A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Crizotinib naive Adult Patients With ALK-activated Non-small Cell Lung Cancer
This is a single-arm, open-label, two-stage multicenter, phase II study.Patients will be pre-screened for ALK positive status. Treatment with LDK378 at 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 anticancer 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.
The study will use a Simon[Right Quote]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 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. 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.
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Histologically or cytologically confirmed diagnosis of stage IIIb or
IV NSCLC that carries an ALK rearrangement defined as 15% or more positive tumor cells
as assessed by the FDA-approved Vysis ALK break-apart 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
new biopsy prior to the first dose of LDK378 according to the above criteria, i.e. with an
FDA-approved assay. The test will be performed at a Novartis designated central
2. Age 18 years or older at the time of informed consent.
3. Patients must have stage IIIb or IV NSCLC that has progressed during or after the last chemotherapy regimen received prior to the first dose of LDK378.
4. Patients must have received cytotoxic chemotherapy to treat their locally advanced or
metastatic stage IIIb or IV NSCLC:
* All patients must have received at least one and a maximum of three prior lines of
* Prior cytotoxic chemotherapy must include a platinum doublet
* Prior erlotinib or gefitinib will not count as a line of cytotoxic chemotherapy (i.e.
patients may have received prior treatment with these drugs)
* (Neo-)adjuvant cytotoxic chemotherapy will count as one prior line of treatment if
relapse occurred within 12 months from the end of the adjuvant cytotoxic
* Note: A cytotoxic chemotherapy line in locally advanced or metastatic (stage IIIb or
IV) disease is defined as an anticancer regimen that contains at least 1 cytotoxic chemotherapy
agent and is given for 21 days or more. If a cytotoxic chemotherapy regimen was
discontinued for a reason other than disease progression and lasted less than 21 days,
then this regimen does not count as a prior line of chemotherapy
5. Patients must have archival tissue, collected either at the time of diagnosis of NSCLC or
any time since, available as a formalin-fixed, paraffin-embedded (FFPE) sample.
6. Patients must have recovered from all toxicities related to prior anticancer therapies to
grade <= 2 (CTCAE v 4.03). The exception to this criterion is for patients with grade 2
nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who will not
be allowed to participate in the study. Patients with any grade of alopecia are allowed to
enter the study.
7. Patients must meet the following laboratory values at the screening visit:
* Absolute neutrophil count (ANC) >= 1.5 x 109/L
* Platelets >= 75 x 109/L
* Hemoglobin (Hgb) > 8 g/dL
* Calculated creatinine clearance (using Cockcroft-Gault formula) > 30 mL/min
* Total bilirubin < 1.5 x ULN (Upper limit of normal), except for patients with Gilbert[Single Quote]s syndrome, who may
only be included if total bilirubin < 3.0 x ULN or direct bilirubin < 1.5 x ULN
* Aspartate transaminase (AST) < 3 x ULN, except for patients with liver metastasis,
who are only included if ALT < 5 x ULN
* Alanine transaminase (ALT) < 3 x ULN, except for patients with liver metastasis,
who are only included if AST < 5 x ULN
* Patients must have the following laboratory values >= lower limit of normal (LLN) or
corrected to within normal limits with supplements during screening:
* Potassium >= LLN
* Magnesium >= LLN
* Phosphorus >= LLN
* Total calcium (corrected for serum albumin) >=LLN
8. Life expectancy >= 12 weeks.
9. World Health Organization (WHO) performance status 0-2.
10. At least one measurable lesion as defined by RECIST v1.1. A previously irradiated site
lesion may only be counted as a target lesion if there is clear sign of progression since the
11. Written informed consent for the main study must be obtained prior to any screening
procedures. If consent cannot be expressed in writing, it must be formally documented and
witnessed, ideally via an independent trusted witness.
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests
and other study procedures.