Clinical trial NCT02374489 (phase 2, status: terminated)
Conditions: cholangiocarcinoma
ICD codes: C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31
Drugs: ldk378
SMILES: CC(C)OC1=C(NC2=NC=C(Cl)C(N2)=NC2=CC=CC=C2S(=O)(=O)C(C)C)C=C(C)C(=C1)C1CCNCC1
Reason stopped: 
    ros1 in ihc and gene rearrangement result can not match。no tumor response。
  
Eligibility criteria:

        Inclusion Criteria:

          -  1.Histological or cytologically confirmed diagnosis of intrahepatic or hilar
             cholangiocarcinoma that demonstrates ALK and/or ROS1 over-expression by IHC (3+).

          -  2.Locally advanced with inoperable or metastatic disease status

          -  3.ECOG performance status 0-2.

          -  4.Aged no less than 20 years and no more than 75 years, at the time of acquisition of
             informed consent 5.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.

             6.The following laboratory criteria have been met:

             •Absolute neutrophil count (ANC) ≥1.5 x 109/L

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Platelets ≥ 75 x 109/L

               -  Serum total bilirubin ≤1.5 x upper limit of normal (ULN), except for patients
                  with biliary tract obstruction statis post drainage or stent 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 7.Patient must
                  have the following laboratory values or have the following laboratory values
                  corrected with supplements to be within normal limits at screening:

               -  Potassium ≥ 1.0 x lower limit of normal (LLN)

               -  Magnesium ≥ 1.0 x LLN

               -  Phosphorus ≥ 1.0 x LLN

               -  Total calcium (corrected for serum albumin) ≥ 1.0 x LLN 8.At least one, not
                  previously irradiated, measurable lesion according to RECIST (version 1.1)
                  9.Willingness and ability to comply with scheduled visits, treatment plans,
                  laboratory tests and other procedures.

        Exclusion Criteria:

          -  1.Patients with known hypersensitivity to any of the excipients of LDK378
             (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and
             magnesium stearate).

             2.Patients with symptomatic CNS metastases who are neurologically unstable or have
             required increasing doses of steroids within the 1 week prior to study entry to manage
             CNS symptoms.

             3.Prior therapy with LDK378. 4.Other anti-tumor agent such as systemic chemotherapy,
             immunotherapy or targeted therapy within 2 weeks before the commencement of study
             treatment.

             5.Presence or history of a malignant disease other than cholangiocarcinoma that has
             been diagnosed and/or required therapy within the past year and is not undergoing
             active anticancer treatment. 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.

             6.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).

             7.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 screening;ventricular arrhythmias; supraventricular
             and nodal arrhythmias not controlled with medication;other cardiac arrhythmia not
             controlled with medication;corrected QTc (male: QTc >450 msec; female: QTc> 470 msec )
             using Bazett correction on the screening ECG.

             8.Impaired GI function or GI disease that may alter absorption of LDK378 or inability
             to swallow up to five LDK378 capsules daily.

             9.Ongoing GI adverse events > grade 2 (e.g. nausea, vomiting, or diarrhea) at the
             start of the study.

             10.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 participation:Medication with a known risk of prolonging the QT interval
             or inducing Torsades de Pointes .Strong inhibitors or strong inducers of CYP3A4/5
             ;Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5,
             CYP2C8 and/or CYP2C9 ;Therapeutic doses of warfarin sodium (Coumadin) or any other
             coumadin-derived anti-coagulant. Anticoagulants not derived from warfarin are allowed
             (eg, dabigatran, rivaroxaban, apixaban).;increasing doses of
             corticosteroids;enzyme-inducing anticonvulsive agents;herbal supplements 11.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.

             12.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. Highly
             effective contraception methods include:Total abstinence (when this is in line with
             the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar,
             ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
             methods of contraception.

        Female sterilization (have had surgical bilateral oophorectomy with or without
        hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case
        of oophorectomy alone, only when the reproductive status of the woman has been confirmed by
        follow up hormone level assessment.

        Male sterilization (at least 6 months prior to screening) with the appropriate
        post-vasectomy documentation of the absence of sperm in the ejaculate. For female subjects
        on the study the vasectomized male partner should be the sole partner for that subject.

        Combination of any two of the following (a+b or a+c or b+c):

          1. Use of oral, injected or implanted hormonal methods of contraception or other forms of
             hormonal contraception that have comparable efficacy (failure rate < 1%), for example
             hormone vaginal ring or transdermal hormone contraception.

          2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

          3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault
             caps) with spermicidal foam/gel/film/cream/vaginal suppository.

        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.

        13.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.