Clinical trial NCT02336451: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: ALK-positive Non-small Cell Lung Cancer
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-01-13
Enrollment: 156
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Response Rate (ORR) Per Investigator Assessment
timeFrame: 43 months
Secondary outcomes:
measure: Disease Control Rate (DCR) Per Investigator Assessment
timeFrame: 43 months
measure: Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment
timeFrame: 43 months
measure: Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment
timeFrame: 43 months
measure: Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16
timeFrame: Week 8 and Week 16
measure: Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall
timeFrame: 43 months
measure: Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16
timeFrame: Week 8 and Week 16
measure: Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall
timeFrame: 43 months
measure: Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment
timeFrame: 43 months
measure: Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment
timeFrame: 43 months
measure: Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment
timeFrame: 43 months
measure: Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall
timeFrame: 43 months
measure: Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16
timeFrame: Week 8 and Week 16
measure: Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment
timeFrame: 43 months
measure: Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment
timeFrame: 43 months
measure: Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment
timeFrame: 43 months
measure: Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment
timeFrame: 43 months
measure: Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
timeFrame: 43 months
measure: Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment
timeFrame: 43 months
measure: Overall Survival (OS)
timeFrame: 24 weeks
measure: Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough)
timeFrame: Cmax: Cycle 2 Day 1 (C2D1); Cmin: C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1 - all 0hr (pre dose)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC Kenneth Norris Comprehensive Cancer Center SC-3
state: California
city: Stanford
country: United States
facility: Stanford Universtiy Medical Center SC-5
state: California
city: South Bend
country: United States
facility: Memorial Hospital of South Bend
state: Indiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC-12
state: Massachusetts
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center Ohio State University
state: Ohio
city: Tulsa
country: United States
facility: Southwestern Regional Medical Center
state: Oklahoma
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Auckland
country: Australia
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: Bahia
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Natal
country: Brazil
facility: Novartis Investigative Site
state: RN
city: Itajai
country: Brazil
facility: Novartis Investigative Site
state: SC
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Marseille cedex 20
country: France
facility: Novartis Investigative Site
state: Bouches Du Rhone
city: Paris
country: France
facility: Novartis Investigative Site
city: Rennes
country: France
facility: Novartis Investigative Site
city: Saint-Herblain Cédex
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Bad Berka
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Pokfulam
country: Hong Kong
facility: Novartis Investigative Site
city: Livorno
country: Italy
facility: Novartis Investigative Site
state: LI
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Messina
country: Italy
facility: Novartis Investigative Site
state: ME
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Aviano
country: Italy
facility: Novartis Investigative Site
state: PN
city: Parma
country: Italy
facility: Novartis Investigative Site
state: PR
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: NKI-AVL, Department of Thoracic-Oncology
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Chow LQM, Barlesi F, Bertino EM, van den Bent MJ, Wakelee HA, Wen PY, Chiu CH, Orlov S, Chiari R, Majem M, McKeage M, Yu CJ, Garrido P, Hurtado FK, Arratia PC, Song Y, Branle F, Shi M, Kim DW. ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges. Clin Cancer Res. 2022 Jun 13;28(12):2506-2516. doi: 10.1158/1078-0432.CCR-21-1838.