Phase I study of Cisplatin, gemcitabin (+ paclitaxel) and lapatinib as first line treatment in advanced/metastatic urothelial cancer

Urothelial cancer is the 5th most common malignancy in Europe. Transitional
cell carcinoma (TCC) comprises 90-95% of the urothelial tumors in Europe. Most
of these tumors are superficial and although frequently recurring, of good
prognosis. However, in patients diagnosed with muscle invasive TCC, only 30-60%
can be cured with adequate local treatment. Others will develop local relapse
or distant metastasis.

Despite the advances in local and systemic therapy, metastatic transitional
cell carcinoma (TCC) remains a largely incurable disease. The overall response
rate to combination chemotherapy with modern agents is on the order of 60-70%,
but median survival remains less than two years with a five year survival of
approximately 10% (Ref. 1). The EORTC has recently completed a trial of
gemcitabine and cisplatin +/- paclitaxel establishing that this triplet can be
given safely in the cooperative group setting. Whether the triplet results in
improved survival is as of yet unknown.

Insights into the biology of malignant transformation and growth suggest novel
targets for therapy which may improve treatment results (Ref. 2).
HER1 is overexpressed in around 70% of bladder cancers. Combined expression of
HER1 and HER2 is found in around 34% of the tumors and 90 % of the patients
have at least one of these receptors overexpressed. Dual HER1/HER2 inhibition
is therefore an attractive therapeutic strategy for epithelial tumors including
bladder cancer, as ligand-induced HER2/HER1 heterodimerization triggers potent
proliferative and survival signals.

Lapatinib is a small molecule inhibitor of tyrosine kinase activity of both
HER1 and HER2. It has been shown that Lapatinib, potently inhibits both HER1
and HER2 tyrosine kinases leading to growth arrest and/or apoptosis in HER1 and
HER2-dependent tumor cell lines. Lapatinib markedly reduced tyrosine
phosphorylation of HER1 and HER2, and inhibited activation of Erk1/2 and AKT,
downstream effectors of proliferation and cell survival, respectively.
Inhibition of activated AKT in
HER1 or HER2-dependent tumors by Lapatinib may lead to tumor regressions and
may enhance the anti-tumor activity of chemotherapeutics since constitutive
activation of AKT has been linked to chemo-resistance.

At ASCO in 2006 some clinical studies were presented which included Lapatinib.
In renal cell cancer a prolongation of overall survival was observed in
Lapatinib treated patients compared to hormone therapy in advanced renal cell
cancer with overexpressed EGFR who had failed prior therapy (Ref. 7). No
responses were seen in biliary cancer but 2 out of 17 patients with
hepatocellular carcinoma obtained PR (Ref. 8). Little activity was seen in head
and neck cancer.

Novel, biologically based cancer therapies with clinically significant
anti-tumor activity, accompanied by significant disease-related symptom
improvement in bladder cancer, would fulfill an unmet medical need. As many
cancer patients bear tumors that express both HER1 and HER2, a dual inhibitor
of the HER receptor family, such as Lapatinib, may be more effective than a
drug that specifically inhibits either receptor. This study is being conducted
to evaluate the pharmacokinetic
profile and toxicity of Lapatinib in combination with cisplatin/gemcitabine and
cisplatin/gemcitabine/paclitaxel and to explore anti-tumor activity of the
combinations.

The primary objective of this trial is to recommend a dose of Lapatinib in
combination with Gemcitabine, Cisplatin and possibly Paclitaxel. In order to
achieve this, the study will first determine the maximum tolerated dose (MTD)
based on the documentation of the acute dose limiting toxicity (DLT) at cycle 1.

Secondary objectives are:
- to determine any relationship between the drug exposure and adverse events,
- to assess the antitumor activity and
- to explore the intra-tumoral expression levels of relevant biomarkers in
patients.

This is a Phase I, multinational, open-label, dose-escalation study of
Lapatinib in combination with Gemcitabine and Cisplatin (and eventually
Paclitaxel) in patients with advanced or metastatic urothelial cancer.

The study will be conducted in 5 centers by the Genito-Urinary Tract Cancer
Group of the European Organisation for Research and Treatment of Cancer (EORTC).
Patients will be registered at the EORTC Data Center prior to start the
treatment, and after verification of their eligibility.
Eligible patients will receive the combined treatment as described in chapter
5, page 22-24.

The doses of Gemcitabine and Cisplatin are fixed and the dose of Lapatinib will
be escalated.
Design: 3+3 scheme with 3 patients per dose level and up to 6 patients in
case of DLTs.

Two combinations will be investigated in this trial:

1.Gemcitabine/Cisplatin/Lapatinib (q4wks)
Gemcitabine: 1000 mg/m² days 1, 8, 15
Cisplatin: 70 mg/m² day 2
Lapatinib: d1-28, 750 mg/d to 1500 mg/d (dose escalation)


2. Gemcitabine/Cisplatin/Lapatinib/Paclitaxel (q3wks)
Gemcitabine: 1000 mg/m² days 1, 8
Cisplatin: 70 mg/m² day 1
Lapatinib: d1-21, dose below recommended dose in combination with Gem-Cis
Paclitaxel: 80 mg/m² days 1, 8

Extra burden is the physical examination, ECG, ejection fraction (page 33/101),
venapunction and possible side effects.