A clinical trial to compare how effective and safe different targeted therapies (alectinib, entrectinib or pralsetinib) are compared with durvalumab in people with a type of lung cancer called non-small cell lung cancer (NSCLC) that has certain genetic mutations (ALK, ROS1 or RET)

A Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Participants With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer (NSCLC)

  • Non-Small Cell Lung Cancer
Trial Status:

Recruiting

This trial runs in
Countries
  • Costa Rica
  • Japan
  • Poland
  • South Korea
  • Turkey
Trial Identifier:

NCT05170204 BO42777

      Show trial locations

      The source of the below information is the publicly available website ClinicalTrials.gov. It has been summarised and edited into simpler language.

      The below information is taken directly from the publicly available website ClinicalTrials.gov within a week of any updates, and has not been edited.

      Results Disclaimer

      Trial Summary

      This study will evaluate the efficacy and safety of multiple therapies in participants with locally advanced, unresectable, Stage III NSCLC with eligible biomarker status as determined by Version 8 of the American Joint Committee on Cancer/Union for International Cancer Control NSCLC staging system.

      Hoffmann-La Roche Sponsor
      Phase 3 Phase
      NCT05170204 , BO42777 Trial Identifier
      All Gender
      ≥18 Years Age
      No Healthy Volunteers

      The aim of this document is to give people interested in this trial the background, treatment plan, scope of participants who are able to take part, benefits and risks. We recommend that this should be read carefully by potential participants and shared with close family members and caregivers. 

      Why is this clinical trial needed?

      Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. This clinical trial is for people with a specific type of NSCLC called locally advanced, unresectable stage III NSCLC (locally advanced means that the cancer is found in the lungs and lymph nodes in the chest, and unresectable means that the cancer cannot be removed by surgery). The current standard of care for people living with locally advanced, unresectable stage III NSCLC is chemoradiotherapy, and may be followed by a treatment with a drug called durvalumab (depending on which country you live in). However, in some people with this type of NSCLC, the cancer can continue to get worse, and there is a need for new therapies. Changes in genetic material, known as mutations, can play an important role in causing this type of lung cancer to grow and spread to other parts of the body. Knowing which type of mutation is present in people's NSCLC can help doctors identify treatments that may specifically target the cancer cells and stop them growing (these treatments are known as targeted therapies). Alectinib, entrectinib and pralsetinib are experimental targeted therapies for the treatment of stage III NSCLC which contains the specific genetic mutations called ALK, ROS1 or RET, and are already approved treatments for advanced NSCLC that has spread to other parts of the body. This clinical trial aims to investigate whether people with these genetic mutations (ALK-positive, ROS1-positive, or RET-positive) may be more likely to respond to one of these targeted therapies compared with durvalumab.

       

      How does this clinical trial work?

      This clinical trial is recruiting people who have a type of lung cancer (called NSCLC) which contains either the ALK, ROS1 or RET gene mutation (confirmed by a laboratory test using a tumour sample that has previously been collected). 

      The purpose of this clinical trial is to compare the effects, good or bad, of experimental targeted therapies (alectinib, entrectinib or pralsetinib) versus durvalumab in people with NSCLC. Participants who take part in this clinical trial will either get one of the experimental targeted therapies or durvalumab. Participants will be given the treatment on a regular basis until either the lung cancer worsens, or they have been receiving an experimental targeted therapy for three years, or durvalumab for one year. 

      Participants will have six hospital visits in the first 12 weeks, then one visit every 4 weeks whilst receiving treatment (the treatment phase). These hospital visits will carry out various assessments which may include scans; assessments of participant's daily functioning; heart and vital signs; blood, urine and tumour samples; physical examination; side effects; and questionnaires. Instead of coming to the clinic, for some of the visits a mobile healthcare professional may be able to visit participants at their homes or another suitable location to make it easier for people taking part (depending on the clinical trial doctor's instructions and different country's requirements).

      After the final dose of treatment, participants will continue to have visits every two to three months as long as their cancer is under control (follow-up phase). Thereafter, the trial doctor will follow up with participants about every three months for as long as they agree to it. Participants' total time in the clinical trial will depend on how the cancer is controlled by the trial treatment and could range from one day to more than five years. Participants are free to stop trial treatment and leave the clinical trial at any time.

