Clinical trial NCT01801111: A Study of Alectinib (RO5424802) in Participants With Non-Small Cell Lung Cancer Who Have Anaplastic Lymphoma Kinase (ALK) Mutation and Failed Crizotinib Treatment
Official title: An Open-Label, Non-Randomized, Multicenter Phase I/II Trial of RO5424802 Given Orally to Non-Small Cell Lung Cancer Patients Who Have ALK Mutation and Who Have Failed Crizotinib Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Non-Small-Cell Lung Carcinoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-02-28
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This open-label, non-randomized, multicenter, Phase 1/2 study will evaluate the safety and efficacy of alectinib in participants with non-small cell lung cancer who have ALK mutation and failed crizotinib treatment. In Part 1, cohorts of participants will receive escalating doses of alectinib orally twice daily. In Part 2, participants will receive the recommended phase 2 dose (RP2D) of alectinib as determined in Part 1. Treatment will continue in Part 1 and Part 2 on the same dose until disease progression. In Part 3, following disease progression, participants without epidermal growth factor receptor (EGFR) mutation will be offered continued treatment with alectinib, participants with EGFR mutations will be offered a combination of alectinib and erlotinib.


Eligibility criteria: Inclusion Criteria:

* Locally advanced or metastatic non-small cell lung cancer (stage IIIB or IV by American Joint Committee on Cancer \[AJCC\])
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Documented ALK rearrangement based on Food and Drug Administration (FDA)-approved test
* Prior treatment with crizotinib and progression according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) criteria. Participants had to have a minimum 1-week wash-out period between the last dose of crizotinib and the first dose of study treatment. Participants can either be chemotherapy-naïve or have received at least one line of platinum-based chemotherapy
* Adequate hematologic, hepatic, and renal function
* Participants with brain or leptomeningeal metastases are allowed if protocol defined criteria are met
* Measurable disease according to RECIST v1.1 prior to administration of first dose of study drug

Exclusion Criteria:

* Receipt of any other ALK inhibitors in addition to crizotinib
* Receipt of any prior cytotoxic chemotherapy for ALK-positive NSCLC within 4 weeks prior to the first dose of study drug
* Participants who received crizotinib or any other tyrosine kinase inhibitors need to have a minimum 1-week washout period before the first dose of study drug
* Active or uncontrolled infectious diseases requiring treatment
* National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) Grade 3 or higher toxicities due to prior therapy that have not shown improvement and are considered to interfere with current study medication
* History of organ transplant
* Co-administration of anti-cancer therapies other than those administered in this study
* Baseline corrected Q-T interval (QTc) greater than (\>) 470 milliseconds, or baseline symptomatic bradycardia (less than 45 heart beats per minute)
* Pregnant or breastfeeding women
* Known Human Immunodeficiency Virus (HIV) positivity or Acquired Immunodeficiency Syndrome (AIDS)-related illness
* History of hypersensitivity to any of the additives in the alectinib formulation
* Any clinically significant concomitant disease or condition that could interfere with, or for which treatment might interfere with, the conduct of the study, or absorption of oral medications, or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in the study

