Study Of Axitinib In Combination With Cisplatin And Capecitabine In Patients With Advanced Gastric Cancer

• ClinicalTrials.gov Identifier: NCT00842244
• Recruitment Status: Completed
• First Posted: February 12, 2009
• Results First Posted: March 26, 2012
• Last Update Posted: November 27, 2013
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: February 11, 2009
• First Posted Date: February 12, 2009
• Results First Submitted Date: February 25, 2012
• Results First Posted Date: March 26, 2012
• Last Update Posted Date: November 27, 2013
• Study Start Date: April 2009
• Actual Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 17, 2013)

Number of Participants With Cycle 1 Dose-limiting Toxicities (DLTs) [ Time Frame: Baseline up to Day 21 of Cycle 1 ]

DLT = Grade (GR) 2 proteinuria; GR3 nonhematological toxicity (NHT) (excluding alopecia and those that can be controlled with appropriate treatment) for greater than or equal to (>=)7 days, GR3 thrombocytopenia with active bleeding; GR >=3 febrile neutropenia (NP) or NP infection; GR 3 or 4 nausea, vomiting or diarrhea despite anti-emetics, anti-diarrheals; GR4 NHT, thrombocytopenia, NP for >=7 days; >= 1/2 teaspoon per day hemoptysis; any treatment related toxicity with >3 consecutive days of capecitabine or 5 consecutive days of axitinib missed doses per cycle; delayed toxicity recovery >14 days.

Original Primary Outcome Measures (submitted: February 11, 2009)

• determination of the safety profile of the combination [ Time Frame: 10 months ]
• determination of the maximum tolerated dose [ Time Frame: 10 months ]

Current Secondary Outcome Measures (submitted: October 17, 2013)

