A single-arm, open-label, multicenter, phase II study. Treatment with LDK378 750 mg qd will continue until the patient experiences unacceptable toxicity that precludes further treatment, discontinues treatment at the discretion of the investigator or patient, starts a new anti-cancer therapy and/or dies. LDK378 may be continued beyond RECIST-defined PD as assessed by the investigator if, in the judgment of the investigator, there is evidence of clinical benefit. In these patients tumor assessment should continue as per the schedule of assessments until treatment with LDK378 is permanently discontinued. Patients who discontinue the study medication in the absence of progression will continue to be followed for tumor assessment until the time of PD as assessed by the investigator
This is a single-arm, open-label, multicenter, phase II study in which the efficacy and safety of LDK378 will be evaluated in patients with locally advanced or metastatic 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 break-apart probes. If documentation of ALK rearrangement by the FDA-approved FISH test is available, no further ALK test is required for inclusion in the study. If such documentation is not available, a new test to assess ALK status by the FDA-approved FISH test should be performed.
Patients must have been pretreated with cytotoxic chemotherapy (1 to 3 prior lines, of which 1 must have been a platinum doublet) and then with crizotinib. Patients may also have received first line treatment with crizotinib followed by cytotoxic chemotherapy and, subsequently, a rechallenge treatment with crizotinib. Patients must have demonstrated progression (regardless of initial response) on the last crizotinib treatment, i.e. the crizotinib regimen received as the last therapy prior to study entry.
The study begins with a screening period to assess eligibility, up to and including 28 days prior to the first dose of LDK378.
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 137 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 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.