Primary outcomes:
measure: Recommended Phase 2 Dose (RP2D) of Alectinib
timeFrame: Cycle 1 (up to 28 days)
measure: Percentage of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (up to 28 days)
measure: Percentage of Participants Achieving Objective Response (Complete Response [CR] or Partial Response [PR]) as Assessed by Independent Radiological Review Committee (IRC) in Response Evaluable (RE) Population
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Pretreated Participants
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Secondary outcomes:
measure: Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Naive Participants
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in RE Population
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Pretreated Participants
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Naive Participants
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Duration of Response (DoR) as Assessed by IRC in RE Population
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants With PD as Assessed by IRC According to RECIST v1.1 or Death From Any Cause in Safety Population
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Progression Free Survival (PFS) as Assessed by IRC in Safety Population
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants Who Died of Any Cause
timeFrame: Baseline up to death from any cause (up to approximately 4 years)
measure: Overall Survival (OS)
timeFrame: Baseline up to death from any cause (up to approximately 4 years)
measure: Percentage of Participants Achieving CR, PR or Stable Disease (SD) According to RECIST v1.1 in RE Population
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants Achieving Central Nervous System (CNS) Objective Response as Assessed by IRC According to RECIST v1.1
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: Percentage of Participants Achieving CNS Objective Response as Assessed by IRC According to Radiology Assessment in Neuro-Oncology (RANO) Criteria
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks)
measure: CNS Duration of Response (CDoR) as Assessed by IRC According to RECIST v1.1
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
measure: CDoR as Assessed by IRC According to RANO Criteria
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks)
measure: Percentage of Participants With CNS Progression as Assessed by IRC According to RECIST v 1.1
timeFrame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks)
measure: Maximum Observed Plasma Concentration (Cmax) of Alectinib
timeFrame: Pre-dose (0 hours [hrs]), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Time to Cmax (Tmax) of Alectinib
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Time to Last Measurable Plasma Concentration (Tlast) of Alectinib
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to 10 Hours Post-dose (AUC[0-10]) of Alectinib
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Tlast (AUC[0-last]) of Alectinib
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Cmax of Alectinib Metabolite
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Tmax of Alectinib Metabolite
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Tlast of Alectinib Metabolite
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: AUC(0-10) of Alectinib Metabolite
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: AUC(0-last) of Alectinib Metabolite
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Metabolite to Parent Ratio Based on AUC(0-10)
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Metabolite to Parent Ratio Based on AUC(0-last)
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
measure: Trough Plasma Concentration (Ctrough) of Alectinib
timeFrame: Pre-dose (0 hrs) on Day 21 of Cycle 1
measure: Ctrough of Alectinib Metabolite
timeFrame: Pre-dose (0 hrs) on Day 21 of Cycle 1
measure: Peak to Trough Ratio of Alectinib
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 21 of Cycle 1
measure: Accumulation Ratio of Alectinib
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1
measure: Accumulation Ratio of Alectinib Metabolite
timeFrame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Fullerton
country: United States
facility: St. Jude Heritage Healthcare
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital
state: California
city: San Luis Obispo
country: United States
facility: Coastal Integrative Cancer Care
state: California
city: Santa Monica
country: United States
facility: UCLA Cancer Center; Premiere Oncology, A Medical Corporation
state: California
city: Miami
country: United States
facility: Advanced Medical Specialties
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Inst
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Zion
country: United States
facility: Midwestern Regional Medical Center; Office of Research
state: Illinois
city: Saint Louis
country: United States
facility: Washington University; Wash Uni. Sch. Of Med
state: Missouri
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: New York
country: United States
facility: Columbia University Medical Center; Department of Hematology/Oncology
state: New York
