Anaplastic Lymphoma Kinase Gene Mutation, Anaplastic Lymphoma Kinase Gene Translocation, Carcinoma, Non-Small-Cell Lung, Drug Monitoring, Lung Cancer
Conditions
Keywords
Alectinib, Randomized Controlled Trial
Brief summary
The ADAPT ALEC randomized controlled trial (RCT) is performed in patients with Anaplastic Lymphoma Kinase (ALK) positive non-small cell lung cancer (NSCLC). The RCT will compare the use of Therapeutic Drug Monitoring (TDM) and dose increases if alectinib 35 ng/Ml (arm A) with standard of care (arm B).
Detailed description
The ADAPT ALEC trial is a phase IV, RCT in patients with ALK positive NSCLC treated with alectinib. A longer median progression free survival (mPFS) is expected in patients treated with standard dose alectinib when minimum plasma concentrations (Cmin) of alectinib exceed 435 ng/mL. The ADAPT ALEC trial will investigate whether using therapeutic drug monitoring (TDM) and increasing the dose of alectinib in patients with Cmin \<435 ng/mL, will raise the mPFS. We will compare mPFS in the subgroup of patients with an alectinib Cmin \<435 ng/mL using TDM and dose increases (arm A) to fixed dosing/standard of care (arm B).
Interventions
DRUGAlectinib
In case of an alectinib plasmaconcentration Cmin \<435 ng/mL, determined by TDM, and manageable toxicity, the alectinib dose will be increased with 150mg BID up to a maximum of 900mg BID. In case of unacceptable toxicity (i.e. unbearable or persistent grade 2 toxicity and grade 3/4 toxicity), the alectinib dose can be reduced by 150mg BID.
Sponsors
Amsterdam University Medical Center
Erasmus Medical Center
Maastricht University Medical Center
Radboud University Medical Center
The Netherlands Cancer Institute
Leiden University Medical Center
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
The alectinib Cmin for patients treated in arm B (standard dose arm) will be blinded to participants and care providers
Intervention model description
Both study-arms will receive oral alectinib (Alecensa®, Roche). In arm A (TDM arm), the alectinib dose will be increased if Cmin \<435 ng/mL and manageable toxicity. In both arms, alectinib dose can be reduced based on toxicity.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with locally advanced or metastatic NSCLC (stage IIIB to stage IV by AJCC 8th) * ECOG performance status 0-4 * Histologically or cytology confirmed NSCLC * Documented ALK rearrangement based on an EMA approved test * Patients can either be chemotherapy-naïve or have received one line of platinum-based chemotherapy * Patients with brain or leptomeningeal metastases are allowed on the study if the lesions are asymptomatic without neurological signs and clinically stable for at least 2 weeks without steroid treatment. Patients who do not meet these criteria are not eligible for the study * Measurable disease (by RECIST criteria version 1.1) prior to the first dose of study treatment * Signed writte Institutional Review Board (IRB)/Ethical Committee (EC) approved informed consent form, prior to performing any study-related procedures * Observational other studies are allwoed for patients included in this study * Local radiotherapy is allowed for pain
Exclusion criteria
* Any significant concomitant disease determined by the investigator to be potentially aggravated by the investigational drug * Consumption of agents which modulate CYP3A4 or agents with potential QT prolonging effects within 14 days prior to admission and during the study (see concomitant medication restrictions) * Any clinically significant concomitant disease or condition that could interfere with, or for which the 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 subject in this study. * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median progression free survival (mPFS) | mPFS will be assessed through study completion, after 12 months of follow-up. | PFS is measured from start of treatment to progressive disease, death or lost to follow-up.Patients who did not die or progress, or lost to follow-up, will be censored at their last available date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | Response will be assessed every 2-3 months. ORR will be determined after total study completion and 12 months of follow-up | ORR is the percentage of patients with partial response or complete response, according to RECIST v1.1, of the total treated population. |
| Median overall survival | Through total study completion, after 12 months of follow-up | mOS is defined as time from randomization to death from any cause in the total population. |
| Intracranial PFS | Progressive disease will be assessed once every 2-3 months. Intracranial PFS will be assessed through total study completion, after 12 months of follow-up | PFS is measured from start of treatment to progressive disease in the brain, death or lost to follow-up. Patients who did not die or progress, or lost to follow-up, will be censored at their last available date. |
| Patient adherence to alectinib treatment | Through study completion, an average of 2 years | This will be estimated by pill counts of returned medication as well as a patient diary on drug intake. |
| Succesfull Therapeutic Drug monitoring | 4 to 6 weeks after dose adjustment based on TDM | The percentage of succesfull TDM interventions, in which successful is defines as tartget attainment and manageable toxicity. |
| European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-C30) and the the Quality of Life Questionnaire-Lung Cancer 13 (EORTC QLQ-LC-13) module | Questionnaires will be filled in at baseline and every 3 months thereafter through study completion, an average of 2 years. | Mean change from baseline in EORTC QLQ-C30 and QLQ-LC13 scores |
| European Quality of Life Five Dimensions with five levels (EQ-5D-5L) questionnaire | Questionnaire will be filled in at baseline and every 3 months thereafter through study completion, an average of 2 years. | Mean change from baseline in EQ-5D-5L score |
| Incremental cost-effectiveness ratio (ICER) | Through total study completion, after 12 months of follow-up | The ICER is the final outcome of the comparative cost-effectiveness analysis performed using a health-state transition model to compare costs and effectiveness between both study arms. |
| Alectinib M4 protein | Through total study completion, after 12 months of follow-up | Alectinib M4 plasmaconcentrations in relation to alectinib plasma concentrations |
| Number of adverse events (AE) related to plasma concentration and dose increases | Through total study completion, after 12 months of follow-up | AE's will be defined using CTCAE v5.0. Number of AE's in the subgroups of patients with Cmin \<435 ng/mL compared to Cmin \>= 435 ng/ML, and in patients who did and who did not receive a TDM-guided dose increase. |
Countries
France, Netherlands
Contacts
Primary ContactM.B. Muntinghe-Wagenaar, Msc
Outcome results
None listed