Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00816634 |
| Other study ID # |
2008-07-059 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
December 30, 2008 |
| Last updated |
April 27, 2017 |
| Start date |
October 2008 |
| Est. completion date |
December 2018 |
Study information
| Verified date |
April 2017 |
| Source |
Samsung Medical Center |
| Contact |
Young-Hyuck Im, MD, PhD |
| Phone |
82-2-3410-3445 |
| Email |
imyh00[@]skku.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Until today, the 5-FU/cisplatin combination is the reference regimen with 30-45% response
rates, which is most commonly used to treat patients with metastatic, recurrent or locally
advanced, unresectable squamous cell carcinoma of the esophagus. Because the classical dose
schedule of this two-drug combination is cisplatin 100 mg/m2 day 1 and 5-FU 1000 mg/m2/day
continuous infusion for 96-120 hr, prolonged administration time and mucosal toxicity are
inconvenient to the patients with the aim of palliation. Capecitabine, which is oral prodrug
of 5-FU and mimic continuously-infused 5-FU, is being investigated in phase I, II and III
trials for the treatment of gastric, gastroesophageal, and esophageal cancers, primarily in
the first-line metastatic setting. In our experience, capecitabine plus cisplatin
combination (XP) as a first-line treatment for 45 patients with advanced or recurrent
esophageal squamous cell carcinoma demonstrated a promising anti-tumor activity with 57% of
response rate and showed tolerable toxicity with convenience.
Paclitaxel has been also investigated as monotherapy and in combination with cisplatin in
patients with advanced esophageal cancer. A Dutch phase II study demonstrated that
paclitaxel combination with carboplatin had shown an encouraging confirmed response rate of
59% with 51 patients with resectable esophageal cancer in neoadjuvant setting. Another Dutch
phase II study showed 43% of response rate including 4% of CR with 8 months of response
duration when paclitaxel plus cisplatin administration was given for patients with
metastatic esophageal cancer. Although recently first-line palliative chemotherapy regimen
in esophageal cancer has been investigated, many trials have failed to show superiority to
5-FU/cisplatin combination. Since we considered that XP or XT is more effective and
convenient chemotherapy regimen than 5-FU/cisplatin, this randomized phase II study was
planned to compare XP with XT in terms of efficacy and tolerability.
Description:
1. Introduction and Study Rationale
1.1 Esophageal squamous cell carcinoma Esophageal cancer is the seventh most common
cancer in Korea, with almost 400,000 new patients diagnosed annually worldwide. There
are large variations in the predominant histological type throughout the world but the
majority of worldwide esophageal cancers are squamous cell carcinoma arising from the
upper and middle thirds of the esophagus. Esophageal cancer is a highly virulent
disease with a five-year survival rate of 10-15% . Metastatic esophageal carcinoma is
an incurable disease with median survival duration of 6 to 8 months .
1.2 5-FU plus Cisplatin (FP) combination chemotherapy Cytotoxic chemotherapy has been
used to control tumor growth, improve quality of life and prolong survival although a
survival advantage for chemotherapy over best supportive care alone in patients with
metastatic cancer of the esophagus has not been proven in randomized trials. Although
there is no standard chemotherapy regimen for metastatic esophageal cancer, various
kinds of chemotherapy regimens have been used to alleviate symptoms caused by cancer
and prolong survival and improve quality of life. Various phase-II trials have been
performed to evaluate the effect of such chemotherapy. The activity of conventional
single agent chemotherapy has been studied for cisplatin, 5-FU and mitomycin, which
induced response rates of 15-30% . In most of these studies, the chemotherapy regimen
consisted of a combination of cisplatin with another agent such as 5-FU or etoposide
for both squamous cell carcinoma and adenocarcinoma. The most commonly used
chemotherapy regimen for patients with advanced esophageal cancer is a combination of
5-FU and cisplatin, with response rates ranging from 15% to 45%, however, the effect on
survival remained undetermined.
1.2 Capecitabine for esophageal cancer Capecitabine is a novel, orally administered
fluoropyrimidine carbamate that is absorbed readily by the gastrointestinal tract and
is metabolized by the liver, where it is converted initially to 5
-deoxy-5-fluorocytidine (5 -DFCR) and subsequently, to 5 -deoxy-5-fluorouridine (5
-DFUR). Designed to mimic continuous intravenous (CIV) 5-FU, oral capecitabine
predominantly concentrates in tumor tissue . Capecitabine currently is approved as a
single agent for the adjuvant treatment of stage III colon cancer, as first-line
treatment for metastatic colorectal cancer, and for metastatic breast cancer both as a
single agent for patients and in combination with docetaxel. Whether oral
fluoropyrimidines may be appropriately substituted, therefore making the therapy less
burdensome to the patient and reducing the need for infusion catheters, is not fully
investigated In patients with advanced esophagogastric cancer, capecitabine
combinations have generally shown good antitumor activity and highlight the potential
of capecitabine as a replacement of infusional 5-FU . Capecitabine has been
investigated in combination with cisplatin and docetaxel in phase II trials in patients
with advanced esophageal cancer with observed response rates of 47.1% and 46%,
respectively . In a recent phase III trial comparing the efficacy of
capecitabine/cisplatin (XP) versus FP in advanced gastric cancer, XP was not inferior
to FP, in terms of progression-free survival (PFS), overall survival (OS), and response
rate (RR) . In our experience, the combination of capecitabine and cisplatin for
esophageal cancer showed encouraging response rate (59%) with tolerable toxicities and
convenience.