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Dallas
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Chermside
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Douglas
country: Australia
facility: Townsville General Hospital
state: Queensland
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Gent
country: Belgium
facility: UZ Gent
city: Roeselare
country: Belgium
facility: AZ Delta (Campus Wilgenstraat)
city: Herlev
country: Denmark
facility: University Hospital Herlev
city: Angers
country: France
facility: CHU Angers - Hôpital Hôtel Dieu
city: Brest
country: France
facility: Hopital Morvan
city: Caen
country: France
facility: Centre Francois Baclesse
city: Dijon
country: France
facility: Centre Georges François Leclerc; Service Pharmacie, Bp 77980
city: Grenoble
country: France
facility: CHU de Grenoble - Hôpital Nord; Service d'Oncologie Thoracique
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille cedex 20
country: France
facility: Hôpital Nord - AP-HM Marseille#; Gastroenterology and Hepatology
city: Pessac
country: France
facility: Groupe Hospitalier Sud - Hôpital Haut Lévêque
city: Rennes
country: France
facility: Hopital Pontchaillou - CHU de Rennes
city: St Herblain
country: France
facility: ICO Rene Gauducheau; CEC
city: Strasbourg
country: France
facility: Nouvel Hopital Civil - CHU Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital Larrey
city: Berlin
country: Germany
facility: Charité Campus Virchow-Klinikum; Department of Cardiology
city: Düsseldorf
country: Germany
facility: Diakonie Kaiserswerth; Florence-Nightingale-Krankenhaus
city: Großhansdorf
country: Germany
facility: LungenClinic Großhansdorf
city: Hemer
country: Germany
facility: Lungenklinik Hemer
city: Koeln
country: Germany
facility: Klinikum Koeln-Merheim
city: Rheine
country: Germany
facility: Mathias-Spital Rheine
city: Parma
country: Italy
facility: A.O. Universitaria Di Parma
state: Emilia-Romagna
city: Aviano
country: Italy
facility: Irccs Centro Di Riferimento Oncologico (CRO)
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena IRCCS
state: Lazio
city: Roma
country: Italy
facility: AO San Camillo Forlanini
state: Lazio
city: Milano
country: Italy
facility: Ospedale San Raffaele
state: Lombardia
city: Milano
country: Italy
facility: Istituto Europeo Di Oncologia
state: Lombardia
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Niguarda (Ospedale Niguarda Ca' Granda)
state: Lombardia
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
state: Toscana
city: Lido Di Camaiore
country: Italy
facility: Ospedale Versilia
state: Toscana
city: Lucca
country: Italy
facility: Presidio Ospedaliero Campo di Marte
state: Toscana
city: Perugia
country: Italy
facility: Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia
state: Umbria
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System; Pharmacy
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Luxembourg
country: Luxembourg
facility: Centre Hospitalier de Luxembourg
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek Ziekenhuis
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Centre; Afdeling Klinische Farmacie en Toxicologie
city: Moskva
country: Russian Federation
facility: FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"; Chemotherapy Departement
state: Moskovskaja Oblast
city: Singapore
country: Singapore
facility: National University Hospital; Investigational Medicine Unit
city: Singapore
country: Singapore
facility: Johns Hopkins Singapore
city: Alicante
country: Spain
facility: Hospital General Univ. de Alicante
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Quiron Dexeus
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Clínico San Carlos; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Zaragoza
country: Spain
facility: Hosp Clinico Univ Lozano Blesa
city: Stockholm
country: Sweden
facility: Karolinska
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung Univ Hosp
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: London
country: United Kingdom
facility: Royal Marsden Hospital;Dept of Haematology Oncology Research
city: London
country: United Kingdom
facility: Royal Marsden Hospital - London
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Ou SI, Gadgeel SM, Barlesi F, Yang JC, De Petris L, Kim DW, Govindan R, Dingemans AM, Crino L, Lena H, Popat S, Ahn JS, Dansin E, Mitry E, Muller B, Bordogna W, Balas B, Morcos PN, Shaw AT. Pooled overall survival and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2020 Jan;139:22-27. doi: 10.1016/j.lungcan.2019.10.015. Epub 2019 Oct 14.
citation: Morcos PN, Nueesch E, Jaminion F, Guerini E, Hsu JC, Bordogna W, Balas B, Mercier F. Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer. Cancer Chemother Pharmacol. 2018 Jul;82(1):129-138. doi: 10.1007/s00280-018-3597-5. Epub 2018 May 10.
citation: Gadgeel SM, Shaw AT, Govindan R, Gandhi L, Socinski MA, Camidge DR, De Petris L, Kim DW, Chiappori A, Moro-Sibilot DL, Duruisseaux M, Crino L, De Pas T, Dansin E, Tessmer A, Yang JC, Han JY, Bordogna W, Golding S, Zeaiter A, Ou SI. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Dec;34(34):4079-4085. doi: 10.1200/JCO.2016.68.4639. Epub 2016 Oct 31.