1Department of Internal Medicine, Seoul National University Hospital and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
2Division of Gastroenterology, National Cancer Center Hospital East, Chiba, Japan
3Department of Medical Oncology, Oita University Faculty of Medicine, Yufu, Japan
4Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
5Department of Internal Medicine, Research Institute and Hospital, National Cancer Center, Goyang, Korea
6Pfizer Oncology, San Diego, CA, USA
7Pfizer Oncology, Milan, Italy
Copyright © 2015 by the Korean Cancer Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ying Chen, Liqiang Yang, and Olga Valota are Pfizer employees and hold Pfizer Inc. stock. Yung-Je Bang has performed consulting services for and received honoraria and research funding from Pfizer Inc. Do-Youn Oh, Toshihiko Doi, Kuniaki Shirao, Sook Ryun Park, and Keun-Wook Lee have no conflicts of interest to disclose. This study was sponsored by Pfizer Inc. Medical writing support was provided by Lilliam Poltorack, PharmD, and Joanna Bloom, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc.
Toxicity | Definition |
---|---|
Missed/delayed doses | Miss > 3 consecutive days of capecitabine and/or > 5 consecutive days of axitinib per cycle due to treatment-related toxicity |
Delay > 2 weeks in administration of cycle 2 due to inadequate recovery from toxicity in cycle 1 | |
Hematologic | Grade 4 neutropenia lasting ≥ 7 days |
Grade ≥ 3a) febrile neutropenia | |
Grade ≥ 3a) neutropenic infection | |
Grade 4 thrombocytopenia | |
Grade 3 thrombocytopenia with active bleeding ≥ 0.5 teaspoon/day hemoptysis without resolution to baseline within 7 days | |
Non-hematologic | Grade 2 proteinuria |
Grade 3 or 4 nausea/vomiting and/or diarrhea despite optimal use of antiemetics and antidiarrheals | |
Grade 3 toxicityb) lasting ≥ 7 days | |
Grade 4 toxicity |
Characteristic | Value |
---|---|
Gender (male/female) | 16 (72.7)/6 (27.3) |
Age (yr) | 59.3 (35-72) |
Weight (kg) | 56.6 (44.5-72.1) |
ECOG PS | |
0 | 6 (27.3) |
1 | 16 (72.7) |
Histology | |
Intestinal adenocarcinoma | 5 (22.7) |
Diffuse adenocarcinoma | 4 (18.2) |
Mixed adenocarcinoma | 3 (13.6) |
Other | 10 (45.5) |
Histologic grade | |
Poorly differentiated | 12 (54.5) |
Moderately differentiated | 6 (27.3) |
Well differentiated | 3 (13.6) |
Not assessed | 1 (4.5) |
Prior cancer therapy | |
Surgery | 13 (59.1) |
Radiation | 0 |
Adjuvant systemic | 3 (13.6) |
Metastatic sitesa) | |
Distant lymph node | 11 (50.0) |
Regional lymph node | 8 (36.4) |
Liver | 8 (36.4) |
Peritoneum | 6 (27.3) |
Lung | 1 (4.6) |
Variable |
Axitinib+cisplatin+capecitabine (n=22) |
|
---|---|---|
All grades | Grade 3/4 | |
Adverse eventsa) | ||
Decreased appetite | 20 (90.9) | 4 (18.2) |
Nausea | 17 (77.3) | 2 (9.1) |
Fatigue | 17 (77.3) | 1 (4.5) |
Hypertension | 16 (72.7) | 8 (36.4) |
Stomatitis | 16 (72.7) | 4 (18.2) |
Diarrhea | 12 (54.5) | 2 (9.1) |
Dysphonia | 12 (54.5) | 0 |
Palmar-plantar erythrodysesthesia | 12 (54.5) | 1 (4.5) |
Hypothyroidism | 10 (45.5) | 0 |
Constipation | 9 (40.9) | 0 |
Vomiting | 7(31.8) | 1 (4.5) |
Abdominal pain, upper | 6 (27.3) | 0 |
Abdominal pain | 5 (22.7) | 1 (4.5) |
Headache | 5 (22.7) | 1 (4.5) |
Hiccups | 5 (22.7) | 0 |
Laboratory abnormalitiesa) | ||
Hematology | ||
Anemia | 21 (95.5) | 2 (9.1) |
Thrombocytopenia | 17 (77.3) | 4 (18.2) |
Neutropenia | 17 (77.3) | 8 (36.4) |
Leukopenia | 15 (68.2) | 3 (13.6) |
Lymphopenia | 13 (59.1) | 0 |