• Maximum Observed Plasma Concentration (Cmax) for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on Cycle 1 (C1) Day -1 (D-1), C1D1; 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 hrs post-capecitabine dose C1D1, C2D1; 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start C1D1, C2D1 ]
  Cmax for axitinib in absence of chemotherapy (axitinib alone) was evaluated on Cycle 1 Day -1 and in combination with chemotherapy on Cycle 1 Day 1. Cmax for cisplatin (assessed by estimating total platinum in plasma ultrafiltrate), capecitabine and capecitabine's metabolites (5-fluorouracil [5-FU], 5-deoxy-5-fluorouridine [5-DFUR] and 5-deoxy-5-fluorocytidine [5-DFC]) in presence of steady-state axitinib were evaluated on Cycle 1 Day 1 and in absence of axitinib (cisplatin/capecitabine alone) on Cycle 2 Day 1. Results for axitinib were normalized to axitinib 5 mg dose, results for capecitabine and its metabolites (5-FU, 5-DFUR and 5-DFC) were normalized to Cycle 1 Day 1 capecitabine dose and results for cisplatin were normalized to Cycle 1 Day 1 cisplatin dose.
• Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on C1D-1, C1D1; 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 hrs post-capecitabine dose C1D1, C2D1; 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start C1D1, C2D1 ]
  Tmax for axitinib in absence of chemotherapy (axitinib alone) was evaluated on Cycle 1 Day -1 and in combination with chemotherapy on Cycle 1 Day 1. Tmax for cisplatin (assessed by estimating total platinum in plasma ultrafiltrate), capecitabine and capecitabine's metabolites (5-FU, 5-DFUR and 5-DFC) in presence of steady-state axitinib were evaluated on Cycle 1 Day 1 and in absence of axitinib (cisplatin/capecitabine alone) on Cycle 2 Day 1.
• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Capecitabine, Capecitabine's Metabolites and Cisplatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 hrs post-capecitabine dose C1D1, C2D1; 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start C1D1, C2D1 ]
  Area under the plasma concentration time-curve from zero to the last measurable concentration (AUClast). AUClast for cisplatin (assessed by estimating total platinum in plasma ultrafiltrate), capecitabine and capecitabine's metabolites (5-FU, 5-DFUR, 5-DFC) in presence of steady-state axitinib were evaluated on Cycle 1 Day 1 and in absence of axitinib (cisplatin/capecitabine alone) on Cycle 2 Day 1. Results for capecitabine and its metabolites (5-FU, 5-DFUR and 5-DFC) were normalized to Cycle 1 Day 1 capecitabine dose and results for cisplatin were normalized to Cycle 1 Day 1 cisplatin dose.
• Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] for Axitinib [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on C1D-1, C1D1 ]
  AUC (0-24) = Area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours. AUC (0-24) for axitinib in absence of chemotherapy (axitinib alone) was evaluated on Cycle 1 Day -1 and in combination with chemotherapy on Cycle 1 Day 1. Results for axitinib were normalized to axitinib 5 mg dose.
• Area Under the Curve From Time Zero Extrapolated to Infinite Time [AUC (0 - ∞)] for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on C1D-1, C1D1; 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 hrs post-capecitabine dose C1D1, C2D1; 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start C1D1, C2D1 ]
  AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) extrapolated to infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞) for axitinib in absence of chemotherapy (axitinib alone) was evaluated on Cycle 1 Day -1 and in combination with chemotherapy on Cycle 1 Day 1. AUC (0 - ∞) for cisplatin (assessed by estimating total platinum in plasma ultrafiltrate), capecitabine and capecitabine's metabolites (5-FU, 5-DFUR and 5-DFC) in presence of steady-state axitinib were evaluated on Cycle 1 Day 1 and in absence of axitinib (cisplatin/capecitabine alone) on Cycle 2 Day 1. Results for axitinib were normalized to axitinib 5 mg dose, results for capecitabine and its metabolites (5-FU, 5-DFUR and 5-DFC) were normalized to Cycle 1 Day 1 capecitabine dose and results for cisplatin were normalized to Cycle 1 Day 1 cisplatin dose.
• Plasma Decay Half-Life (t1/2) for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on C1D-1, C1D1; 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 hrs post-capecitabine dose C1D1, C2D1; 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start C1D1, C2D1 ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half life for axitinib in absence of chemotherapy (axitinib alone) was evaluated on Cycle 1 Day -1 and in combination with chemotherapy on Cycle 1 Day 1. Plasma decay half life for cisplatin (assessed by estimating total platinum in plasma ultrafiltrate), capecitabine and capecitabine's metabolites (5-FU, 5-DFUR and 5-DFC) in presence of steady-state axitinib were evaluated on Cycle 1 Day 1 and in absence of axitinib (cisplatin/capecitabine alone) on Cycle 2 Day 1.
• Apparent Oral Clearance (CL/F) for Axitinib, Capecitabine and Capecitabine's Metabolites [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on C1D-1, C1D1; 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 hrs post-capecitabine dose on C1D1, C2D1 ]
  Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Clearance is defined as the volume of blood from which drug can be completely removed per unit of time. CL/F for axitinib in absence of chemotherapy (axitinib alone) was evaluated on Cycle 1 Day -1 and in combination with chemotherapy on Cycle 1 Day 1. CL/F for capecitabine in presence of steady-state axitinib was evaluated on Cycle 1 Day 1 and in absence of axitinib (capecitabine alone) on Cycle 2 Day 1.
• Clearance (CL) for Cisplatin [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start on C1D1, C2D1 ]
  Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. It is defined as the volume of blood from which drug can be completely removed per unit of time. Clearance for cisplatin (assessed by estimating total platinum in plasma ultrafiltrate) in presence of steady-state axitinib was evaluated on Cycle 1 Day 1 and in absence of axitinib (cisplatin alone) on Cycle 2 Day 1.
• Apparent Volume of Distribution (Vz/F) for Axitinib, Capecitabine and Capecitabine's Metabolites [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on C1D-1, C1D1; 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 hrs post-capecitabine dose on C1D1, C2D1 ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vz/F is influenced by the fraction absorbed. Vz/F for axitinib in absence of chemotherapy (axitinib alone) was evaluated on Cycle 1 Day -1 and in combination with chemotherapy on Cycle 1 Day 1. Vz/F for capecitabine in presence of steady-state axitinib was evaluated on Cycle 1 Day 1 and in absence of axitinib (capecitabine alone) on Cycle 2 Day 1.
• Volume of Distribution (Vz) for Cisplatin [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start on C1D1, C2D1 ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Clearance for cisplatin (assessed by estimating total platinum in plasma ultrafiltrate) in presence of steady-state axitinib was evaluated on Cycle 1 Day 1 and in absence of axitinib (cisplatin alone) on Cycle 2 Day 1.
• Drug Metabolizing Enzyme Genotyping [ Time Frame: Day 1 of Cycle 1 ]
  Genetic variants of uridine diphosphate (UDP)- glucuronosyl transferase 1A1 (UGT1A1) gene which were assessed for genotyping included UGT1A1*60, UGT1A1-3156, UGT1A1 Promoter thymine adenine (TA) repeat (UGT1A1*28, UGT1A1*36, UGT1A1*37), UGT1A1*6 and UGT1A1*27.
• Percentage of Participants With Objective Response (OR) [ Time Frame: Baseline up to disease progression or withdrawal, assessed on Day 21 of every other cycle starting from Cycle 2 up to Day 784 ]
  Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed response are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR are those with disappearance of all target lesions. PR are those with at least 30 percent (%) decrease in sum of the longest dimensions of target lesions taking the baseline sum of the longest dimensions as a reference.
• Duration of Response (DR) [ Time Frame: Baseline up to disease progression or withdrawal, assessed on Day 21 of every other cycle starting from Cycle 2 up to Day 784 ]
  Time in months from the first documentation of objective tumor response to objective tumor progression or death due to any cause. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 30.4. DR was calculated for the subgroup of participants with a confirmed objective tumor response. CR = disappearance of all target lesions. PR = at least 30% decrease in sum of the longest dimensions of target lesions taking the baseline sum of the longest dimensions as a reference.
• Progression-Free Survival (PFS) [ Time Frame: Baseline up to disease progression or withdrawal, assessed on Day 21 of every other cycle starting from Cycle 2 up to Day 784 ]
  Time in months from start of study treatment to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.4. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was "Death"). PD was a>=20% increase in sum of the longest dimensions of target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of 1 or more new lesions.