       

      What are the main endpoints of the clinical trial?

      The main clinical trial endpoint (the main result that is measured in the trial to see if the treatment has worked) is the length of time participants live without their cancer worsening (progression-free survival).

      The other clinical trial endpoints include: how long it takes for participants to begin to develop additional tumours; how many participants have a reduction in the size of their tumour, and how long this lasts; how long participants live in total; how the experimental targeted therapies enter and move through the body; the safety of the trial treatments; and the impact of the trial treatments on participant's quality of life.

       

      Who can take part in this clinical trial?

      People can take part in this trial if they are at least 18 years old and have been diagnosed with NSCLC that is locally advanced (is found in the lungs and lymph nodes in the chest), and is not suitable for surgery (unresectable), and have been previously treated with at least two cycles of chemoradiotherapy. People's lung cancer will be first tested for genetic mutations and must be positive for ALK, ROS1 or RET mutations.

      People may not be able to take part in this trial if they have certain other medical conditions or have previously received certain treatments. People with NSCLC that are found to have certain mutations cannot take part in this trial. Women cannot take part in this trial if they are pregnant or breastfeeding or are planning to become pregnant. People may not be able to take part if they are enrolled in another clinical trial.

       

      What treatment will participants be given in this clinical trial?

      Everyone who joins this clinical trial will be split into three groups. Which group they join will depend on which mutation is present in their lung cancer (ALK, ROS1 or RET) and will be given either:

      Group A1 (participants with ALK-positive NSCLC)

      • Alectinib given as oral tablets twice a day for up to three years
      • OR durvalumab given as infusions into the vein every four weeks for up to one year

      Group A2 (participants with ROS1-positive NSCLC)

      • Entrectinib given as oral tablets once a day for up to three years
      • OR durvalumab given as infusions into the vein every four weeks for up to one year

      Group A3 (participants with RET-positive NSCLC)

      • Pralsetinib given as oral tablets once a day for up to three years
      • OR durvalumab given as infusions into the vein every four weeks for up to one year

      Participants in each group (A1, A2 or A3) will have an equal chance of receiving one of the targeted therapies or durvalumab.

      Are there any risks or benefits in taking part in this clinical trial?

      The safety or effectiveness of the experimental treatment or use may not be fully known at the time of the trial. Most trials involve some risks to the participant, although it may not be greater than the risks related to routine medical care or the natural progression of the health condition. Potential participants will be told about any risks and benefits of taking part in the clinical trial, as well as any additional procedures, tests, or assessments they will be asked to undergo. These will all be described in an informed consent document (a document that provides people with the information they need to make a decision to volunteer for a clinical trial). A potential participant should also discuss these with members of the research team and with their usual healthcare provider. Anyone interested in taking part in a clinical trial should know as much as possible about the trial and feel comfortable asking the research team any questions about the trial.

      Risks associated with the clinical trial drugs

      Participants may have side effects (an unwanted effect of a drug or medical treatment) from the drugs used in this clinical trial. Side effects can be mild to severe and even life-threatening and can vary from person to person.

      Alectinib, entrectinib and pralsetinib

      Potential participants will be told about the known side effects of alectinib, entrectinib or pralsetinib, and where relevant, also potential side effects based on human and laboratory studies or knowledge of similar drugs. Alectinib, entrectinib or pralsetinib will be given as oral tablets (given by mouth) and participants will be told about any known side effects of oral administration.  

      Durvalumab

      Potential participants will be told about the side effects of durvalumab, and where relevant, also potential side effects based on human and laboratory studies or knowledge of similar drugs. Durvalumab will be given by intravenous injection at hospital (involves inserting a needle into a vein to allow the medicine to enter the bloodstream right away). Participants will be told about any known side effects of intravenous delivery. 

      Potential benefits associated with the clinical trial

      Participants' health may or may not improve from participation in the clinical trial, but the information that is collected may help other people who have a similar medical condition in the future. 

       

      For more information about this clinical trial see the ForExpert tab on the specific ForPatients page or follow this link to ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05170204

      Trial Summary

      This study will evaluate the efficacy and safety of multiple therapies in participants with locally advanced, unresectable, Stage III NSCLC with eligible biomarker status as determined by Version 8 of the American Joint Committee on Cancer/Union for International Cancer Control NSCLC staging system.

