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

Study Overview
=================
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.

Official Title
-----------------
A Phase 1 Study Of Axitinib In Combination With Cisplatin And Capecitabine In Patients With Advanced Gastric Cancer

Conditions
-----------------
Stomach Neoplasms, Advanced Gastric Cancer

Intervention / Treatment
-----------------
* Drug: axitinib
* Drug: capecitabine
* Drug: cisplatin


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: axitinib<br>* 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.<br>Drug: capecitabine<br>* 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.<br>Drug: cisplatin<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Cycle 1 Dose-limiting Toxicities (DLTs) | 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. | Baseline up to Day 21 of Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin | 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. | 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 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin | 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. | 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 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Capecitabine, Capecitabine's Metabolites and Cisplatin | 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. | 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 Curve From Time Zero to 24 Hours [AUC (0-24)] for Axitinib | 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. | 0 (pre-dose), 1, 2, 3, 4, 6, 8 hrs post-axitinib dose on C1D-1, C1D1 | 
| Area Under the Curve From Time Zero Extrapolated to Infinite Time [AUC (0 - ∞)] for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin | 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. | 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 (t1/2) for Axitinib, Capecitabine, Capecitabine's Metabolites and Cisplatin | 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. | 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 | 
| Apparent Oral Clearance (CL/F) for Axitinib, Capecitabine and Capecitabine's Metabolites | 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. | 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) for Cisplatin | 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. | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start on C1D1, C2D1 | 
| Apparent Volume of Distribution (Vz/F) for Axitinib, Capecitabine and Capecitabine's Metabolites | 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. | 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 (Vz) for Cisplatin | 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. | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 hrs post-cisplatin infusion start on C1D1, C2D1 | 
| Drug Metabolizing Enzyme Genotyping | 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. | Day 1 of Cycle 1 | 
| Percentage of Participants With Objective Response (OR) | 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. | Baseline up to disease progression or withdrawal, assessed on Day 21 of every other cycle starting from Cycle 2 up to Day 784 | 
| Duration of Response (DR) | 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. | Baseline up to disease progression or withdrawal, assessed on Day 21 of every other cycle starting from Cycle 2 up to Day 784 | 
| Progression-Free Survival (PFS) | 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. | Baseline up to disease progression or withdrawal, assessed on Day 21 of every other cycle starting from Cycle 2 up to Day 784 |