Chemistry | ||
Hyperbilirubinemia | 10 (45.5) | 1 (4.5) |
Hypoalbuminemia | 10 (45.5) | 1 (4.5) |
Alkaline phosphatase elevation | 9 (40.9) | 0 |
ALT elevation | 9 (40.9) | 0 |
AST elevation | 7 (31.8) | 2 (9.1) |
Creatinine elevation | 7 (31.8) | 0 1 |
Hyperglycemia | 20 (90.9) | 2 (9.1) |
Hypoglycemiab) | 6 (28.6) | 0 |
Hypocalcemia | 19 (86.4) | 0 |
Hypophosphatemia | 8 (36.4) | 3 (13.6) |
Hyponatremia | 15 (68.2) | 2 (9.1) |
Hypokalemia | 7 (31.8) | 2 (9.1) |
Hyperkalemia | 4 (18.2) | 1 (4.5) |
Hypermagnesemia | 11(50.0) | 3 (13.6) |
Hypomagnesemiac) | 9 (47.4) | 0 |
Variable |
Geometric mean (95% CI) (except where noted) |
|||||
---|---|---|---|---|---|---|
Cmax (ng/mL)a) | AUC24 (ng·hr/mL)a),b) | Tmax (hr)c) | CL/F (L/hr)d) | Vz/F (L)d) | t1/2 (hr)e) | |
Axitinibf) (n=10) | ||||||
Alone | 16.1 (9.94-26.1) | 206 (109-389) | 3.98 (0.00-7.97) | 48.6 (25.7-91.7) | 345 (202-588) | 5.76 (64) |
+Cisplatin/capecitabine | 24.3 (15.0-39.4) | 266 (141-502) | 4.00 (1.00-6.00) | 37.7 (20.0-71.2) | 172 (101-293) | 3.50 (53) |
Cisplating) (+capecitabine) (n=8) | ||||||
Alone | 1,665 (1,407-1,970) | 3,979 (3,578-4,426) | 2.00 (1.00-2.20) | 30.9 (26.0-36.8) | 55.4 (41.1-74.5) | 1.25 (8) |
+Axitinib | 1,865 (1,576-2,207) | 3,990 (3,588-4,438) | 1.02 (0.97-2.33) | 32.5 (27.4-38.6) | 70.3 (52.2-94.7) | 1.61 (48) |
Capecitabine (+cisplatin) (n=8) | ||||||
Capecitabineh) | ||||||
Alone | 5,256 (3,155-8,754) | 14,307 (8,284-24,710) | 2.45 (0.50-4.00) | 218 (118-400) | 191 (89.1-409) | 0.71 (62) |
+Axitinib | 2,275 (1,366-3,789) | 8,229 (4,764-14,211) | 3.12 (0.50-4.02) | 368 (201-677) | 425 (198-911) | 0.89 (58) |
5-FUi) | ||||||
Alone | 220 (132-367) | 665 (382-1,155) | 2.50 (0.50-4.07) | - | - | 1.11 (41) |
+Axitinib | 91.0 (54.6-152) | 493 (283-856) | 2.62 (0.50-4.02) | - | - | 1.05 (48) |
PK, pharmacokinetic; 5-FU, 5-fluorouracil; CI, confidence interval; Cmax, maximum observed plasma concentration; AUC24, area under the curve from time 0 to 24 hours; Tmax, time at which Cmax was observed; CL/F, apparent oral clearance; Vz/F, apparent volume of distribution during elimination phase; t1/2, terminal half-life.
a) Dose normalized to cycle 1, day 1 dose for cisplatin and capecitabine,
b) AUC from time 0 extrapolated to infinite time (AUCinf) for total platinum in plasma ultrafiltrate,
c) Median (range),
d) Systemic clearance (CL) and volume of distribution during elimination phase (Vz) for platinum in plasma ultrafiltrate,
e) Arithmetic mean (% coefficient of variation),
f) One patient was excluded from summary statistics for AUC24, CL/F, Vz/F, and t1/2 because of a non-estimable half-life,
g) PK parameters are for platinum in plasma ultrafiltrate. Two patients were excluded from summary statistics for all PK parameters because PK samples from matching cycle 1 and cycle 2 were not completed. One patient was excluded from summary statistics for AUCinf, CL, Vz, and t1/2 due to non-estimable half-life,
h) Two patients were excluded from summary statistics for all PK parameters because PK samples from matching cycle 1 and cycle 2 were not completed. Two patients were excluded from summary statistics for AUC24, CL/F, Vz/F, and t1/2 due to non-estimable half-life,
i) Two patients were excluded from summary statistics for all PK parameters because PK samples from matching cycle 1 and cycle 2 were not completed. Five patients were excluded from summary statistics for AUC24, CL/F, Vz/F, and t1/2 due to non-estimable half-life.
Toxicity | Definition |
---|---|
Missed/delayed doses | Miss > 3 consecutive days of capecitabine and/or > 5 consecutive days of axitinib per cycle due to treatment-related toxicity |
Delay > 2 weeks in administration of cycle 2 due to inadequate recovery from toxicity in cycle 1 | |
Hematologic | Grade 4 neutropenia lasting ≥ 7 days |
Grade ≥ 3 |
|
Grade ≥ 3 |
|
Grade 4 thrombocytopenia | |
Grade 3 thrombocytopenia with active bleeding ≥ 0.5 teaspoon/day hemoptysis without resolution to baseline within 7 days | |
Non-hematologic | Grade 2 proteinuria |
Grade 3 or 4 nausea/vomiting and/or diarrhea despite optimal use of antiemetics and antidiarrheals | |
Grade 3 toxicity |
|
Grade 4 toxicity |
Characteristic | Value |
---|---|
Gender (male/female) | 16 (72.7)/6 (27.3) |
Age (yr) | 59.3 (35-72) |
Weight (kg) | 56.6 (44.5-72.1) |
ECOG PS | |
0 | 6 (27.3) |
1 | 16 (72.7) |
Histology | |
Intestinal adenocarcinoma | 5 (22.7) |
Diffuse adenocarcinoma | 4 (18.2) |
Mixed adenocarcinoma | 3 (13.6) |
Other | 10 (45.5) |
Histologic grade | |
Poorly differentiated | 12 (54.5) |
Moderately differentiated | 6 (27.3) |
Well differentiated | 3 (13.6) |
Not assessed | 1 (4.5) |
Prior cancer therapy | |
Surgery | 13 (59.1) |
Radiation | 0 |
Adjuvant systemic | 3 (13.6) |
Metastatic sites |
|
Distant lymph node | 11 (50.0) |
Regional lymph node | 8 (36.4) |
Liver | 8 (36.4) |
Peritoneum | 6 (27.3) |
Lung | 1 (4.6) |
Variable | Axitinib+cisplatin+capecitabine (n=22) |
|
---|---|---|
All grades | Grade 3/4 | |
Adverse events |
||
Decreased appetite | 20 (90.9) | 4 (18.2) |
Nausea | 17 (77.3) | 2 (9.1) |
Fatigue | 17 (77.3) | 1 (4.5) |
Hypertension | 16 (72.7) | 8 (36.4) |
Stomatitis | 16 (72.7) | 4 (18.2) |
Diarrhea | 12 (54.5) | 2 (9.1) |
Dysphonia | 12 (54.5) | 0 |
Palmar-plantar erythrodysesthesia | 12 (54.5) | 1 (4.5) |
Hypothyroidism | 10 (45.5) | 0 |
Constipation | 9 (40.9) | 0 |
Vomiting | 7(31.8) | 1 (4.5) |
Abdominal pain, upper | 6 (27.3) | 0 |
Abdominal pain | 5 (22.7) | 1 (4.5) |
Headache | 5 (22.7) | 1 (4.5) |
Hiccups | 5 (22.7) | 0 |
Laboratory abnormalities |
||
Hematology | ||
Anemia | 21 (95.5) | 2 (9.1) |
Thrombocytopenia | 17 (77.3) | 4 (18.2) |
Neutropenia | 17 (77.3) | 8 (36.4) |
Leukopenia | 15 (68.2) | 3 (13.6) |
Lymphopenia | 13 (59.1) | 0 |
Chemistry | ||
Hyperbilirubinemia | 10 (45.5) | 1 (4.5) |
Hypoalbuminemia | 10 (45.5) | 1 (4.5) |
Alkaline phosphatase elevation | 9 (40.9) | 0 |
ALT elevation | 9 (40.9) | 0 |
AST elevation | 7 (31.8) | 2 (9.1) |
Creatinine elevation | 7 (31.8) | 0 1 |
Hyperglycemia | 20 (90.9) | 2 (9.1) |
Hypoglycemia |
6 (28.6) | 0 |
Hypocalcemia | 19 (86.4) | 0 |
Hypophosphatemia | 8 (36.4) | 3 (13.6) |
Hyponatremia | 15 (68.2) | 2 (9.1) |
Hypokalemia | 7 (31.8) | 2 (9.1) |
Hyperkalemia | 4 (18.2) | 1 (4.5) |
Hypermagnesemia | 11(50.0) | 3 (13.6) |
Hypomagnesemia |
9 (47.4) | 0 |
Variable | Geometric mean (95% CI) (except where noted) |
|||||
---|---|---|---|---|---|---|
Cmax (ng/mL) |
AUC24 (ng·hr/mL) |
Tmax (hr) |
CL/F (L/hr) |
Vz/F (L) |
t1/2 (hr) |
|
Axitinib |
||||||
