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

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Brief Title

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

Official 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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall Response Rate (ORR) Per Investigator Assessment

Secondary Outcome

 Disease Control Rate (DCR) Per Investigator Assessment

Condition

ALK-positive Non-small Cell Lung Cancer

Intervention

Ceritinib

Study Arms / Comparison Groups

 Arm 1 (PrALKi=Y, PrBRad=Y)
Description:  Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

156

Start Date

April 1, 2015

Completion Date

February 6, 2019

Primary Completion Date

February 6, 2019

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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Novartis Pharmaceuticals, , 

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT02336451

Organization ID

CLDK378A2205

Secondary IDs

2014-000578-20

Responsible Party

Sponsor

Study Sponsor

Novartis Pharmaceuticals


Study Sponsor

Novartis Pharmaceuticals, Study Director, Novartis Pharmaceuticals


Verification Date

April 2020