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Amino Acids

Alectinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

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.

M.B. Muntinghe-Wagenaar, Msc

B. Besse, PhD

M.M. van den Heuvel, PhD

L.E.L. Hendriks, PhD

A.J. de Langen, PhD

S.M.S. Hashemi, Msc

E.F. Smit, PhD

A.C. Dingemans, PhD

A.J. van der Wekken, PhD

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).

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).

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.

The alectinib Cmin for patients treated in arm B (standard dose arm) will be blinded to participants and care providers

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

Standard Dosed Alectinib Versus Therapeutic Drug Monitoring Guided Alectinib Dosing

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.

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.

The percentage of succesfull TDM interventions, in which successful is defines as tartget attainment and manageable toxicity.

ORR is the percentage of patients with partial response or complete response, according to RECIST v1.1, of the total treated population.

mOS is defined as time from randomization to death from any cause in the total population.

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.

This will be estimated by pill counts of returned medication as well as a patient diary on drug intake.

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.

Mean change from baseline in EORTC QLQ-C30 and QLQ-LC13 scores

Mean change from baseline in EQ-5D-5L score

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 plasmaconcentrations in relation to alectinib plasma concentrations

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

Antineoplastic Agents

Crizotinib

* The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits.
* Phase 1 (the dose-finding portion of the study) will follow a standard 3+3 design. Enrollment to the different study arms will occur in parallel.

  * Lorlatinib will be administered orally once daily at a predetermined dose for 28 days
  * Crizotinib will be administered orally twice daily at a predetermined dose for 28 days
* Phase II patients will be treated with Lorlatinib and Crizotinib at a dose recommended based on the phase I study.

* The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits.
* The phase I part of the study will follow a standard 3+3 design. Enrollment to the different study arms will occur in parallel.

  * Lorlatinib will be administered orally once daily at a predetermined dose for 28 days
  * Binimetinib will be administered orally twice daily at a predetermined dose for 28 days.
* Phase II patients will be treated with Lorlatinib + Binimetinib at a dose recommended based on the phase I study.

* The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits.
* The phase I part of the study will follow a standard 3+3 design. Enrollment to the different study arms will occur in parallel.

  * Lorlatinib will be administered orally once daily at a predetermined dose for 21 days
  * TNO155 will be administered orally once daily at a predetermined dose for 14 out of 21 days.
* Phase II patients will be treated with Lorlatinib + TNO155 at a dose recommended based on the phase I study.

Lorlatinib will be taken orally once daily for 28 days when combined with crizotinib or binimetinib. Lorlatinib will be taken orally once daily for 21 days when combined with TNO155.

Crizotinib taken orally twice daily for 28 days.

Lorlatinib

Crizotinib will be taken orally twice daily for 28 days.

Binimetnib taken orally twice daily for 28 days.

Binimetinib will be taken orally twice daily for 28 days.

Binimetinib

TNO155 will be taken orally once daily for 14 days.

TNO155

Ibiayi Dagogo-Jack, MD

Elizabeth Kennedy

Ibiayi Dagogo-Jack

Daniel Costa, MD

This research study is evaluating Lorlatinib in combination with Crizotinib, Binimetinib, or TNO155 as a possible treatment for either anaplastic lymphoma kinase (ALK)-positive lung cancer or ROS1-positive lung cancer.

* This research study involves four study drugs.
* Lorlatinib
* Binimetinib
* Crizotinib
* TNO155

This is a Phase I/II clinical trial of three investigational combinations for treatment of either anaplastic lymphoma kinase (ALK)-positive or ROS1-positive lung cancer. The three drug combinations being tested are (1) Lorlatinib combined with Crizotinib and (2) Lorlatinib combined with Binimetinib and (3) Lorlatinib combined with TNO155.

* Lorlatinib is an oral ALK and ROS1 inhibitor. The US Food and Drug Administration (FDA) has approved Lorlatinib for treatment of ALK-positive lung cancer. The FDA has not approved Lorlatinib for treatment of ROS1-positive lung cancer.
* Crizotinib is an oral ALK and MET inhibitor. The FDA has approved Crizotinib for treatment of ALK-positive lung cancer. Crizotinib is not approved by the FDA for the treatment of MET-positive lung cancer. This study will test crizotinib's ability to block MET signaling. Crizotinib is not approved by the FDA for treatment of ROS1-positive lung cancer.
* Binimetinib is an oral MEK inhibitor. The FDA has not approved binimetinib for treatment of ALK-positive or ROS1-positive lung cancer but it has been approved for other uses.
* TNO155 is an oral SHP2 inhibitor. The FDA has not approved TNO155 for the treatment of any disease, including ALK-positive or ROS1-positive lung cancer. It is an investigational drug.
* The FDA has not approved the combination of Lorlatinib with Binimetinib, Crizotinib, or TNO155 as a treatment for any disease.

The research study procedures include screening for eligibility and study treatment which will include evaluations and follow up visits.

* Patients will undergo screening and those who fulfill the eligibility criteria will be assigned to receive either the combination of Lorlatinib and Crizotinib, the combination of Lorlatinib and Binimetinib, or the combination of Lorlatinib and TNO155. Patients with ALK-positive or ROS1-positive lung cancer who have extra copies of the MET growth signal (MET amplification) will be assigned to receive the Lorlatinib and Crizotinib combination. All other patients will be randomly assigned to receive one of the combinations.
* This study consists of 2 parts:

  * Phase I:

    * The investigators are looking to determine whether combining Lorlatinib with either Binimetinib, Crizotinib, or TNO155 is well tolerated and to understand how treatment with the two drugs affects cancer cells and impacts growth signals.
    * Not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study prior and how well the dose was tolerated.
  * Phase II:

    * The Phase II study will test the safest doses of the combinations (as established in the Phase I study) in a larger group of patients.
    * It is expected that about 96 people will take part in this research study

Lorlatinib Combinations in Lung Cancer

A Phase IB/II Study of Lorlatinib Combinations in Anaplastic Lymphoma Kinase-Rearranged Lung Cancer

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

The highest dose of the combinations that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses in different groups of patients until the highest dose with acceptable side effects is found.

Objective response rate (partial and complete responses) will be evaluated according to RECIST v1.1 criteria.

Number of patients with treatment-related side effects, according to CTCAE v5.0

PFS will defined as the time from the start of treatment to the date of the first documented progression or death due to disease. The distribution of PFS will be estimated using the Kaplan-Meier method.

Duration of response to treatment is measured from the time that measurement criteria (RECIST v1.1) are met for complete response or partial response (whichever is recorded first) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started), or death due to any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels	NCT05525338	Drug Monitoring Carcinoma, Non-... Lung Cancer Anaplastic Lymp... Anaplastic Lymp...	Alectinib	18 Years -	University Medical Center Groningen
Lorlatinib Combinations in Lung Cancer	NCT04292119	Lung Cancer Anaplastic Lymp... ROS1 Rearrangem... Relapsed Cancer MET Amplificati... Resistant Cance... NSCLC	Lorlatinib Crizotinib Binimetinib TNO155	18 Years -	Massachusetts General Hospital
Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels	NCT05525338	Drug Monitoring Carcinoma, Non-... Lung Cancer Anaplastic Lymp... Anaplastic Lymp...	Alectinib	18 Years -	University Medical Center Groningen
Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels	NCT05525338	Drug Monitoring Carcinoma, Non-... Lung Cancer Anaplastic Lymp... Anaplastic Lymp...	Alectinib	18 Years -	University Medical Center Groningen

Spots Global Cancer Trial Database for anaplastic lymphoma kinase gene translocation