      Hoffmann-La Roche Sponsor
      Phase 3 Phase
      NCT05170204 , BO42777 Trial Identifier
      Alectinib, Entrectinib, Pralsetinib, Durvalumab Treatments
      Non-Small Cell Lung Cancer Condition
      Official Title

      A Phase I-III, Multicenter Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Patients Selected According to Biomarker Status, With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer

      Eligibility Criteria

      All Gender
      ≥18 Years Age
      No Healthy Volunteers
      Inclusion Criteria

      Inclusion Criteria (All Cohorts):

      • Body weight >/= 30 kg at screening
      • Willingness and ability to use the electronic device(s) or application(s) for the electronic patient-reported outcome (PRO)
      • Whole-body positron emission tomography/computed tomography scan (PET/CT) (from the base of skull to mid-thighs) for the purposes of staging, performed prior and within 42 days of the first dose of cCRT or sCRT
      • Histologically or cytologically documented locally advanced, unresectable Stage III NSCLC of either squamous or non-squamous histology
      • Prior receipt of at least two prior cycles of platinum-based chemotherapy given concurrently with radiotherapy (cCRT); or at least two prior cycles of platinum-based chemotherapy given prior to radiotherapy (sCRT)
      • The RT component in the cCRT or sCRT must have been at a total dose of radiation of 60 (+/-10%) Gy (54 Gy to 66 Gy) administered by intensity-modulated radiotherapy (preferred) or three dimension (3D)-conforming technique
      • No disease progression during or following platinum-based cCRT or sCRT
      • Life expectancy >/= 12 weeks
      • Confirmed availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen
      • Documented tumor PD-L1 status (TC score < 1% vs. >/= 1% vs. unknown) as determined: centrally with the SP263 IHC assay on the confirmed available FFPE tumor specimen; locally, with the SP263 (preferred) or 22C3 IHC assays
      • Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
      • Adequate hematologic and end-organ function
      • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined by the protocol
      • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined by the protocol

      Inclusion criteria specific to Cohort A1:

      • Documented ALK fusion positivity by an eligible result from: centralized multiplex molecular testing of tumor tissue at the Sponsor's designated central laboratory under Study BX43361 or available results from a Sponsor pre-approved local, appropriately validated ALK fusion test on tumor tissue performed in a Clinical Laboratory Improvement Amendments certified or equivalent laboratory

      Inclusion criteria specific to Cohort A2:

      • Documented ROS1 fusion positivity by an eligible result from: centralized multiplex molecular testing of tumor tissue at the Sponsor's designated central laboratory under Study BX43361 or available results from a Sponsor pre-approved local, appropriately validated ROS1 fusion test on tumor tissue performed in a Clinical Laboratory Improvement Amendments certified or equivalent laboratory
      • Ability to swallow entrectinib intact, without chewing, crushing, or opening the capsules

      Inclusion criteria specific to Cohort A3:

      • Documented RET fusion positivity by an eligible result from: centralized multiplex molecular testing of tumor tissue at the Sponsor's designated central laboratory under Study BX43361 or available results from a Sponsor pre-approved local, appropriately validated RET fusion test on tumor tissue performed in a Clinical Laboratory Improvement Amendments certified or equivalent laboratory
      Exclusion Criteria

      Exclusion Criteria (All Cohorts):

