Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced

Phase I/II study of refametinib (BAY 86-9766) in combination with gemcitabine in advanced pancreatic cancer

Targeted Oncology

Jean-Luc Van Laethem • Hanno Riess • JacekJassem • Michael Haas • Uwe M Martens • Colin Weekes • MarcPeeters • Paul Ross • John Bridgewater • BohuslavMelichar • Stefano Cascinu • Piotr Saramak • Patrick Michl • David Van Brummelen • Alberto Zaniboni • WollfSchmiegel • SveinDueland • Marius Giurescu • Vittorio L Garosi • Katrin Roth • Anke Schulz • Henrik Seidel • PrabhuRajagopalan • Michael Teufel • Barrett H Childs

Correspondence: Professor Jean-Luc Van Laethem, Erasme University Hospital, CP 572/10, route de Lennik 808, 1070 Brussels, Belgium. E-mail:

Online Resource 1 Gene expression analysis for C-MYC (A) and KAT6A (B) (primary analysis set)

CN, copy number; CAN, copy number alteration; FPKM, fragments per kilobase of exon per million fragments mapped

Online Resource 2 MicroRNA expression analysis in KRAS mutational subgroups (primary analysis set)

aFalse discovery rate = 0.33

Online Resource 3 Primary reason for discontinuation from treatment and summary of treatment-emergent adverse events

n (%) / Patients
(N=80)
Primary reason for treatment discontinuation
AEs associated with clinical disease progression / 4 (5.0)
AEs not associated with clinical disease progression / 31 (38.8)
Clinical disease progression / 2 (2.5)
Radiological disease progression / 26 (32.5)
Consent withdrawn / 8 (10.0)
Switched to another therapy / 1 (1.3)
Physician decision / 2 (2.5)
Death / 6 (7.5)
Any treatment-emergent AE / 80 (100)
Worst grade by CTCAE version 4.0
1 / 0
2 / 7 (8.8)
3 / 39 (48.8)
4 / 18 (22.5)
5 (death)a / 16 (20.0)
Any treatment-emergent SAE / 53 (66.3)
Treatment-emergent AEs leading to dose modificationb / 71 (88.8)
Treatment-emergent AEs leading to permanent discontinuation of study drug / 34 (42.5)
AEs considered related to refametinib / 77 (96.3)
Worst grade by CTCAE version 4.0
1 / 7 (8.8)
2 / 13 (16.3)
3 / 44 (55.0)
4 / 13 (16.3)
5 (death)a / 0
Any treatment-emergent SAE / 19 (23.8)
Treatment-emergent AEs leading to dose modificationb / 57 (71.3)
Treatment-emergent AEs leading to permanent discontinuation of study drug / 23 (28.8)
AEs considered related to gemcitabine / 74 (92.5)
Worst grade by CTCAE version 4.0
1 / 4 (5.0)
2 / 13 (16.3)
3 / 42 (52.5)
4 / 14 (17.5)
5 (death)a / 1 (1.3)
Any treatment-emergent SAE / 21 (26.3)
Treatment-emergent AEs leading to dose modificationb / 60 (75.0)
Treatment-emergent AEs leading to permanent discontinuation of study drug / 15 (18.8)

aIncludes during treatment or within 30 days after the last dose of study treatment was taken; bIncludes interruptions and reductions

AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; SAE,serious adverse event

Online Resource 4 Phase I multiple-dose geometric mean plasma concentration–time profiles for refametinib at cycle 1, day 21 (without gemcitabine) and cycle 1, day 22 (with gemcitabine) (A), and for gemcitabine at cycle 1, day 1 (without refametinib) and cycle 1, day 22 (with refametinib) (B)

BID, twice daily

Online Resource 5 Refametinib and metabolite M-17 geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data atcycle1,day 21 (without gemcitabine) and cycle 1,day 22 (with gemcitabine)

Dose level 1a / Dose level 2b
Cycle 1,day 21
(n=8) / Cycle 1, day 22
(n=8) / Cycle 1, day 21
(n=6) / Cycle 1, day 22
(n=6)
Refametinib
AUC(0–tlast), µg×h/L / 2844 (80) / 2979 (85) / 5186 (58) / 4629 (65)
AUC(0–8), µg×h/L / 2857 (80) / 2838 (85) / 5193 (58) / 4457 (61)
Cmax, µg/L / 489 (66) / 511 (79) / 1046 (37) / 900 (67)
tmax, hc / 3.5 [2–4] / 2.8 [2–4.5] / 2 [1–4] / 1.8 [1–4.5]
Metabolite M-17
AUC(0–tlast), µg×h/L / 498 (28) / 595 (37) / 907 (68) / 850 (96)
AUC(0–8), µg×h/L / 499 (30) / 563 (31) / 909 (67) / 814 (87)
Cmax, µg/L / 82.9 (31) / 100 (30) / 175 (75) / 164 (108)
tmax, hc / 4 [2–4] / 2.5 [2–4.5] / 2 [1–4] / 2 [1.6–8.5]

aRefametinib 30 mg twice daily + gemcitabine 1000 mg/m2; bRefametinib 50 mg twice daily + gemcitabine 1000 mg/m2; cMedian [range]

AUC(0–8) , area under the curve from 0 to 8 hours; AUC(0–tlast), area under the curve from time zero to the last data point above the lower limit of quantification; Cmax, maximum drug concentration; Tmax, time to maximum drug concentration

Online Resource 6 Gemcitabine and metabolite difluorodeoxyuridine geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data atcycle 1,day 1 (without refametinib) and cycle 1,day 22 (with refametinib)

Dose level 1a / Dose level 2b
Cycle 1,day 1
(n=10) / Cycle 1, day 22
(n=7) / Cycle 1,day 1
(n=10) / Cycle 1, day 22
(n=5)
Gemcitabine
AUC(0–tlast), µg×h/L / 2.40 (117) / 4.93 (81) / 2.39 (132) / 2.79 (177)
AUC(0–8), µg×h/L / 1.35 (182)c / 5.89 (69)d / 2.41 (144)e / 2.83 (239)c
Cmax, µg/L / 2.49 (163) / 6.06 (88) / 2.74 (197) / 3.50 (248)
tmax, hf / 0.8 [0.5–1] / 1 [0.5–1] / 1 [0.4–1.5] / 1 [0.5–1.2]
Metabolite difluorodeoxyuridine
AUC(0–tlast), µg×h/L / 198 (38) / 212 (45) / 143 (26) / 146 (41)
AUC(0–8), µg×h/L / 111 (34) / 120 (27) / 88.5 (25) / 81.6 (44)
Cmax, µg/L / 28.0 (22) / 26.2 (19) / 26.6 (25) / 21.5 (46)
tmax, hf / 1 [0.5–2] / 1 [1–2] / 1.2 [0.7–2.2] / 1.2 [0.5–1.5]

aRefametinib 30 mg twice daily + gemcitabine 1000 mg/m2; bRefametinib 50 mg twice daily + gemcitabine 1000 mg/m2; cn=4; dn=5; en=9; fMedian [range]

AUC(0–8), area under the curve from 0 to 8 hours; AUC(0–tlast), area under the curve from time zero to the last data point above the lower limit of quantification; Cmax, maximum drug concentration; Tmax, time to maximum drug concentration

Online Resource 7 Overall change from baseline in CA 19-9 serum level (primary analysis set)

CA 19-9,carbohydrate antigen 19-9

Online Resource 8 Plasma CA 19-9 levels in patients with and without detectable KRAS mutations at baseline (A) and cycle 1, day 29 (B) (primary analysis set)

CA19-9,carbohydrate antigen 19-9