1.3 Paclitaxel for esophageal cancer Paclitaxel in combination with cisplatin has shown
favorable results for advanced esophageal carcinoma . A recent phase II study of
bi-weekly administration of paclitaxel and cisplatin in 51 patients resulted in
complete response in 4%, partial response in 39%, stable disease in 43% and progressive
disease in 14% of patients, and a one-year survival of 43% . Several phase II trials
have assessed combinations of taxanes (paclitaxel and docetaxel) and cisplatin and
other agents, with response rates of 40-56% .
1.4 Capecitabine plus Paclitaxel combination for esophageal cancer Capecitabine in
combination with docetaxel has greater efficacy than single-agent docetaxel; the
combination increased survival significantly compared with single-agent docetaxel (14.5
v 11.5 months) in patients with metastatic breast cancer who experienced disease
progression after anthracycline therapy . The most common treatment-related adverse
events (TRAEs), with capecitabine 1,250 mg/m2 bid and docetaxel 75 mg/m2 were alopecia,
hand-foot skin reaction (HFS), nausea, and fatigue. Neutropenia (15%) and HFS (11%)
were the only grade 3 or 4 TRAEs that occurred in more than 10% of patients. In this
trial the tolerable delivered dose of capecitabine for most patients was 950 mg/m2 bid
for 14 days. Lorenzen et al. treated 24 patients with capecitabine at a dose of 1000
mg/m2 twice daily on Days 1 through 14 and docetaxel 75 mg/m2 on Day 1 of 3-week
cycles. The RR was 46% and median survival was 15.8 months. However, the toxicity
profile was high with two 2 treatment-related deaths, a high incidence of Grade 3 or 4
neutropenia (42%), and a high incidence of Grade 3 HFS (29%).
There is a theoretical advantage to using paclitaxel on a weekly schedule in
conjunction with capecitabine based on the duration of the upregulation of thymidine
phosphorylase (dThPase) by paclitaxel in model systems. The metabolism of capecitabine
to the active agent, FU, provides insight into the rationale for combining capecitabine
with taxanes in this phase II study . The rationale for combining paclitaxel with
capecitabine is based on the upregulation of dTHPase, which has been demonstrated in a
model of athymic mice bearing capecitabine-resistant human colon cancer xenografts.
Treatment with paclitaxel led to a 7.9-fold increase in intratumoral dThPase. An
increase in dThPase activity occurred 4 days after treatment with paclitaxel and
persisted for 10 days . These data led to the current concept for this clinical trial,
using paclitaxel on days 1 and 8 during a 14-day exposure to capecitabine in patients
with MBC. Moreover, these agents have nonoverlapping toxicities and therefore can be
combined with reasonable tolerability. It was anticipated that by allowing a week off
from weekly paclitaxel therapy, the frequency of sensory neuropathy could be reduced.
Given the high degree of efficacy of the docetaxel/capecitabine combination, but the
significant toxicity observed with 1,250 mg/m2 bid capecitabine schedule, as well as
the promising efficacy and safety observed with weekly paclitaxel/capecitabine in the
phase I study by Uhlmann et al [27], we choose weekly paclitaxel for combination
regimen with capecitabine. Practically, our study regimen is capecitabine plus
paclitaxel(XT) combination chemotherapy.
1.5 XP vs XT for esophageal cancer Based on the rationale and our experience, we are
going to conduct randomized phase II trial for metastatic esophageal cancer to evaluate
the efficacy and feasibility comparing XP with XT.
2. Study Objectives
2.1 Primary Objective: To evaluate response rate for each treatment group (XP vs XT) for
metastatic esophageal cancer.
2.2 Secondary Objectives:
1. toxicity
2. progression-free survival
3. quality of life
4. overall survival
5. predictive marker study influencing response and survival
3. Study Design 3.1 Randomization
1. Timing of randomization: Randomization will be performed after inclusion of the patient
2. Stratification factor: performance status (ECOG 0, 1 vs 2) & weight loss of 10% or more
3.2 Overview of Study Design This study is a prospective, randomized, phase II study
comparing response rate between patients with XP chemotherapy versus XT chemotherapy for
patients with metastatic squamous cell carcinoma.
Chemotherapy regimen (XP):
D1- D14 Capecitabine 1000 mg/m2 bid p.o. D1 Cisplatin 75 mg/m2 + NS 150mL MIV over 1hr Pre &
Post medication D0 N/S 1500 mL IV overnight hydration D1 DNK2 1000 mL IV over 2 hours, pre &
post hydration (if Mg < WNL, mix MgSO4 1 amp) 5-HT3 antagonist 1 amp + dexamethasone 20 mg +
D5W 100 mL MIV 20% Mannitol 70 mL IV full dripping, 30 mins before cisplatin D2-D5 5-HT3
antagonist 1T QD D2-D3 Dexamethasone 8 mg PO bid D4-D5 Dexamethasone 4 mg PO bid every 3
weeks
Chemotherapy regimen (XT):
D1- D14 Capecitabine 1000 mg/m2 bid p.o. D1, D8 Paclitaxel 80 mg/m2 + D5W 500mL MIV over
3hrs Pre & Post medication D1, D8 Solucortef 100 mg IV push before Paclitaxel Avil 1A + D5W
50mL MIV 30mins before Taxol Ranitidine 50mg IV + D5W 50mL MIV 30mins before Paclitaxel HT3
antagonist 1A + D5W 50 mL MIV 30mins before Paclitaxel Followed by 1 week off every 3 weeks
3.3 Study Duration and Dates The duration of this study is expected to be 36 months, with
subject recruitment proposed to start in October 2008. The actual overall study duration or
subject recruitment period may vary.
3.4 Number of Patients/Assignment to Treatment Groups 94 patients will be recruited in
total. Patients will be randomized to a treatment arm by permutated method. Chemotherapy
should be started within 14 days after randomization.
