A Phase II Study to Evaluate the Efficacy and Safety of Oral Ceritinib in Patients With ALK-positive NSCLC Metastatic to the Brain and/or to Leptomeninges
Condition: ALK-positive Non-small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Ceritinib
Intervention description: LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.
Intervention MeSH terms: Ceritinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 156.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ALK-positive; NSCLC; non-small cell lung cancer; brain metastasis; metastatic to the brain and/or to leptomeninges; ceritinib; LDK378; NSCLC metastatic to the brain; leptomeninges harboring a confirmed ALK rearrangement

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.
    

Eligibility criteria:

        Inclusion 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

          -  At least one extracranial measurable lesion as defined by RECIST 1.1. 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.

        Exclusion Criteria:

          -  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.