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 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: CLDK378A22052014-000578-20
• Study Type: interventional
• Target: 156
• Locations: 17 countries
• Sites: 57

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.

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

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR) Per Investigator Assessment

  Overall response rate (ORR) is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (\< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed \& non-target lesions are not in progression or in complete response.

  43 months

Secondary Outcomes (27)

• Disease Control Rate (DCR) Per Investigator Assessment

  43 months

• Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment

  43 months

• Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment

  43 months

• Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16

  Week 8 and Week 16

• Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall

  43 months

Study Arms (5)

Arm 1 (PrALKi=Y, PrBRad=Y)

EXPERIMENTAL

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).

Drug: Ceritinib

Arm 2 (PrALKi=Y, PrBRad=N)

EXPERIMENTAL

Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 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).

Drug: Ceritinib

Arm 3 (PrALKi=N, PrBRad=Y)

EXPERIMENTAL

Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

Drug: Ceritinib

Arm 4 (PrALKi=N, PrBRad=N)

EXPERIMENTAL

Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

Drug: Ceritinib

Arm 5 (LepDis)

EXPERIMENTAL

Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.

Drug: Ceritinib

Interventions

Ceritinib DRUG

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.

Also known as: LDK378

Arm 1 (PrALKi=Y, PrBRad=Y); Arm 2 (PrALKi=Y, PrBRad=N); Arm 3 (PrALKi=N, PrBRad=Y); Arm 4 (PrALKi=N, PrBRad=N); Arm 5 (LepDis)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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 must have been diagnosed with leptomeningeal carcinomatosis.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (57)

USC Kenneth Norris Comprehensive Cancer Center SC-3

Los Angeles, California, 90033, United States

Location

Stanford Universtiy Medical Center SC-5

Stanford, California, 94304, United States

Location

Memorial Hospital of South Bend

South Bend, Indiana, 46601, United States

Location

Dana Farber Cancer Institute SC-12

Boston, Massachusetts, 02215, United States

Location

The Ohio State University Comprehensive Cancer Center Ohio State University

Columbus, Ohio, 43221, United States

Location

Southwestern Regional Medical Center

Tulsa, Oklahoma, 74133, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98105, United States

Location

Novartis Investigative Site

Auckland, Australia

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Salvador, Estado de Bahia, 41253-190, Brazil

Location

Novartis Investigative Site

Natal, Rio Grande do Norte, 59075 740, Brazil

Location

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90610-000, Brazil

Location

Novartis Investigative Site

Itajaí, Santa Catarina, 88301-229, Brazil

Location

Novartis Investigative Site

Barretos, São Paulo, 14784 400, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 01246 000, Brazil

Location

Novartis Investigative Site

São Paulo, 01236 030, Brazil

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Marseille, Bouches Du Rhone, 13915, France

Location

Novartis Investigative Site

Paris, 75970, France

Location

Novartis Investigative Site

Rennes, 35043, France

Location

Novartis Investigative Site

Saint-Herblain Cédex, 44805, France

Location

Novartis Investigative Site

Strasbourg, 67091, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Bad Berka, 99437, Germany

Location

Novartis Investigative Site

Cologne, 50937, Germany

Location

Novartis Investigative Site

Pokfulam, Hong Kong, Hong Kong

Location

Novartis Investigative Site

Livorno, LI, 57124, Italy

Location

Novartis Investigative Site

Monza, MB, 20900, Italy

Location

Novartis Investigative Site

Messina, ME, 98158, Italy

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Milan, MI, 20141, Italy

Location

Novartis Investigative Site

Perugia, PG, 06129, Italy

Location

Novartis Investigative Site

Aviano, PN, 33081, Italy

Location

Novartis Investigative Site

Parma, PR, 43100, Italy

Location

Novartis Investigative Site

Roma, RM, 00155, Italy

Location

Novartis Investigative Site

Orbassano, TO, 10043, Italy

Location

Novartis Investigative Site

Verona, VR, 37126, Italy

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

NKI-AVL, Department of Thoracic-Oncology

Amsterdam, 1066 CX, Netherlands

Location

Novartis Investigative Site

Saint Petersburg, 192148, Russia

Location

Novartis Investigative Site

Singapore, 169610, Singapore

Location

Novartis Investigative Site

Seoul, Korea, 05505, South Korea

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Seoul, 06351, South Korea

Location

Novartis Investigative Site

Málaga, Andalusia, 29010, Spain

Location

Novartis Investigative Site

Barcelona, 08041, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Madrid, 28040, Spain

Location

Novartis Investigative Site

Madrid, 28222, Spain

Location

Novartis Investigative Site

Tainan, Taiwan ROC, 70403, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Taipei, 11217, Taiwan

Location

Novartis Investigative Site

Istanbul, TUR, 34098, Turkey (Türkiye)

Location

Novartis Investigative Site

Ankara, 06100, Turkey (Türkiye)

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Novartis Investigative Site

Birmingham, B9 5SS, United Kingdom

Location

Novartis Investigative Site

London, SE1 9RT, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 35091443 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Brain Neoplasms

Interventions

ceritinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 8, 2015
• First Posted: January 13, 2015
• Study Start: April 1, 2015
• Primary Completion: February 6, 2019
• Study Completion: February 6, 2019
• Last Updated: April 21, 2020
• Results First Posted: February 21, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share

Locations

BR (7); GB (3); SG (1); ES (5); FR (6); IT (12); TU (2); US (7); KR (3); TW (3); BE (1); RU (1); AU (1); HK (1); NL (1); DE (2); CA (1)