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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

NCT02336451

Description:

This is a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment will be 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 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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: CLDK378A2205
  • SECONDARY ID: 2014-000578-20
  • NCT ID: NCT02336451

Conditions

  • ALK-positive Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
LDK378CeritinibLDK378

Purpose

This is a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment will be 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 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.

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 will be 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 may be 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 is slow.

        -  Arm 1 will include 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 will include 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 will include 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 will include 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 will include any patients with leptomeningeal carcinomatosis with or without
           evidence of active lesion at the baseline Gadoliniumenhanced brain MRI. Note: Previous
           treatment with ALK inhibitors other than crizotinib is not allowed in Arms 1, 2, and 5.

      Ceritinib will be administered orally once daily at a dose of 750 mg (five 150 mg capsules)
      on a continuous dosing schedule. The treatment period will start on Cycle 1 Day 1.

      Complete tumor assessments including gadolinium enhanced brain MRI will be 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 will include (S)AEs, physical examination, vital
      signs, ECGs, laboratory parameters and WHO performance status. Blood and CSF samples for PK
      will also be collected.
    

Trial Arms

NameTypeDescriptionInterventions
LDK378ExperimentalLDK378 will be administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule. The treatment period will start on Cycle 1 Day 1.
  • LDK378

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 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

          -  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.

          -  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.

          -  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.

          -  Patient has life expectancy ≥ 6 weeks.

          -  Patient has a WHO performance status 0-2.

        Patients in Arm 1 to 4 must also meet the following inclusion criteria:

        - Patients must have active brain metastases from NSCLC, confirmed by Gadolinium-enhanced
        MRI without concomitant leptomeningeal carcinomatosis. Dose of steroids must be stable for
        5 days before the baseline brain MRI.

        Patients in Arm 5 must also meet the following inclusion criteria:

        - Patients must be diagnosed with leptomeningeal carcinomatosis.

        Exclusion Criteria:

          -  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.

          -  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 has been diagnosed and/or required therapy within the past 3 years.
             Exceptions to this exclusion include the following: completely resected basal cell and
             squamous cell skin cancers, and completely resected carcinoma in situ of any type.

          -  Patient has impairment of GI function or GI disease that may significantly alter the
             absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting,
             diarrhea, or malabsorption syndrome).

          -  Patient is receiving unstable or increasing doses of corticosteroids.

          -  Patient has other severe, acute, or chronic medical conditions including uncontrolled
             diabetes mellitus or psychiatric conditions or laboratory abnormalities that in the
             opinion of the investigator may increase the risk associated with study participation,
             or that may interfere with the interpretation of study results.

        Other protocol-defined inclusion/exclusion criteria may apply.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:24 weeks
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Disease Control Rate (DCR)
Time Frame:24 weeks
Safety Issue:
Description:The DCR is defined as the proportion of patients with a best overall response of CR, PR or SD in the whole body, as assessed per RECIST 1.1 by the investigator.
Measure:Overall Intracranial Response Rate (OIRR) per modified RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:• Overall Intracranial Response Rate (OIRR) by Investigator and BIRC for patients with measurable brain metastases at baseline
Measure:Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1
Time Frame:8 and 16 weeks
Safety Issue:
Description:Intracranial Disease Control Rate (IDCR) at 24 weeks and overall by Investigator and BIRC
Measure:Time to intracranial tumor response (TTIR) per modified RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Time to intracranial tumor response (TTIR) by Investigator and BIRC for patients with measurable brain metastases at baseline
Measure:Duration of intracranial response (DOIR) per modified RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Duration of intracranial response (DOIR) by Investigator and BIRC for patients with measurable brain metastases at baseline
Measure:Overall Extracranial Response Rate (OERR) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Overall Extracranial Response Rate (OERR) by Investigator and BIRC
Measure:Extracranial Disease Control Rate (EDCR) per RECIST 1.1
Time Frame:8 and 16 weeks
Safety Issue:
Description:Extracranial Disease Control Rate (EDCR) at 24 weeks by Investigator and BIRC
Measure:Time to extracranial tumor response (TTER) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Time to extracranial tumor response (TTER) by Investigator and BIRC
Measure:Duration of extracranial response (DOER) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Duration of extracranial response (DOER) by Investigator and BIRC
Measure:Overall response rate (ORR) (whole body) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Overall response rate (ORR) by BIRC
Measure:Disease control rate (DCR) (whole body) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Disease control rate (DCR) by BIRC
Measure:Time to tumor response (TTR) (whole body) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Time to tumor response (TTR) by Investigator and BIRC
Measure:Duration of response (DOR) (whole body) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Duration of response (DOR) by Investigator by BIRC
Measure:Progression free survival (PFS) (whole body) per RECIST 1.1
Time Frame:24 weeks
Safety Issue:
Description:Progression free survival (PFS) by Investigator by BIRC
Measure:Overal survival
Time Frame:24 weeks
Safety Issue:
Description:Overal survival (OS)
Measure:Overall Safety
Time Frame:24 weeks
Safety Issue:
Description:AEs, ECGs and laboratory abnormalities
Measure:Pharmacokinetics of ceritinib in study population
Time Frame:24 weeks
Safety Issue:
Description:Cmax on C2D1 and Cmin concentrations of ceritinib in plasma.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • ALK-positive
  • NSCLC
  • brain metastasis
  • metastatic to the brain and/or to leptomeninges.

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