A phase II, multicenter, single-arm study of oral LDK378 in adult patients with ALK-activated non-small cell lung cancer previously treated with chemotherapy and crizotinib

Lung cancer has been the most common cancer in the world. Non-small cell lung
cancer (NSCLC) accounts for more than 85% of all lung cancer cases. The
prognosis continues to be poor despite chemotherapy treatment, with a 5-year
overall survival rate of only 15%.
During the last few years, improved knowledge of NSCLC biology led to the
identification of molecular events crucial for malignant transformation and
cancer cell survival.
Multiple large randomized clinical trials have demonstrated that patients
harboring activating EGFR mutations benefit more from EGFR TKIs than from
standard chemotherapy. The success of EGFR TKIs highlights the importance of
identifying specific NSCLC molecular drivers to appropriately direct targeted
agents to specific patient populations.
The discovery of anaplastic lymphoma kinase (ALK) rearrangement in NSCLC in
2007 represents another important milestone in the era of molecular targeted
therapy in NSCLC.
The frequency of EML4-ALK rearrangement in patients with NSCLC is relatively
low; it is present in approximately 2-8% of tumors tested. However, considering
the high incidence of lung cancer, this small percentage translates into about
10,000 patients in the United States alone.
Crizotinib, an orally available small-molecule inhibitor of ALK and MET
tyrosine kinases, has been rapidly and successfully developed in patients with
advanced NSCLC who have EML4-ALK rearrangements
While crizotinib has impressive activity in patients with ALK rearranged NSCLC,
these cancers invariably progress, typically within 1 year, because of the
development of resistance to crizotinib. For these patients there is no
alternative ALK-targeted therapy. Therefore, the development of ALK TKIs with
clinical activity against ALK-positive NSCLC resistant to crizotinib is
crucial.

The primary objective of the study is to demonstrate the antitumor activity of
LDK378.

This is a single-arm, open-label, multicenter, phase II study.

LDK378 will be administered orally once daily at a dose of 750 mg on a
continuous dosing schedule.

* Study duration in principle until disease progression. Thereafter follow-up
for survival.
* The screening phase with extensive assessments. Bi-weekly visits during the
first cycle and a monthly visit thereafter.
* PK blood sampling on day 1 of the first 6 cycles and extra PK blood sampling
until 6hours post dose and the next day (24hrs post dose) on day one of cycle 1
and 2 for a limited number of patient at selected sites (in the Netherlands
this will be only at the UMCG).
* Physical examination at every visit.
* There will be extra blood drawn during the study visits. Approximately 3-4ml
per visit and an additional 10ml for extra PK samples.
* Pregnancy test at screening.
* ECG at every visit and additional ECGs for patients were extra PK samples are
taken.
* Optional tumor biopsy at the screening and at the end of treatment.
* Optional donation of left-over tumor tissue for future testing.