Original Secondary Outcome Measures (submitted: February 11, 2009)

• pharmacokinetic analysis [ Time Frame: 12 months ]
• anti-tumor activity [ Time Frame: 15 months ]

Current Other Pre-specified Outcome Measures (submitted: October 17, 2013)

Maximum Tolerated Dose (MTD) of Axitinib (AG-013736) in Combination With Cisplatin and Capecitabine [ Time Frame: Baseline up to Day 21 of Cycle 1 ]

MTD = highest dose at which no more than 30 percent (%) of 12 participants experience DLT during Cycle 1. DLT = GR2 proteinuria; GR3 NHT (excluding alopecia and those that can be controlled with appropriate treatment)for >=7 days, GR3 thrombocytopenia with active bleeding; GR >=3 febrile NP/NP infection; GR 3 or 4 nausea, vomiting or diarrhea despite anti-emetics, anti-diarrheals; GR4 NHT, thrombocytopenia, NP for >=7 days; >= 1/2 teaspoon per day hemoptysis; any treatment-related toxicity with >3 consecutive days of capecitabine or 5 consecutive days of axitinib missed doses per cycle; delayed toxicity recovery >14 days.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Of Axitinib In Combination With Cisplatin And Capecitabine In Patients With Advanced Gastric Cancer
• Official Title: A Phase 1 Study Of Axitinib In Combination With Cisplatin And Capecitabine In Patients With Advanced Gastric Cancer
• Brief Summary: The purpose of this study is to determine the safe and tolerable dose of axitinib given together with cisplatin and capecitabine in patients with advanced gastric cancer who have not received prior chemotherapy for their advanced cancer.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Stomach Neoplasms
• Advanced Gastric Cancer

Intervention

• Drug: axitinib
  Twice daily oral dose of axitinib continuously depending upon side effects observed. Starting dose is 5mg twice daily. Each 21 day cycle is repeated until progression of disease or unacceptable toxicity is observed.
• Drug: capecitabine
  Given orally twice daily for 14 days followed by 7 days of drug free period. Starting dose is 1000mg/m^2 twice daily. Each 21 day cycle is repeated until progression of disease or unacceptable toxicity is observed.
• Drug: cisplatin
  Given through a vein on Day 1 of every 21 days. Each 21 day cycle is repeated until progression of disease or unacceptable toxicity is observed. The starting dose is 80 mg/m^2 on day 1.

Study Arms

Experimental: A

Interventions:

• Drug: axitinib
• Drug: capecitabine
• Drug: cisplatin

• Publications *: Oh DY, Doi T, Shirao K, Lee KW, Park SR, Chen Y, Yang L, Valota O, Bang YJ. Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer. Cancer Res Treat. 2015 Oct;47(4):687-96. doi: 10.4143/crt.2014.225. Epub 2015 Feb 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 23, 2012): 22
• Original Estimated Enrollment (submitted: February 11, 2009): 30
• Actual Study Completion Date: October 2012
• Actual Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• confirmed diagnosis of stomach cancer
• advanced stomach cancer of stage IV
• adequate blood chemistry, blood counts and kidney function
• willing to participate to study requirements and sign an informed consent document

Exclusion Criteria:

• prior chemotherapy for stomach cancer in its advanced stage
• excessive toxicities related to prior therapies
• pregnant or breastfeeding patients

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, Korea, Republic of

Administrative Information

• NCT Number: NCT00842244
• Other Study ID Numbers: A4061055
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: October 2013