LDK378 Versus Chemotherapy in ALK Rearranged (ALK Positive) Patients Previously Treated With Chemotherapy (Platinum Doublet) and Crizotinib
- Conditions
- Non-Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT01828112
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The primary purpose of the study was to compare the antitumor activity of LDK378 vs. chemotherapy in patients previously treated with chemotherapy (platinum doublet) and crizotinib. Patients in the chemotherapy arm were given the option to switch to LDK378 after confirmed progressive disease (PD), while also had the choice to continue with pemetrexed treatment.
- Detailed Description
A total of 231 patients were randomized to one of the two treatment arms in a 1:1 ratio. Randomization was stratified by World Health Organization (WHO) performance status (0 versus 1-2) and whether the patient had brain metastases at screening. The study was planned to be ended once the final overall survival (OS) analysis was performed (at the earliest of approximately 196 deaths observed or statistical significance reached at earlier OS interim analysis).
Following an agreement between Novartis and European Medicines Agency (EMA) in May 2023 to terminate the trial earlier, this study was completed when the total number of deaths was 190. Patients who had Response Evaluation Criteria In Solid Tumors (RECIST)-defined disease progression as confirmed by the Blinded Independent Review Committee (BIRC), but who, in the opinion of the Investigator, had continued clinical benefit from study treatment on either the chemotherapy arm or the ceritinib arm, continued to receive treatment. These patients continued assessments in the treatment phase. In addition, only patients randomized to the chemotherapy arm were allowed to crossover to receive ceritinib therapy (extension treatment \[ET\] phase) after BIRC-confirmed, RECIST-defined disease progression, and provided they met the eligibility requirements.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 231
- Patient has a histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as assessed by the FDA approved Abbott FISH Test.
- Patient has stage IIIB or IV diagnosis and must have received one or two prior regimens (including platinum- doublet) of cytotoxic chemotherapy for the treatment of locally advanced or metastatic NSCLC.
- Patient has at least one 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 must have received previous treatment with crizotinib for the treatment of locally advanced or metastatic NSCLC.
- Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
- Patient with a history of severe hypersensitivity reaction to pemetrexed or docetaxel or any known excipients of these drugs.
- Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ceritinib Ceritinib Ceritinib 750 mg Chemotherapy Pemetrexed Chemotherapy as determined by BIRC Chemotherapy Docetaxel Chemotherapy as determined by BIRC
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC) From the date of randomization to the date of first radiologically documented disease progression or death due to any cause up to approximately 24 months PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Up to approximately 114 months OS was defined as time from date of randomization to date of death due to any cause.
Progression Free Survival (PFS) Per Investigator Assessment Up to approximately 84 months PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
Overall Response Rate (ORR) Per BIRC Up to approximately 54 months ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Overall Response Rate (ORR) Per Investigator Assessment Up to approximately 93 months ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Duration of Response (DOR) Per BIRC Up to approximately 54 months DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Duration of Response (DOR) Per Investigator Assessment Up to approximately 93 months DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Disease Control Rate (DCR) Per BIRC Up to approximately 54 months DCR was defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Disease Control Rate (DCR) Per Investigator Assessment Up to approximately 93 months DCR was defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time to Response (TTR) Per BIRC Up to approximately 52 weeks TTR was defined as the time from date of randomization to date of first documented response (CR or PR). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time to Response (TTR) Per Investigator Assessment Up to approximately 45 weeks TTR was defined as the time from date of randomization to date of first documented response (CR or PR). CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Overall Intracranial Response Rate (OIRR) Per BIRC Up to approximately 18 months OIRR was defined as the ORR based on lesions in brain (target, nontarget lesions (and new lesions, if applicable) and calculated as the percentage of patients with a best overall confirmed response of CR or PR in the brain per modified RECIST 1.1 as assessed by BIRC neuroradiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Intracranial Disease Control Rate (IDCR) Per BIRC Up to approximately 18 months IDCR was defined as the DCR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated as the proportion of patients with a best overall response of CR or PR or SD (or non-CR/nonPD) in the brain per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Duration of Intracranial Response (DOIR) Per BIRC Up to approximately 18 months DOIR was defined as the DOR based on lesions in brain (target, non-target lesions (and new lesions, if applicable) and calculated from the time of first documented response of CR or PR to the date of the first documented disease progression in the brain or death due to any cause per modified RECIST 1.1 as assessed by BIRC neuro-radiologist. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30) Screening and treatment phase up to 92 months The EORTC QLQ-C30 questionnaire contained 30 items and was composed of both multi-item scales and single item measures. These included five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global health status/quality of life (QoL) scale.
