Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels (ADAPT ALEC)

Standard Dosed Alectinib Versus Therapeutic Drug Monitoring Guided Alectinib Dosing

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).

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung; Lung Cancer; Drug Monitoring; Anaplastic Lymphoma Kinase Gene Mutation; Anaplastic Lymphoma Kinase Gene Translocation
• Intervention / Treatment: Drug: Alectinib

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).

• Study Type: Interventional
• Enrollment (Anticipated): 196
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: M.B. Muntinghe-Wagenaar, Msc; Phone Number: +31503616161; Email: adaptalec@umcg.nl

Study Locations

• France
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France, 94805
      • Not yet recruiting
      • Gustave Roussy
      • Contact: B. Besse, PhD
• Netherlands
  • Groningen, Netherlands, 9713GZ
    • Recruiting
    • University Medical Center Groningen
    • Contact: A.J. van der Wekken, PhD
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Not yet recruiting
      • Radboud University Medical Center
      • Contact: M.M. van den Heuvel, PhD
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Recruiting
      • Maastricht University Medical Center +
      • Contact: L.E.L. Hendriks, PhD
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
      • Recruiting
      • Amsterdam University Medical Center
      • Contact: S.M.S. Hashemi, Msc
    • Amsterdam, Noord-Holland, Netherlands, 1066 CX
      • Recruiting
      • The Netherlands Cancer Institute
      • Contact: A.J. de Langen, PhD
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands, 2333 ZA
      • Recruiting
      • Leiden University Medical Center
      • Contact: E.F. Smit, PhD
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Recruiting
      • Erasmus Medical Center
      • Contact: A.C. Dingemans, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TDM-guided dosing arm	Drug: Alectinib; 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.
No Intervention: Standard dose arm; 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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Radboud University Medical Center; Maastricht University Medical Center; Erasmus Medical Center; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); The Netherlands Cancer Institute; Leiden University Medical Center
• Investigators: Principal Investigator: A.J. van der Wekken, PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2022
• Primary Completion (Anticipated): December 31, 2025
• Study Completion (Anticipated): December 31, 2026

Study Registration Dates

• First Submitted: August 26, 2022
• First Submitted That Met QC Criteria: August 30, 2022
• First Posted (Actual): September 1, 2022

Study Record Updates

• Last Update Posted (Estimate): February 21, 2023
• Last Update Submitted That Met QC Criteria: February 20, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Alectinib
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Lymphoma; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: 202000251; 2020-001737-13 (EudraCT Number); NL9411 (Registry Identifier: Nederlands Trial Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results will only be shared upon reasonable request from the Principal Investigator at the UMCG, who will discuss the request with the ADAPT ALEC study team.
• IPD Sharing Time Frame: The study protocol will be available after ending of the study and publication of the manuscript ending 5 years after article publication.
• IPD Sharing Access Criteria: For individual participant data meta-analysis
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No