A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer

Trial Information

A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer

This is a single-arm, open-label, two-stage, multicenter, phase II study in which the
efficacy and safety of LDK378 will be evaluated in patients with stage IIIb or IV NSCLC
harboring a confirmed ALK rearrangement, defined as 15% or more positive tumor cells as
assessed by the FDA-approved FISH test (Abbott Molecular Inc.) using Vysis breakapart
probes.

Patients will be pre-screened to test for ALK positivity. The test to confirm ALK
rearrangement must be performed either using archival tissue or, preferably, using a fresh
biopsy prior to study entry according to the above criteria, i.e. with an FDA-approved
assay. The test will be performed at a Novartis designated central laboratory.

After confirmation of ALK positivity, the study begins with a screening period to assess
eligibility, up to and including 28 days prior to the first dose of LDK378.

Patients must not have received prior crizotinib. Patients must have been pretreated with
cytotoxic chemotherapy (1 to 3 prior lines, of which 1 must have been a platinum doublet).

The study will use a Simon's optimal two-stage design. Stage 1 will consist of 43 patients
and their data up to 6 cycles of treatment unless a patient has discontinued treatment
earlier or a confirmed response to treatment has been observed prior to completing 6 cycles.
The trial will be stopped at Stage 1 for futility if 16 or fewer responses are observed. If
at the time that the last patient is enrolled to Stage 1 a minimum of 17 responses have not
yet been observed, accrual may be temporarily suspended during the analysis of Stage 1. The
Data Monitoring Committee will periodically review response data and will make the
appropriate recommendation regarding transition into Stage 2 or stopping enrollment. Stage 2
will include an additional 62 patients. The primary analysis will occur when all 105
patients have completed 6 cycles of treatment or discontinued treatment earlier.

The treatment period begins on Day 1 of Cycle 1. All patients will be treated with LDK378,
administered orally, at a starting dose of 750 mg. A total of approximately 105 patients
will be enrolled in the study. Patients will take LDK378 once daily, at approximately the
same time each day. On days when a PK sample is obtained, the patient will take LDK378
during the clinic visit as instructed by the study staff. Treatment with LDK378 will
continue until the patient experiences unacceptable toxicity that precludes further
treatment, discontinues treatment at the discretion of the patient or investigator, starts a
new anti-cancer therapy or dies. If the patient experiences RECIST-defined progressive
disease (PD) on LDK378 as assessed by the investigator, treatment with the study drug may be
continued if, in the judgment of the investigator, there is still evidence of clinical
benefit. These patients will be counted as PD for ORR, DOR, DCR and PFS calculations.

Assessments of tumor response and progression will be performed every 8 weeks (i.e. every 2
cycles), starting from the first day of treatment with LDK378. This schedule of tumor
assessment every 8 weeks must continue regardless of dose interruptions. Tumor assessment
should continue until:

- For patients who experience PD as assessed by the investigator, tumor assessments
should continue every 8 weeks until LDK378 is permanently discontinued (i.e. if the
patient continues treatment with LDK378 after PD, tumor assessments should continue
until LDK378 is permanently discontinued).

- For patients who discontinue treatment in the absence of PD, tumor assessments should
continue every 8 weeks from the EOT visit until PD is assessed by the investigator.

Tumor evaluations will always cease if the patient starts a new anti-cancer therapy,
withdraws consent (unless the patient agrees to continue efficacy assessments in absence of
dosing with LDK378, or dies.

All tumor imaging assessments will be submitted for independent radiological assessment of
response by a Blinded Independent Review Committee (BIRC).

Clinical and laboratory assessments will be performed.

When the patient discontinues from study treatment an End of Treatment (EOT) visit must be
performed as soon as possible and within 7 days of the last dose of LDK378. Patients will be
contacted for the safety follow-up 30 days after their last dose of LDK378 to determine if
they have experienced any new AEs and/or to follow resolution of ongoing AEs.

Following the end of tumor assessments, the Study Phase Completion Disposition eCRF must be
completed. Patients will be contacted every 3 months to obtain information pertaining to
survival status until death, loss to follow-up, withdrawal of consent to survival follow-up,
or the end of the study. Patients do not need to visit the clinic during the survival
follow-up.