A clinical study of oral ceritinib in patients with ALK-Positive Non-Small Cell Lung Cancer metastatic to the brain and/or to leptomeninges.

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2014-000578-20-ES
• Date of registration: 09/02/2015
• Prospective Registration: Yes
• Primary sponsor: Novartis Farmacéutica, S.A.
• Public title: A clinical study of oral ceritinib in patients with ALK-Positive Non-Small Cell Lung Cancer metastatic to the brain and/or to leptomeninges.
• Scientific title: A phase II, multi-center, open-label, five-arm study to evaluate the efficacy and safety of oral ceritinib treatment for patients with ALK-Positive Non-Small Cell Lung Cancer (NSCLC) metastatic to the brain and/or to leptomeninges
• Date of first enrolment: 16/03/2015
• Target sample size: 125
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000578-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 5
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, France, Germany, Hong Kong, Israel, Italy, Korea, Democratic People's Republic of, Netherlands, New Zealand, Russian Federation, Singapore, Spain, Taiwan, United Kingdom, United States

Contacts

• Name: Departamento Médico Oncología (GMO)
• Affiliation: Novartis Farmacéutica, S.A.

• Name: Departamento Médico Oncología (GMO)
• Affiliation: Novartis Farmacéutica, S.A.

Key inclusion & exclusion criteria

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, assessed at a Novartis designated central laboratory using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). Patients must wait for the central result of the ALK rearrangement status before initiating treatment with ceritinib.
2. All patients 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 to send to the Novartis designated central laboratory. If that is not possible, any tumor biopsy obtained at or since the time of diagnosis can be used.
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, biologic therapy or other investigational agents including other ALK inhibitors. 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 other investigational agent (except ALK inhibitors) must have discontinued the treatment at least 2 weeks (14 days) prior to starting study drug. In case last chemotherapy contains nitroso-urea 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 ALK inhibitors (including crizotinib) must discontinue treatment at least 1 week (7 days) prior to the first dose of study drug.

Other protocol-defined inclusion criteria may apply.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 105
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Non-small cell lung cancer
MedDRA version: 18.0 Level: LLT Classification code 10024233 Term: Leptomeningeal metastases System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.0 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.0 Level: LLT Classification code 10006128 Term: Brain metastases System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: ceritinib
Product Code: LDK378
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ceritinib
CAS Number: LDK378
Current Sponsor code: LDK378
Other descriptive name: LDK378
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Primary Outcome(s)

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.

Main Objective: 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.

Timepoint(s) of evaluation of this end point: Week 8 (on Cycle 3 Day1) and every 8 weeks (i.e. every 2 cycles)

Secondary Objective: - 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) overall and for each of Arms 1 through 4
-To evaluate extracranial tumor-response related endpoints as assessed by investigators and BIRC (using RECIST 1.1 criteria) overall and for each of Arms 1 through 4
-To evaluate whole body tumor-response related endpoints as assessed by investigators and BIRC(using RECIST 1.1 criteria) overall and for each of Arms 1 through 4
-To evaluate overall survival (OS) overall and for each of Arms 1 through 5
-To evaluate safety overall and for each of Arms 1 through 5
-To characterize the PK of Ceritinib in this patient population

Secondary Outcome(s)

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

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 24 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 24 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 and laboratory abnormalities
-Cmax on C2D1 and Cmin concentrations of Ceritinib in plasma.

Secondary ID(s)

CLDK378A2205

Source(s) of Monetary Support

Novartis Pharma Services AG

Ethics review

Status: Approved
Approval date:
Contact: