Novartis-sponsored, open-label, multi-center, interventional ETP to provide LDK378 to
patients with ALK (+)NSCLC, who have been pre-treated with an ALK inhibitor; except in
countries where ALK inhibitors are not approved or available. The protocol will further
evaluate the safety of LDK378 in patients with ALK(+) NSCLC.
Inclusion Criteria (patients eligible for inclusion in this early treatment protocol have
to meet all of the following criteria):
1. Histologically or cytologically confirmed diagnosis of NSCLC that demonstrates ALK
positivity as assessed by approved FISH test (Abbott Molecular Inc), using Vysis
breakapart probes (defined as 15% or more positive tumor cells); or the Ventana IHC
test. If documentation of ALK positivity is not available, the test to confirm ALK
positivity must be performed according to the above criterion, using a new tumor
biopsy obtained prior to the first dose of ETP treatment (LDK378).
2. Stage IIIB or IV NSCLC patient with documented disease progression at enrollment, and
who does not qualify or have access to LDK378 through a clinical trial.
3. Age 18 years or older at the time of informed consent.
4. WHO performance status 0-3.
5. Patients who have been pre-treated with an ALK inhibitor for locally advanced or
metastatic NSCLC. Patients may be enrolled without prior exposure to an ALK inhibitor
in countries where ALK inhibitors are not approved or available. Exposure to prior
chemotherapy is not required.
6. Patients must have recovered from all toxicities related to prior anticancer therapies
to grade ≤ 2 (CTCAE v 4.03), provided that concomitant medication is given prior to
initiation of treatment with LDK378. Exception to this criterion: patients with any
grade of alopecia are allowed to enter the treatment.
7. The following laboratory criteria have been met:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Hemoglobin (Hgb) ≥ 8 g/dL
- Platelets ≥ 75 x 109/L
- Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients
with Gilbert's syndrome who may be included if total bilirubin ≤ 3.0 x ULN and
direct bilirubin ≤ 1.5 x ULN
- Aspartate transaminase (AST) < 3.0 x ULN, except for patients with liver
metastasis, who are only included if AST < 5 x ULN; alanine transaminase (ALT) <
3.0 x ULN, except for patients with liver metastasis, who are only included if
ALT < 5 x ULN.
- Calculated or measured creatinine clearance (CrCL) ≥ 30 mL/min
8. Patient must have the following laboratory values or have the following laboratory
values corrected with supplements to be within normal limits at screening:
- Potassium ≥ LLN
- Magnesium ≥ LLN
- Phosphorus ≥ LLN
- Total calcium (corrected for serum albumin) ≥ LLN
9. Written informed consent for the ETP protocol 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.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other ETP procedures.
Exclusion Criteria (patients eligible for this ETP must not meet any of the following
1. Patients with known hypersensitivity to any of the excipients of LDK378
(microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and
2. Patients with symptomatic CNS metastases who are neurologically unstable or have
required increasing doses of steroids within the 1 week prior to ETP entry to manage
3. Prior therapy with LDK378.
4. The patient is less than 5 half-lives from prior ALK inhibitor or targeted therapy
(for adequate wash-out) without recovery from treatment toxicities to ≤ grade 1 or to
their pretreatment levels.
5. Chemotherapy or an investigational therapy ≤ 3 weeks prior to starting the LDK378
treatment who have not recovered from side effects of such treatment toxicities to ≤
grade 2 or to their pre- treatment toxicities levels, with the exception of liver and
cardiac functions which must be ≤ grade 1.
6. Patients who have received thoracic radiotherapy to lung fields ≤ 4 weeks prior to
starting the study treatment or patients who have not recovered from
radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy
to thoracic vertebrae and ribs) radiotherapy ≤ 2 weeks prior to starting the LDK378
treatment or have not recovered from radiotherapy-related toxicities. Palliative
radiotherapy for bone lesions ≤ 2 weeks prior to starting LDK378 treatment is allowed.
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks
prior (2 weeks for resection of brain metastases) to starting LDK378 treatment or who
have not recovered from side effects of such procedures. Video-assisted thoracic
surgery (VATS) and mediastinoscopy will not be counted as major surgery, and patients
can be enrolled in the ETP ≥ 2 weeks after the procedure.
8. Presence or history of a malignant disease other than NSCLC that has been diagnosed
and/or required therapy within the past 3 years. Exceptions to this exclusion include
the following: completely resected basal cell and squamous cell skin cancers, and
completely resected carcinoma in situ of any type.
9. Patients with known history of extensive disseminated bilateral interstitial fibrosis
or interstitial lung disease, including a history of pneumonitis, hypersensitivity
pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically
significant radiation pneumonitis (i.e. affecting activities of daily living or
requiring therapeutic intervention).
10. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac
event (within 6 months), such as:
- unstable angina within 6 months prior to screening;
- myocardial infarction within 6 months prior to screening;
- history of documented congestive heart failure (New York Heart Association
functional classification III-IV);
- uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without
antihypertensive medication -
- initiation or adjustment of antihypertensive medication(s) is allowed prior to
- ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled
- other cardiac arrhythmia not controlled with medication;
- corrected QTc > 450 msec using Fridericia correction on the screening ECG
11. Impaired GI function or GI disease that may alter absorption of LDK378 or inability to
swallow up to five LDK378 capsules daily
12. Ongoing GI adverse events > grade 2 (e.g. nausea, vomiting, or diarrhea) at the start
of the ETP.
13. Receiving medications that meet one of the following criteria and that cannot be
discontinued at least 1 week prior to the start of treatment with LDK378 and for the
duration of the ETP participation (see Appendix 1: Tables 14-1, Table 14-2, Table
14-3, and Table 14-4):
- Medication with a known risk of prolonging the QT interval or inducing Torsades
de Pointes (please refer to
- Strong inhibitors or strong inducers of CYP3A4/5 (please refer to
- Medications with a low therapeutic index that are primarily metabolized by
CYP3A4/5, CYP2C8 and/or CYP2C9 (please refer to
- Therapeutic doses of warfarin sodium (Coumadin) or any other coumadin-derived
anti-coagulant. Anticoagulants not derived from warfarin are allowed (eg,
dabigatran, rivaroxaban, apixaban).
- Unstable or increasing doses of corticosteroids
- enzyme-inducing anticonvulsive agents
- herbal supplements
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test.
15. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 3 months after the last dose of study treatment.
In case of use of oral contraception, women should have been stable on the same pill
for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior
to screening. In the case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment is she considered
not of child bearing potential.
16. Sexually active males unless they use a condom during intercourse while taking drug
and for 3 months after the last dose of study treatment. Male patients for 3 months
should not father a child in this period. A condom is required to be used also by
vasectomized men in order to prevent delivery of the drug via seminal fluid.