E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer |
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E.1.1.1 | Medical condition in easily understood language |
Non small cell lung cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024233 |
E.1.2 | Term | Leptomeningeal metastases |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006128 |
E.1.2 | Term | Brain metastases |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate the antitumor activity of Ceritinib in patients with ALK-positive NSCLC metastatic to the brain and/or to leptomeninges. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate Disease Control Rate (DCR) in patients with ALK-positive NSCLC metastatic to the brain and/or to leptomeninges based on investigator assessment per RECIST 1.1
-To evaluate intracranial tumor-response related endpoints as assessed by investigators and Blinded Independent Review Committee (BIRC) (using modified RECIST 1.1 criteria)
-To evaluate extracranial tumor-response related endpoints as assessed by investigators and BIRC (using RECIST 1.1 criteria)
-To evaluate whole body tumor-response related endpoints as assessed by investigators and BIRC(using RECIST 1.1 criteria)
-To evaluate overall survival (OS) in this patient population
-To evaluate safety in this patient population
-To characterize the PK of Ceritinib in this patient population
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed diagnosis of metastatic NSCLC according to the 7th edition of the AJCC Cancer Staging Manual.
In addition, the NSCLC must harbor an ALK rearrangement, as assessed using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria).
If documentation of ALK rearrangement as described above is not locally available, a test to confirm ALK rearrangement must be performed by a Novartis designated central laboratory. Patients must wait for the
central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib.
2a. Patients that require ALK rearrangement testing by a Novartis designated central laboratory must have a tumor tissue sample available as an archival sample (if possible obtained after the completion of the patient's last therapeutic regimen) or as a new biopsy. If that is not possible, any tumor biopsy obtained at or since the time of diagnosis can be used (a maximum of two years from biopsy excision is preferred).
3. At least one extracranial measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation.
4. Patient is 18 years of age or older at the time of informed consent.
5. Patients may or may not have neurological symptoms but must:
• Be able to swallow and retain oral medication.
• Be neurologically stable within at least 1 week prior to the first dose of study drug. Neurologically stable is defined as improved or stable neurological examination without increased doses of steroids to manage CNS symptoms within the last 5 days..
6. Patients may have received prior chemotherapy, crizotinib (other ALK inhibitors are not allowed), biologic therapy or other investigational agents. Patients must have recovered from all toxicities related to prior
anticancer therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the study.
• Patients who have been treated with chemotherapy, with biological therapy or otherinvestigational agent must have discontinued the treatment at least 2 weeks (14 days) prior to starting study drug. In
case last chemotherapy contains nitrosourea or mitomycin C, the treatment must be discontinued at least 6 weeks prior to the first dose of study drug.
• Patients, if previously treated with crizotinib must discontinue treatment at least 1 week (7 days) prior to the first dose of study drug.
7a. Patient must meet the following laboratory values at the screening visit:
- Absolute Neutrophil Count ≥ 1.5 x 109/L
- Platelets ≥ 75 x 109/L
- Hemoglobin (Hgb) ≥ 8 g/dL
- Serum creatinine < 1.5 mg/dL and /or calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 30 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 ALT ≤ 5 x ULN
- Alkaline phosphatase (ALP) ≤ 5.0 x ULN
- Serum amylase ≤ 2 x ULN
- Serum lipase ≤ ULN
- Fasting plasma glucose ≤ 200 mg/dL (≤ 11.1 mmol/L)
Other protocol-defined inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
1. Patient with a history of treatment with ceritinib. Patient with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
2. Patients who need whole brain radiation to control the brain metastases. Patients will not be eligible unless treated brain lesions are progressive or new brain lesions are observed since the post whole brain radiation therapy MRI.
3. In case active brain lesions (single or not) require local treatment but other active brain lesions do not and are not treated, patients will be excluded only if the local treatment (neurosurgical treatment or Stereotactic Radiosurgery ) for the brain metastases is conducted within 2 weeks prior to starting study drug. Patients must have recovered from
relevant toxicities related to these procedures to grade ≤ 1(CTCAE v 4.03) prior to receiving the first dose of study drug.
4. Planning of any brain local treatment (including but not limited to surgery, stereotactic radiosurgery, whole brain radiation, intrathecal chemotherapy) following the administration of the first dose of study drug.
5. 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 the first dose of study drug is allowed.
6. Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to the first dose of study drug 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 study treatment ≥1 week after the
procedure.
Other protocol-defined exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR), defined as the proportion of patients with a best overall confirmed response of CR or PR in the whole body as assessed per RECIST 1.1 by the investigator. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 8 (on Cycle 3 Day1) and every 8 weeks (i.e. every 2 cycles) |
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E.5.2 | Secondary end point(s) |
- Disease Control Rate (DCR) in the whole body as assessed per RECIST 1.1 by the Investigator
-The following intracranial endpoints will be evaluated per modified RECIST 1.1:
*Overall Intracranial Response Rate (OIRR) by Investigator and BIRC for patients with measurable brain metastases at baseline
*Intracranial Disease Control Rate (IDCR) at 8, 16 weeks and overall by Investigator and BIRC
*Time to intracranial tumor response (TTIR) by Investigator and BIRC for patients with measurable brain metastases at baseline
*Duration of intracranial response (DOIR) by Investigator and BIRC for patients with measurable brain metastases at baseline
-The following extracranial endpoints will be evaluated per RECIST 1.1:
*Overall Extracranial Response Rate (OERR) by Investigator and BIRC
*Extracranial Disease Control Rate (EDCR) at 8, 16 weeks by Investigator and BIRC
*Time to extracranial tumor response (TTER) by Investigator and BIRC
*Duration of extracranial response (DOER) by Investigator and BIRC
-The following whole body tumor-response related endpoints will be evaluated per RECIST 1.1:
*Overall response rate (ORR) by BIRC
*Disease control rate (DCR) by BIRC
*Time to tumor response (TTR) by Investigator and BIRC
*Duration of response (DOR) by Investigator by BIRC
*Progression free survival (PFS) by Investigator by BIRC
-Overall survival (OS)
-AEs, ECGs, vital signs and laboratory abnormalities
-Cmax on C2D1 and Cmin concentrations of Ceritinib in plasma.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Week 8 (on Cycle 3 Day1) and every 8 weeks (i.e. every 2 cycles) except for IDCR and EDCR at 24 weeks
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
France |
Germany |
Hong Kong |
Italy |
Korea, Democratic People's Republic of |
Netherlands |
New Zealand |
Russian Federation |
Singapore |
Spain |
Sweden |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will end at the later of 24 weeks after last patient treated in the study or once at least 75% of patients have died, have been lost to follow-up or have withdrawn consent for survival follow-up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 14 |