Managed Access Programs for LDK378, Ceritinib

This is an expanded access trial for Anaplastic Lymphoma Kinase (ALK)- Positive Tumors focused on measuring MAP, Manage access program, ceritinib, ALK positive tumors, Non-small cell lung cancer (NSCLC), Anaplastic large cell lymphoma (ALCL), Inflammatory myofibroblastic tumour (IMT),, LDK378 Read More

Inclusion Criteria:

Patients eligible for inclusion in this Treatment Plan have to meet all of the following criteria:

1. The patient is diagnosed with ALK-positive tumor.
2. The patient has been previously pre-treated with ALK inhibitor or naive.
3. The patient has progression of disease at screening or is intolerant to prior therapy and does not qualify or have access to LDK378 through a clinical trial.
4. The patient has a performance status (WHO) of 0-2.

5. The following laboratory criteria have been met:

   • Absolute neutrophil count (ANC) ≥1.5 x 10^9/L
   • Hemoglobin (Hgb) ≥ 8 g/dL
   • Platelets ≥75 x 10^9/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 or 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 ≤ 5.0 x ULN;
   • Alanine transaminase (ALT) ≤3.0 x ULN, except for patients with liver metastasis, who are only included if ALT ≤ 5.0 x ULN;
   • alkaline phosphatase (ALP) ≤ 5.0 x ULN
   • Serum creatinine <1.5 mg/dL and or Calculated creatinine clearance (CrCL) (using Cockcroft-Gault formula) ≥ 30 mL/min
   • Serum amylase ≤ 2 x ULN
   • Serum lipase ≤ ULN
   • Fasting plasma glucose ≤175 mg/dL (≤9.8 mmol/L)

6. Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of ceritinib:

   • Potassium
   • Magnesium
   • Phosphorus
   • Total calcium (corrected for serum albumin) Written patient informed consent must be obtained prior to start of treatment.

Exclusion Criteria:

Patients eligible for this Treatment Plan must not meet any of the following criteria:

1. A history of pancreatitis or history of increased amylase or lipase that was due to pancreatic disease.
2. Other concurrent severe, acute, or chronic and/or uncontrolled medical conditions (e.g. diabetes mellitus or psychiatric conditions or laboratory abnormalities uncontrolled heart disease in the last 6 months, active or uncontrolled infection) that, in the opinion of the treating physician, could cause unacceptable safety risks, interfere with the interpretation of the results or compromise compliance with the treatment plan.
3. Patient who has 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 study treatment or has not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤2 weeks prior to starting study treatment is allowed.
4. Known history of interstitial lung disease or interstitial pneumonitis including clinically significant radiation pneumonitis (i.e. affecting activities of daily living or requiring therapeutic intervention).

5. 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 QT (QTcF) >470 ms using Fridericia's correction on the screening ECG (as mean of triplicate ECGs).
6. Known hypersensitivity to any excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
7. Impaired GI function or GI disease that may significantly alter absorption of LDK378 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
8. Patient must not be participating in other ongoing trials, or ALK inhibitors trials or other compassionate use programs. Patients eligible for this program are also ineligible for other ALK inhibitors trials.

9. 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 program:

   • Strong inhibitors or strong inducers of CYP3A4/5
   • Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5 and/or CYP2C9
   • Medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
   • Receiving treatment with warfarin sodium (Coumadin) or any other coumadinderived anti-coagulant
   • Receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms (non- CNS), dose must have been stabilized (or decreasing) for at least 5 days before first dose of treatment.
   • Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to starting treatment or has not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and patients can receive treatment ≥1 week after these procedures
   • Receiving enzyme-inducing anticonvulsives that cannot be discontinued at least 1 week before first dose of treatment, and for the duration of the treatment. Patients on non-enzyme-inducing anticonvulsants are eligible.
10. Sexually active males unless they use a condom during intercourse while taking the drug and for 3 months after the last dose of program drug. Patient 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.
11. Pregnant or nursing (lactating) women

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 stopping medication. Highly effective contraception methods include:

    • Total abstinence (no sexual relations), when this is in line with your preferred and usual lifestyle. Periodic abstinence like calendar, ovulation, symptothermal, postovulation methods, and withdrawal are not acceptable methods of contraception.
    • Female sterilization, when you have been already surgically sterilized prior to the program by surgical removal of both ovaries (woman's reproductive system that stores and releases eggs for fertilization and produces female sex hormones), total hysterectomy (surgical removal of the uterus and cervix), or tubal ligation (getting your "tubes tied") at least six weeks before taking program treatment.
    • Your male partner has already been sterilized at least 6 months prior to screening with the appropriate documentation. The sterilized male partner should be your sole partner.
    • Use of oral, injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception (in case of oral contraception you should have been using the same pill on a stable dose for a minimum of 3 months before taking program 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.