Study of Plasma NGS for Assessment, Characterization, Evaluation of Patients With ALK Resistance

Study Overview
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Brief Summary
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ALK-positive lung cancer is a subtype of lung cancer which carries a change in a gene called ALK (anaplastic lymphoma kinase). There are now many drugs for patients with ALK-positive lung cancer that slow cancer growth. However, after some time, just as bacteria evolve resistance to antibiotics, ALK-positive lung cancers evolve ways to avoid the therapies by developing new mutations so the drugs lost their effectiveness. These new mutations can potentially be treated with a different drug. For these new therapies, the range of mutations that can develop at resistance is not well understood. It is now possible to detect the presence of mutations or changes in the genetic structure in lung cancer by analyzing a patient's blood for bits of material shed by tumor. This approach is often called a liquid biopsy. Recently, researchers have shown that looking at tumor molecules through liquid biopsies can provide doctors with some of the same information that tissue biopsies provide. For example, liquid biopsies can be used to detect mutations that cause drug resistance. Obtaining liquid biopsies on patients with ALK-positive lung cancers at resistance to therapy may help better understand the different mutations that develop and guide therapy decisions. In this research study, a blood specimen will be collected and submitted for liquid biopsy analysis at a commercial diagnostic company. This company specializes in analyzing tumor material found in blood. Specifically, it will look for genetic changes in the ALK gene that could help understand why a cancer has developed drug resistance. This research study is for lung cancer patients with ALK-positive lung cancer who had been on a newer ALK targeted treatment (such as ceritinib, alectinib, brigatinib, or lorlatinib) to determine whether they have developed ALK resistance mutations. The investigators will collect a blood sample to examine these mutations. Participants will not have to have a tissue biopsy to participate in this study. Participants do not have to visit Dana-Farber Cancer Institute (DFCI) to participate. All study procedures will be performed remotely.

Detailed Description
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SPACEWALK is an innovative remote consent and participation study using next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) to characterize resistance mechanisms arising in ALK-positive non-small cell lung cancer (NSCLC) after progression while on a next generation ALK tyrosine kinase inhibitor (TKI). Additionally, the study will capture the potential of genomic-driven resistance therapy approach for effecting outcomes in patients with advanced ALK-positive NSCLC and TKI resistance. Finally, the study will assess the role of repeat plasma NGS in evaluating drug response. The study will accrue patients with advanced ALK-positive NSCLC on systemic progression (outside the brain) while on treatment with a next-generation ALK TKI. Any patient interested in the study will find information about the study on the study website. The patient will consent remotely through the study website and documentation of advanced ALK-positive NSCLC and systemic progression while on a next-generation ALK TKI. The study team will then reach out to the patient to confirm eligibility and send a blood collection kit. In the study kit the study participants will find all the necessary materials for local blood draws and collected specimens will be sent directly to the central study laboratory (Resolution Bioscience) for plasma NGS. Plasma NGS of cfDNA will involve sequencing of 19 genes, including ALK, permitting remote tumor genotyping. Plasma NGS analysis and results will be done following standard procedures of the Resolution Bioscience CLIA-certified laboratory. Results will take 1-2 weeks to be sent back to study participants, their physicians and study team. Those plasma NGS reports will not include any specific treatment recommendations but will describe the presence of an ALK rearrangement, ALK resistance mutation, or other relevant mutations. Study participants are then followed remotely. The study coordinator will contact the participants weekly for 4 weeks after enrolled into the study to learn of any new treatment initiation and to release an additional plasma collection kit 2-4 weeks after starting treatment. Study participants will then be remotely contacted every 3 months to follow clinical outcomes on therapy for up to 2 years. If the cancer begins to grow again on the participant's new treatment, the patient will have the option to provide a third blood specimen. Medical records and local imaging will be collected and studied. The primary objective of the study is to characterize ALK TKI resistance to next-generation ALK TKIs in patients with advanced ALK-positive NSCLC. Secondarily, the investigators will assess the potential of plasma NGS to impact outcome on treatment by studying time to treatment discontinuation (TTD). Serial plasma NGS will also be assessed as a response biomarker. A total of 300 patients will be enrolled, with the expectation that approximately 200 will have tumor-related mutations detected in plasma NGS.

Official Title
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ALCMI-011: Study of Plasma Next Generation Sequencing for Assessment, Characterization, Evaluation of Patients With ALK Resistance (SPACEWALK)

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Diagnostic Test: Plasma Next Generation Sequencing (NGS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women older than 18 years at the time of consent. Demonstration of having advanced ALK positive NSCLC. Systemic progression (not CNS only progression) within the past 30 days while receiving a next generation ALK TKI. Patient must not have started a new line of therapy before signing the informed consent form. Willingness to provide a blood specimen prior to the initiation of a new line of treatment. Willing to provide clinical and medical information to the study team as required. Ability to read, write and communicate in English. Ability to sign a web-based informed consent form. Exclusion Criteria: Participants who are unable to provide informed consent. Participants who are 18 years of age or younger. Participants who are unable to comply with the study procedures. Known existence of an uncontrolled intercurrent illness including, but not limited to, psychiatric illness or social situations that would impair compliance with study requirements. Participants who have previously enrolled to the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Plasma Next Generation Sequencing (NGS)<br>Subjects will be sent blood collection kits with the necessary materials for local draws and those specimens will be sent directly by the subjects to the central laboratory (Resolution Bioscience) for plasma NGS. Plasma NGS results will be returned to the subject, their treating physician and study team, aiming to return results within 2 weeks by Resolution Bioscience. | Diagnostic Test: Plasma Next Generation Sequencing (NGS)<br>* Liquid biospys<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of ALK resistance mutations after different ALK targeted therapies | To study the relationship between specific ALK resistance mutations measured through plasma NGS and a specific next gneration ALK TKI received before progression and/or the number of ALK TKIs received | 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity of plasma NGS for ALK TKI resistance | To study the feasibility, sensitivity, and turnaround time of plasma NGS in lung cancer patients with ALK TKI resistance. | 32 months | 
| Time until treatment discontinuation on subsequent therapy | To study the survival data of patients with ALK TKI resistance mechanism detected and subsequent therapy received. | 32 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALK positive