | PD | TP53 (0) | PTEN, TERT | ||
119 | PD | 0 | CDKN2A (0), CDKN2B (0), EGFR (60) | TERT | |
120 | PD | 0 | CCND2 (45), CDK4 (47), EGFR (16), FGF23 (10), FGF6 (10), FRS2 (102), MDM2 (93) | PTEN, TERT | |
121 | PD | 0 | CDKN2A (0), CDKN2B (0), EGFR (45) | LRP1B, PTEN, TERT | EGFR |
122 | PD | 55 | |||
123 | PD | 80 | CDKN2A (0), CDKN2B (0), EGFR (92) | EGFR, TERT | EGFR |
124 | PD | 100 | CDKN2A (0), CDKN2B (0) | PTEN, STAG2, TERT | |
125 | PD | 30 | STK11, TERT | ||
126 | PD | ||||
127 | PD | 65 | PTEN, TERT | ||
128 | SD* | 100 | CDK4 (61), KIT (6), PDGFRA (6) | TP53 | |
129 | PD | 100 | CDKN2A (0), CDKN2B (0), EGFR (125) | EGFR | EGFR |
130 | UNK | ||||
131 | PD | 90 | CDKN2A (0) | BCOR | |
132 | PD | 100 | CDKN2A (0), CDKN2B (0), EGFR (72) | EGFR, GLI1, PTEN, TERT | |
133 | UNK | 0 | CDKN2A (0), CDKN2B (0), EGFR (42), JUN (9), PTEN (0) | EGFR, TERT | EGFR |
Safety
Phase Ib dose escalation
Cohort | Total daily doses INC280 (BID) + buparlisib (QD) | No. of patients treated | No. of patients in the dose-determining set | No. of DLTs in cycle 1 |
---|---|---|---|---|
INC280 capsule formulation | ||||
1 | 200 mg + 50 mg | 5 | 4 | 0 |
2 | 400 mg + 50 mg | 6 | 5 | 1 |
3 | 500 mg + 50 mg | 4 | 3 | 0 |
4 | 500 mg + 80 mg | 6 | 4 | 0 |
INC280 tablet formulation | ||||
5 | 300 mg + 80 mg | 7 | 7 | 1 |
6 | 400 mg + 80 mg | 5 | 4 | 2 |
Phase II
Pharmacokinetics
Cycle 1, Day 15 | INC 200 mg Cap BID + bup 50 mg QD | INC 400 mg Cap BID + bup 50 mg QD | INC 500 mg Cap BID + bup 50 mg QD | INC 500 mg Cap BID + bup 80 mg QD | INC 300 mg Tab BID + bup 80 mg QD | INC 400 mg Tab BID + bup 80 mg QD |
---|---|---|---|---|---|---|
INC280 | ||||||
N | 5 | 4 | 3 | 2 | 3 | 4 |
AUCtau (h*ng/mL) | 6260 | 8580 | 12,800 | 2650 | 12,200 | 15,300 |
Geo-mean (Geo-CV%) | (45) | (79) | (99) | (46) | (33) | (19) |
Cmax (ng/mL) | 1350 | 1850 | 3400 | 494 | 3460 | 3870 |
Geo-mean (Geo-CV%) | (59) | (78) | (114) | (71) | (39) | (55) |
Buparlisib | ||||||
N | 5 | 5 | 3 | 2 | 4 | 4 |
AUCtau (h*ng/mL) | 8210 | 5190 | 6270 | 10,047 | 9950 | 7180 |
Geo-mean (Geo-CV%) | (33) | (50) | (18) | (61) | (13) | (39) |
N | 5 | 5 | 3 | 2 | 5 | 4 |
Cmax (ng/mL) | 680 | 429 | 580 | 779 | 853 | 799 |
Geo-mean (Geo-CV%) | (13) | (38) | (29) | (19) | (28) | (67) |