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
Description
Brief Summary
This was a phase II, multi-center, open-label, five-arm study in which the efficacy and
safety of oral ceritinib treatment was assessed in patients with NSCLC metastatic to the
brain and/or to leptomeninges harboring a confirmed ALK rearrangement, 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 was
not locally available, a test to confirm ALK rearrangement was performed by a Novartis
designated central laboratory. Patients waited for the central laboratory result of the ALK
rearrangement status before initiating treatment with ceritinib.
Detailed Description
Approximately 160 patients diagnosed with ALK-positive metastatic NSCLC (according to the 7th
edition of the AJCC [American Joint Committee on Cancer] Cancer Staging Manual) and active
lesions in the brain and/or diagnosed with leptomeningeal carcinomatosis were included in the
study, approximately 40 patients in Arm 1 and Arm 2, approximately 30 patients in Arms 3 and
Arm 4, and approximately 20 patients in Arm 5. Additional patients were enrolled in Arm 4 to
achieve approximately 60 patients in Arms 3 and 4 together (i.e. ALKi naïve patients), if
enrollment rate in Arm 3 was slow.
- Arm 1 included patients with metastases in the brain without evidence of leptomeningeal
carcinomatosis, previously treated with radiation to the brain and with prior exposure
to an ALKi.
- Arm 2 included patients with metastases in the brain without evidence of leptomeningeal
carcinomatosis, previously untreated with radiation to the brain but with prior exposure
to an ALKi.
- Arm 3 included patients with metastases in the brain without evidence of leptomeningeal
carcinomatosis, previously treated with radiation to the brain but with no prior
exposure to an ALKi.
- Arm 4 included patients with metastases in the brain without evidence of leptomeningeal
carcinomatosis, previously untreated with radiation to the brain and with no prior
exposure to an ALKi
- Arm 5 included any patients with leptomeningeal carcinomatosis with or without evidence
of active lesion at the baseline Gadolinium-enhanced brain MRI.
Note: Previous treatment with ALK inhibitors other than crizotinib was not allowed in Arms 1,
2, and 5.
Ceritinib was administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a
continuous dosing schedule. The treatment period started on Cycle 1 Day 1.
Complete tumor assessments including gadolinium enhanced brain MRI was repeated at Week 8 (on
Cycle 3 Day 1) and every 8 weeks (i.e. every 2 cycles) thereafter or earlier if clinically
indicated. Safety evaluations included (S)AEs, physical examination, vital signs, ECGs,
laboratory parameters and WHO performance status. Blood and CSF samples for PK were also
collected.
Phase
Phase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.Inclusion and Exclusion Criteria
- - 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 was not locally available, a test to confirm ALK rearrangement was to be performed by a Novartis designated central laboratory. Patients had to wait for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib
- A previously irradiated site lesion could only be counted as a target lesion if there was clear sign of progression since the irradiation. - Patients could or could not have neurological symptoms but must have been able to swallow and retain oral medication. - Patients had to be neurologically stable within at least 1 week prior to the first dose of study drug. - Patients could have received prior chemotherapy, crizotinib (other ALK inhibitors were 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 were allowed to enter the study. - Patient had life expectancy ≥ 6 weeks. - Patient had a WHO performance status 0-2. Patients in Arm 1 to 4 had to also meet the following inclusion criteria: - Patients had to have active brain metastases from NSCLC, confirmed by Gadolinium-enhanced MRI without concomitant leptomeningeal carcinomatosis. Dose of steroids had to be stable for 5 days before the baseline brain MRI. Patients in Arm 5 had to also meet the following inclusion criteria: - Patients must have been diagnosed with leptomeningeal carcinomatosis.
- Patients who needed whole brain radiation to control the brain metastases. Patients were not eligible unless treated brain lesions were progressive or new brain lesions were observed since the post whole brain radiation therapy MRI.
- 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.
- Patient with a concurrent malignancy or history of a malignant disease other than NSCLC that had been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion included the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.
- Patient had impairment of GI function or GI disease that could significantly alter the absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
- Patient was receiving unstable or increasing doses of corticosteroids.
- Patient had other severe, acute, or chronic medical conditions including uncontrolled diabetes mellitus or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator could increase the risk associated with study participation, or that could interfere with the interpretation of study results.
Sites
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