Alone | 16.1 (9.94-26.1) | 206 (109-389) | 3.98 (0.00-7.97) | 48.6 (25.7-91.7) | 345 (202-588) | 5.76 (64) |
+Cisplatin/capecitabine | 24.3 (15.0-39.4) | 266 (141-502) | 4.00 (1.00-6.00) | 37.7 (20.0-71.2) | 172 (101-293) | 3.50 (53) |
Cisplatin |
||||||
Alone | 1,665 (1,407-1,970) | 3,979 (3,578-4,426) | 2.00 (1.00-2.20) | 30.9 (26.0-36.8) | 55.4 (41.1-74.5) | 1.25 (8) |
+Axitinib | 1,865 (1,576-2,207) | 3,990 (3,588-4,438) | 1.02 (0.97-2.33) | 32.5 (27.4-38.6) | 70.3 (52.2-94.7) | 1.61 (48) |
Capecitabine (+cisplatin) (n=8) | ||||||
Capecitabine |
||||||
Alone | 5,256 (3,155-8,754) | 14,307 (8,284-24,710) | 2.45 (0.50-4.00) | 218 (118-400) | 191 (89.1-409) | 0.71 (62) |
+Axitinib | 2,275 (1,366-3,789) | 8,229 (4,764-14,211) | 3.12 (0.50-4.02) | 368 (201-677) | 425 (198-911) | 0.89 (58) |
5-FU |
||||||
Alone | 220 (132-367) | 665 (382-1,155) | 2.50 (0.50-4.07) | - | - | 1.11 (41) |
+Axitinib | 91.0 (54.6-152) | 493 (283-856) | 2.62 (0.50-4.02) | - | - | 1.05 (48) |
Common Terminology Criteria for Adverse Events ver. 3.0 definition, Except alopecia or those adverse events that could be controlled to grade ≤ 2 with appropriate treatment.
Values are presented as number (%) or mean (range). ECOG PS, Eastern Cooperative Oncology Group performance status. Target and non-target.
Values are presented as number (%). ALT, alanine aminotransferase; AST, aspartate aminotransferase. Reported in ≥ 20% of patients, n=21, n=19.
PK, pharmacokinetic; 5-FU, 5-fluorouracil; CI, confidence interval; Cmax, maximum observed plasma concentration; AUC24, area under the curve from time 0 to 24 hours; Tmax, time at which Cmax was observed; CL/F, apparent oral clearance; Vz/F, apparent volume of distribution during elimination phase; t1/2, terminal half-life. Dose normalized to cycle 1, day 1 dose for cisplatin and capecitabine, AUC from time 0 extrapolated to infinite time (AUCinf) for total platinum in plasma ultrafiltrate, Median (range), Systemic clearance (CL) and volume of distribution during elimination phase (Vz) for platinum in plasma ultrafiltrate, Arithmetic mean (% coefficient of variation), One patient was excluded from summary statistics for AUC24, CL/F, Vz/F, and t1/2 because of a non-estimable half-life, PK parameters are for platinum in plasma ultrafiltrate. Two patients were excluded from summary statistics for all PK parameters because PK samples from matching cycle 1 and cycle 2 were not completed. One patient was excluded from summary statistics for AUCinf, CL, Vz, and t1/2 due to non-estimable half-life, Two patients were excluded from summary statistics for all PK parameters because PK samples from matching cycle 1 and cycle 2 were not completed. Two patients were excluded from summary statistics for AUC24, CL/F, Vz/F, and t1/2 due to non-estimable half-life, Two patients were excluded from summary statistics for all PK parameters because PK samples from matching cycle 1 and cycle 2 were not completed. Five patients were excluded from summary statistics for AUC24, CL/F, Vz/F, and t1/2 due to non-estimable half-life.