Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels

Study Overview
=================
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).

Official Title
-----------------
Standard Dosed Alectinib Versus Therapeutic Drug Monitoring Guided Alectinib Dosing

Conditions
-----------------
Drug Monitoring, Carcinoma, Non-Small-Cell Lung, Lung Cancer, Anaplastic Lymphoma Kinase Gene Mutation, Anaplastic Lymphoma Kinase Gene Translocation

Intervention / Treatment
-----------------
* Drug: Alectinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TDM-guided dosing arm<br> | Drug: Alectinib<br>* 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.<br>|
| No Intervention: Standard dose arm<br>Alectinib plasmaconcentration will be blinded untill the end of the trial. No intervention based on the alectinib plasmaconcentrion will be performed. 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. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median progression free survival (mPFS) | 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. | mPFS will be assessed through study completion, after 12 months of follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Succesfull Therapeutic Drug monitoring | The percentage of succesfull TDM interventions, in which successful is defines as tartget attainment and manageable toxicity. | 4 to 6 weeks after dose adjustment based on TDM | 
| Overall response rate (ORR) | ORR is the percentage of patients with partial response or complete response, according to RECIST v1.1, of the total treated population. | Response will be assessed every 2-3 months. ORR will be determined after total study completion and 12 months of follow-up | 
| Median overall survival | mOS is defined as time from randomization to death from any cause in the total population. | Through total study completion, after 12 months of follow-up | 
| Intracranial PFS | 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. | 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 | 
| Patient adherence to alectinib treatment | This will be estimated by pill counts of returned medication as well as a patient diary on drug intake. | Through study completion, an average of 2 years | 
| Number of adverse events (AE) related to plasma concentration and dose increases | 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. | Through total study completion, after 12 months of follow-up | 
| 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 | Mean change from baseline in EORTC QLQ-C30 and QLQ-LC13 scores | Questionnaires will be filled in at baseline and every 3 months thereafter through study completion, an average of 2 years. | 
| European Quality of Life Five Dimensions with five levels (EQ-5D-5L) questionnaire | Mean change from baseline in EQ-5D-5L score | Questionnaire will be filled in at baseline and every 3 months thereafter through study completion, an average of 2 years. | 
| Incremental cost-effectiveness ratio (ICER) | 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. | Through total study completion, after 12 months of follow-up | 
| Alectinib M4 protein | Alectinib M4 plasmaconcentrations in relation to alectinib plasma concentrations | Through total study completion, after 12 months of follow-up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Alectinib, Randomized Controlled Trial