A clinical study of oral LDK378 in adult patients with ALK-activated non small cell lung cancer and who have not been previously treated with crizotinib
- Conditions
- on small-cell lung cancer (NSCLC)MedDRA version: 14.1Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2012-003474-36-IT
- Lead Sponsor
- OVARTIS FARMA
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 105
1. Histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC that carries an ALK rearrangement defined as 15% or more positive tumor cells as assessed by the FDA-approved FISH test (Abbott Molecular Inc) using Vysis breakapart probes. 2. Age 18 years or older at the time of informed consent. 3. Patients must have NSCLC that has progressed during prior chemotherapy. 4. Patients must have received cytotoxic chemotherapy to treat their locally advanced or metastatic NSCLC: ??All patients must have received at least one and a maximum of three prior lines of cytotoxic chemotherapy ??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 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). 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) > 50 mL/min ??Total bilirubin < 1.5 x ULN, except for patients with Gilbert’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 AST < 5 x ULN ??Alanine transaminase (ALT) < 3 x ULN, except for patients with liver metastasis, who are only included if AST < 5 x ULN 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. 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.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 85
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 20
1. Prior treatment with crizotinib, or any other ALK inhibitor investigational agent, for NSCLC 2. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms. 3. History of carcinomatous meningitis. 4. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. 5. Clinically significant, uncontrolled heart disease, 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 (QTc) > 470 msec using Fredericia correction (QTcF) on the screening ECG 6. Radiotherapy = 2 weeks prior to starting the study treatment or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions = 2 weeks prior to starting study 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 study drug or who have 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 be enrolled in the study =1 week after the procedure. 8. Patients receiving treatment with medications that meet one of the following criteria and that can not be discontinued at least 1 week prior to the start of treatment with LDK378 and for the duration of the study:• Strong inhibitors or strong inducers of CYP3A4/5 (Appendix I) • Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, CYP2C8 and/or CYP2C9 (Appendix I) 9. Impairment of GI function or GI disease that may significantly alter the absorption of LDK378 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome). 10. Patients who are currently receiving treatment with warfarin sodium (Coumadin) or any other coumarin-derivative anticoagulants. 11. Patients receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms, dose must have been stabilized (or decreasing) for at least 5 days before first dose of study treatment. 12. Patients receiving treatment with any enzyme-inducing anticonvulsant (Appendix I) that cannot be discontinued at least 1 week before first dose of study treatment, and for the duration of the study. Patients on non enzyme-inducing anticonvulsants are eligible. 13. Investigational agents within 4 weeks or = 10 x half life of the agent (whichever is longer) before first dose of study treatment. 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 po
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To demonstrate the antitumor activity of LDK378, as measured by overall response rate (ORR) to LDK378 by investigator assessment;Secondary Objective: To evaluate response related endpoints as assessed by investigator and Blinded Independent Review Committee (BIRC): - Duration of response (DOR) - Disease control rate (DCR) - Time to response (TTR) To assess ORR by BIRC assessment To evaluate the safety profile of LDK378 To evaluate progression-free survival (PFS) To evaluate overall survival (OS);Primary end point(s): ORR per RECIST v1.1 calculated as the proportion of patients with a best overall response defined as complete response or partial response (CR+PR) as assessed by investigator;Timepoint(s) of evaluation of this end point: 6 cycles of 28 days up to 24 weeks
- Secondary Outcome Measures
Name Time Method Secondary end point(s): - DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to underlying cancer, by investigator and BIRC assessment - DCR, calculated as the proportion of patients with best overall response of CR, PR, or SD, by investigator and BIRC assessment - TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by investigator and BIRC assessment - ORR (CR+PR) per RECIST v1.1 as assessed by BIRC - Adverse events and laboratory abnormalities - PFS, defined as time from first dose of LDK378 to progression or death due to any cause, as assessed by BIRC and investigator assessment - OS, defined as time from first dose of LDK378 to death due to any cause;Timepoint(s) of evaluation of this end point: 6 cycles of 28 days up to 24 weeks for all