Trial Information

A Randomized Phase II Study of Weekly Docetaxel Plus Cisplatin Followed by Gemcitabine vs. Gemcitabine Plus Cisplatin Followed by Weekly Docetaxel in the Treatment of Advanced Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death in men and women worldwide. Shifting trends
in the incidence of lung cancer closely follow the patterns of cigarette smoking, although
other carcinogens have been implicated. Despite intensive over the past several decades, the
5-yr lung-cancer survival rate remains a dismal 8-14%.

Although lung cancer is not the most common cancer, as the leading cause of cancer-related
deaths in men and women, it is the most deadly (American Cancer Society 2000). Lung cancer
is also the leading cause of cancer deaths in Taiwan. According to the vital statistics of
Department of Health in Taiwan, the incidence of lung cancer is rank of 5th. However, the
rank of cancer fatality is the second and first in men and women, respectively. The
mortality of lung cancer have significant increasing trend in men and women during the
two-decade period. There are 6,555 persons die for lung cancer in 2001.

There is only 25% of cases resectable when diagnosed and only 15~18% of cases can be
surgical removed. The postoperative recurrence rate and metastasis rate are also high for
NSCLC. Chemotherapy is used primarily to palliate disease symptoms and prolong survival in
patients with unresectable disease (stage IIIB and IV). However, overall survival benefit
is modest.

Gemcitabine has shown good activity in NSCLC, both as a single agent and in combination with
various other cytotoxic drugs (Eli Lilly and Company 1999). A number of phase I and II
studies in NSCLC have shown good safety and efficacy of two-drug combinations of Gemcitabine
with agents other than cisplatin, including carboplatin, paclitaxel, vinorelbine, and
docetaxel (Eli Lilly and Company 1999).

Gemcitabine plus cisplatin (GC) is one of the most active regimens in the treatment fir
stage IIIB/IV NSCLC patients. In phase II studies, 26-54% stage IIIB/IV NSCLC patients
respond to GC treatment. Good median and 1-year survival have been consistently observed
(Abratt et al, 1997; Crino et al, 1997; Einhorn, 1997; Shepherd et al, 1997) In randomized
phase III studies, GC demonstrated the superior survival versus cisplatin alone (Sandler A
et al. 2000), significantly higher response rate versus a three-drug combination of
cisplatin, mitomycin C and ifosfamideb (Crino L et al. 1999).

Schiller JH et al. conducted a randomized study to determine whether any of three
chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced
non-small-cell lung cancer (Schiller JH et al. 2000). Patients with advanced non-small-cell
lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to
one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or
carboplatin and paclitaxel. However, none of four chemotherapy regimens offered a
significant advantage over the others in the treatment of advanced non-small-cell lung
cancer. GC provided longer time to progression than other three regimens.

Abratt et al (1997) used GC in stage IIIB/IV patients delivering cisplatin on day 15
resulted in goodresponse rate (52%), median survival (13 months) associated with low
haematological toxicity and very few dose modifications of either gemicitabine or ciplatin.
This schedule seems to be feasible for induction treatment.

Docetaxel plus cisplatin is one of options of front line treatment. TAX326- a phase III
trial studied docetaxel + cisplatin or carboplatin vs vinorelbine/cisplatin (VC) as
first-line therapy for advanced non-small cell lung cancer (NSCLC). The schedule of
chemotherapy was 75 mg/m² of docetaxel followed by 75 mg/m² of cisplatin repeated every 3
weeks and Vinorelbine 25 mg/m2 IV day 1, 8, 15, 22 and Cisplatin 100 mg/m2 IV day 1 every 4
weeks. The overall response rate were 32% (docetaxel+cisplatin) and 25%(VC). Docetaxel plus
cisplatin showed survival benefit compared to VC (1-year survival rate: 46% v.s. 41%).

Several phase II trials have investigated the efficacy and safety of Gemcitabine as a single
agent, second-line therapy. Table below summarizes the results of the phase II trials.These
trials concluded that gemcitabine has a modest activity as second-line chemotherapy for
NSCLC. It has the advantage to be well tolerated and may thus be one drug to be proposed to
the patients who have disease progression after a first-line chemotherapy and who ask for
further treatment.

In the initial development of docetaxel and paclitaxel, these drugs routinely were
administered once every 3 weeks. However, weekly administration of both these agents appears
to offer several advantages in terms of toxicity. Both agents can be administered weekly
with markedly decreased myelosuppression, while maintaining the same or increased dose
intensity( Fennelly D et al 1997; Seidman AD et al 1998; Hainsworth JD et al 1998).

A Phase I trial demonstrated that docetaxel could be administered weekly at a maximum
tolerated dose of 43 mg/m2/week, with fatigue and asthenia as the dose-limiting toxicities
(Hainsworth JD et al 1998). At a weekly dose of 36 mg/m2, docetaxel was extremely well
tolerated, with no significant myelosuppression and only occasional NCIC-CTG Grade 3 or 4
non-hematologic toxicities. The recommended dose was 36 mg/m2.

Four clinical studies of single-agent weekly docetaxel in patients with NSCLC have been
reported. As second-line therapy for NSCLC, weekly docetaxel has been studied by 3 groups
(Baylor-Charles 2000; Serke M et al 2001; Garcia-Lopez JL et al 2000 ), and Hainsworth JD
and his colleagues studied weekly docetaxel as first-line treatment of NSCLC (Hainsworth JD
et al 2000).

The 3 studies of weekly docetaxel as a single agent, second-line consistently demonstrated
efficacy and similar toxicity profiles. Objective response rates ranged from 11% to 26.7%,
and the percentage of patients who responded or maintained stable disease ranged from 37.5%
to 66.7%. Docetaxel was generally well tolerated in each study.

Weekly docetaxel is being studied in combination with other commonly used NSCLC
chemotherapeutic agents including carboplatin, navelbine, and gemcitabine. These
combinations are being studied in both first- and second-line settings. Second line
chemotherapy with docetaxel may affect survival (TAX 318, 1 year survival 37% vs. 11%).
However, the optimal sequence of chemotherapy was rarely explored. Weekly docetaxel may
offer better tolerability vs. 3-weekly schedule when combining docetaxel to cisplatin. Based
upon these studied, we choose weekly docetaxel in combination with cisplatin as our regimen.
We expected the regimen would be effective and well tolerated.

Based on the data above, this study proposed to compare the efficacy and safety of the two
regimens (weekly docetaxel plus cisplatin followed by gemcitabine vs. gemcitabine plus
cisplatin followed by weekly docetaxel) in metastatic of locally advanced non-small cell
lung cancer.