A multi-center, randomized open label study to assess the systemic exposure, efficacy, and safety of 450 mg ceritinib taken with a low-fat meal and 600 mg ceritinib taken with a low-fat meal as compared with that of 750 mg ceritinib taken in the fasted state in adult patients with ALK rearranged (ALK-positive) metastatic non-small cell lung cancer (NSCLC) (CLDK378A2112)

Cisplatin or carboplatin in combination with other chemotherapy agents, with or
without bevacizumab is standard first-line treatment of locally advanced or
metastatic non-small cell lung cancer (NSCLC), unless a patient has a known
targetable gene mutation or aberration, and is therefore a candidate for a
targeted therapy.
Although chemotherapy has led to clinical improvements in patients with locally
advanced or metastatic NSCLC, the outcome of treatment in the first-line
setting remains poor, with median progression-free survival (PFS) and overall
survival (OS) of 5-7 months and 10-16 months, respectively.
A clinically relevant molecular subset of NSCLC is driven by the anaplastic
lymphoma kinase (ALK) translocation. It ALK is translocated, mutated, or
amplified, it plays a key role in the pathogenesis in several tumor types,
including NSCLC.
Metastatic ALK-positive NSCLC remains an incurable disease. Recent studies have
demonstrated the efficacy of ALK inhibitors in ALK-positive NSCLC and of
immunotherapy with PD-1 antibodies/blocking agents, such as nivolumab, in NSCLC
patients.
Ceritinib is an orally available potent ALK inhibitor. Ceritinib shows potent
antitumor activity in animal models. Efficacy was seen in the ongoing phase I
clinical trial in patients, which led to the approval of ceritinib by the EMA
and FDA for the treatment of patients with ALK-positive metastatic NSCLC who
have progressed on or are intolerant to crizotinib.
However, safety data from this study showed a high frequency of overall GI
adverse effects when ceritinib was administered on an empty stomach at a dose
of 750 mg daily, the recommended phase II/III dose. The majority of GI events
were mild to moderate. However, GI symptoms can affect patients* general
well-being as well as drug absorption.
A food effect study conducted in healthy subjects showed that the
bioavailability of ceritinib is increased when given with a meal. Compared to
the fasted condition, a low-fat meal increased Cmax and AUCinf by 43% and 58%,
respectively, whereas a high-fat meal increased Cmax and AUCinf by 41% and 73%,
respectively.
The primary aim of this study is to assess the steady-state PK of 450 mg or 600
mg ceritinib taken daily with a low-fat meal as compared with that of 750 mg
ceritinib taken daily in the fasted state in subjects with metastatic
ALK-positive NSCLC.

Primary: To assess the steady-state PK of 450 mg or 600 mg ceritinib taken
daily with a low-fat meal as compared with that of 750 mg ceritinib taken daily
in the fasted state in patients with metastatic ALK-positive NSCLC.
Secondary: Overall response rate (ORR), duration of response (DOR), disease
control rate (DCR), time to response (TTR), PFS, OS. Safety and tolerability.
Single dose PK.

Multicenter open-label parallel group phase I study. Food effect part and
efficacy part. Randomization (1:1:1) to
4. Ceritinib once daily 450 mg in the morning within 30 minutes following a
low-fat meal. Patients should refrain from eating one hour after dosing.
5. Ceritinib once daily 600 mg in the morning within 30 minutes following a
low-fat meal. Patients should refrain from eating one hour after dosing.
6. Ceritinib once daily 750 mg in the morning on an empty stomach.
At least 90 patients (up to 150) who satisfy the PK evaluability criteria for
the primary objective, will be randomized (see protocol page 43-44).
After these 90 evaluable patients have been confirmed, enrollment into the
study will be restricted to treatment-naive ALK-positive NSCLC patients
(approximately n=210) for the key secondary efficacy endpoint.
Treatment until disease progression or unacceptable side effects. Patients who
discontinue study treatment for any reason other than disease progression will
be followed up for progression of disease and all patients will be followed for
survival.
Approx. 300 subjects.

Treatment with ceritinib.

Risk: Adverse effects of study drug.
Burden: Cycles of 3 weeks. Cycle 1: 4 visits, cycle 2: 2 visits, from cycle 3
onwards: 1 visit. Duration mostly 2 hours. 2 visits 8 hours.
Low-fat diet for treatment groups 1-2 (incl. meal record on PK days).
Physical examination: cycle 1: 3 times, from cycle 2 onwards once/cycle.
Blood tests (10-15 ml/occasion): nearly every visit. PK (9 times); 2-12 ml
extra. Biomarkers: 10 ml (screening 16 ml) extra (screening plus every 4th
cycle).
Pregnancy test: once/cycle.
Urine testing once.
Tumor measurements: every 2 cycles for the 1st 9 cycles, every 4 cycles
thereafter.
ECG: cycle 1: 3 times, cycle 2: twice, from cycle 3 onwards once/cycle.
Tumor biopsy: 0-2 times (1st mandatory if no archival sample is available, 2nd
optional).