      • Any history of previous NSCLC and/or any history of prior treatment for NSCLC (patients must be newly diagnosed with unresectable Stage III disease)
      • Any evidence of Stage IV disease, including, but not limited to, the following: pleural effusion, pericardial effusion, brain metastases, history of intracranial hemorrhage or spinal cord hemorrhage, bone metastases, distant metastases
      • If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (T4 disease): when pleural fluid is visible on both the CT scan and chest X-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative; participants with exudative pleural effusions are excluded regardless of cytology; participants with effusions that are minimal (i.e., not visible on chest X-ray) that are too small to safely tap are eligible
      • NSCLC known to have a known or likely oncogenic-driver mutation in the EGFR gene, as identified by site local testing or Sponsor central testing
      • Liver disease, characterized by any of the following: impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease, such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices or active viral or active autoimmune, alcoholic, or other types of acute hepatitis
      • Positive hepatitis B surface antigen (HBsAg) test at screening
      • Participants known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with the following exception: participants who are HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible
      • HIV infection: participants are excluded if not well-controlled as defined by the protocol
      • Known active tuberculosis
      • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest CT scan
      • Grade >/= 2 pneumonitis from prior cCRT or sCRT
      • Any Grade > 2 unresolved toxicity from prior cCRT or sCRT
      • Any gastrointestinal (GI) disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection
      • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
      • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: participants with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study; participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
      • History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer
      • Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
      • Major surgical procedure, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
      • Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
      • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment
      • Treatment with investigational therapy within 28 days prior to initiation of study treatment
      • Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with exceptions defined by the protocol
      • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein 4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies
      • Prior allogeneic stem cell or solid organ transplantation
      • Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
      • Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results
      • Any prior Grade >/= 3 immune-mediated adverse event or any unresolved Grade > 1 immune-mediated adverse event while receiving any previous immunotherapy agent other than immune checkpoint blockade agents

      Exclusion criteria specific to Cohort A1:

      • Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)
      • NSCLC known to have one or more of the following ALK point mutations, as identified by site local testing or Sponsor central testing: I1171X (where X is any other amino acid), V1180L, G1202R
      • Symptomatic bradycardia
      • Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina; participants with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
      • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
      • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
      • Prior treatment with ALK inhibitors
      • History of hypersensitivity to alectinib, durvalumab, or any of their excipients
      • Inability to swallow oral study drug
      • Known hereditary problems of galactose intolerance, a congenital lactase deficiency, or glucose-galactose malabsorption
      • Pregnancy or breastfeeding, or intending to become pregnant during the study treatment or within 90 days after the final dose of alectinib or durvalumab

      Exclusion criteria specific to Cohort A2:

      • Symptomatic bradycardia
      • Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina; participants with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
      • Left ventricular ejection fraction less than or equal to 50% observed during the screening for the study
      • History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 ms from ECGs performed at least 24 hours apart)
      • History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome)
      • Familial or personal history of congenital bone disorders or bone metabolism alterations
      • Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of the treatment
      • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
      • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
      • Prior treatment with ROS1 inhibitors
      • History of hypersensitivity to entrectinib, durvalumab, and their excipients
      • Grade >/= 3 toxicities due to any prior therapy (e.g., RT) (excluding alopecia) that have not shown improvement or are not stable and are considered to interfere with current study drug
      • Known hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
      • Grade >/= 2 peripheral neuropathy
      • Pregnancy or intention of becoming pregnant during study treatment, within 35 days after the final dose of entrectinib, or within 90 days after the final dose of durvalumab

      Exclusion criteria specific to Cohort A3:

      • Participant has significant cardiovascular disease, as evidenced by any of the following conditions: QT interval corrected through the use of Fridericia's formula (QTcF) > 480 ms; history of prolonged QT syndrome or torsades de pointes; familial history of prolonged QT syndrome
      • Total serum phosphorous > 5.5 mg/dL
      • Participant has clinically significant, uncontrolled, cardiovascular disease, including Grade III or IV congestive heart failure according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g., Type II second-degree or third-degree heart block)
      • Treatment with a prohibited medication (i.e., strong inhibitors of CYP3A4, strong inducers of CYP3A4, combined P-glycoprotein and strong CYP3A4 inhibitors) or herbal remedy, within 2 weeks prior to the start of study drug administration
      • Participant with a serious infection requiring IV or systemic antibiotics within 7 days prior to initiation of study treatment, or any active infection that, in the opinion of the investigator, could impact patient's safety. In the setting of a pandemic or epidemic, screening for active infections should be considered according to local or institutional guidelines or applicable guidelines (e.g., NCCN, ESMO)
      • Participant has an active, uncontrolled infection (viral, bacterial, or fungal)
      • Prior treatment with RET inhibitors
      • History of hypersensitivity to pralsetinib, durvalumab, or any of their excipients
      • Inability to swallow oral study drug
      • Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 2 weeks after the final dose of pralsetinib or 3 months after the final dose of durvalumab

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