Cancer Res Treat.  2015 Oct;47(4):687-696. 10.4143/crt.2014.225.

Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer

• Oh DY
• Doi T
• Shirao K
• Lee KW
• Park SR
• Chen Y
• Yang L
• Valota O
• Bang YJ

• KMID: 2403387
• DOI: http://doi.org/10.4143/crt.2014.225

Abstract

PURPOSE
This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination.
MATERIALS AND METHODS
Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which < or = 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data.
RESULTS
Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months.
CONCLUSION
In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

Keyword

Axitinib; Stomach neoplasms; Cisplatin; Capecitabine; Pharmacokinetics; Clinical trial; Phase I

MeSH Terms

Acute Kidney Injury
Aortic Aneurysm, Abdominal
Appetite
Cisplatin*
Cohort Studies
Disease-Free Survival
Fluorouracil
Humans
Hypertension
Maximum Tolerated Dose
Pharmacokinetics
Stomach Neoplasms*
Stomatitis
Thrombocytopenia
Cisplatin
Fluorouracil

Figure

• 

  Fig. 1. Study design for patients in the pharmacokinetic (PK) subgroup. b.i.d., twice a day; D, day; C, cycle. a)Morning doses on day 1 were administered at the start of cisplatin infusion, b)1,000 mg/m2, c)80 mg/m2.

• 

  Fig. 2. Median plasma concentration-time profiles, semi-log scale, for steady-state axitinib (A), cisplatin (platinum in plasma ultrafiltrate [PUF]) (B), capecitabine (C), and 5-fluorouracil (5-FU) (D). The lower limit of quantification was 0.500 ng/mL for axitinib, 1.00 ng/mL for platinum in PUF, 20.0 ng/mL for capecitabine, and 5.00 ng/mL for 5-FU. Two patients were excluded from median concentration profile plots for platinum in PUF, capecitabine, and 5-FU because cycle 2 (C2), day 1 (D1) pharmacokinetic samples were not collected.

• 

  Fig. 3. Waterfall plot of tumor response for each patient (n=20) with at least one post-baseline scan. Two patients were not evaluable, and one patient had a maximum percent change from baseline of 0.

Reference

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