All of the scales and single items ranged from 0 to 100. A high scale score represented a higher response level. Thus, a high score for a functional scale indicated a high/healthy level of functioning, a high score for the QoL indicated high QoL, but a high score for a symptom scale/single item indicated a high level of symptomatology/problems. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.EORTC QLQ-LC13 Time to Definitive Deterioration Screening and treatment phase up to 92 months The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores ranged from 0 to 100. A high score indicated a high level of symptoms. QLQ-LC13 time to definitive deterioration was defined as the time from randomization to the earliest date a patient shows a 10 point or higher increase from baseline in any of the ALCLC13 scores related to pain in chest, cough, or dyspnea (with no later change below this threshold), or death due to any cause. Each cycle was 21 days.
Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS) Screening and treatment phase up to 92 months The LCSS patient scale uses a 24-hour recall period and contains nine items: six measuring major symptoms for lung cancer (appetite loss, fatigue, cough, dyspnea, hemoptysis, pain), and three summary items related to total symptom distress, normal activity status, and overall quality of life. The total scale used is a 100 mm visual analog scale to measure the intensity of patient responses, with zero corresponding to the lowest rating (best status) and 100 representing the highest rating (worst status). The total score was calculated as the mean of the 9 items. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.
Least Squares Mean Scores on the EQ-5D-5L Index Screening and treatment phase up to 92 months The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ-5D-5L index scores can range from -0.59 to 1, where 1 is the best possible health state. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.
Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS) Screening and treatment phase up to 92 months The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. EQ VAS scores can range from 0 to 100, where 100 is the best possible health state. Data from all collected time points were combined and presented using a repeated measures model for longitudinal data.
Cmax for Ceritinib Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. The observed maximum plasma concentration following administration
Tmax for Ceritinib Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. The time to reach peak or maximum concentration
Tlast for Ceritinib Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. The time to last quantifiable concentration
AUC0-24h for Ceritinib Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. The area under the plasma concentration-time curve calculated from time zero to 24 hours
Mean Accumulation Ratio (Racc) for Ceritinib Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. Accumulation ratio calculated using AUC0-24 values obtained from a dosing interval at steady-state (Cycle 2, Day 1) divided by AUC0-24 on Cycle 1, Day 1.
Clearance Rate at Steady State (CLss/F) for Ceritinib Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days. The apparent total body clearance from plasma. CLss/F is calculated from AUC0-24 assuming steady state (CLss/F=Dose/AUC0-24).
Post-Hoc: All Collected Deaths Pre-treatment and on-treatment deaths: Up to approximately 8 years. Post-treatment survival follow-up deaths: Up to an additional 2.5 years. Pre-treatment deaths: from day of patient's informed consent to the day before first dose of study treatment. On-treatment deaths: from first dose of study treatment to 30 days following the last dose of study treatment at the end of treatment phase. For crossover patients, from first dose of ceritinib at the extension treatment phase to 30 days following the last dose. Survival Follow-up deaths: from Day 31 after last dose of study treatment to the data cut-off date.
Trial Locations
- Locations (14)
Uni Of Iowa Hospitals And Clinics
šŗšøIowa, Iowa, United States
Highlands Oncology Group
šŗšøFayetteville, Arkansas, United States
Memorial Cancer Institute
šŗšøHollywood, Florida, United States
Cancer Specialists of North Florida
šŗšøJacksonville, Florida, United States
University Of Miami
šŗšøMiami, Florida, United States
Loyola University Medical Center
šŗšøMarywood, Illinois, United States
Massachusetts General Hospital
šŗšøBoston, Massachusetts, United States
Oklahoma Cancer Specialists and Research Institute
šŗšøTulsa, Oklahoma, United States
Sarah Cannon Research Institute
šŗšøNashville, Tennessee, United States
Texas Oncology-Sugarland
šŗšøSugar Land, Texas, United States
Texas Oncology Cancer Care and Research Center
šŗšøWaco, Texas, United States
Virginia Cancer Specialists
šŗšøFairfax, Virginia, United States
Swedish Cancer Institute
šŗšøSeattle, Washington, United States
Novartis Investigative Site
š¬š§Southampton, United Kingdom