Alectinib in Neo-adjuvant Treatment of Stage III NSCLC

Study Overview
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Brief Summary
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Stage III NSCLC is a heterogeneous group of tumors with a wide spectrum of clinical presentations. Across this wide spectrum of heterogeneity, there is no single deﬁnitive therapeutic approach and the definition of the most effective treatment approach needs a multidisciplinary approach. In this trial we want to test in ALK positive stage III locally advanced NSCLC patients, the efficacy of Alectinib to induce tumor shrinkage when administered before surgery and to reduce the possibility of disease recurrence, with a limited risk of toxicity related, in long term administration after surgery.

Official Title
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Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of ALectinib as NEO-adjuvant Therapy in Patients With Anaplastic Lymphoma Kinase-positive (ALK+) Locally Advanced Stage III Non-Small Cell Lung Cancer (NSCLC): ALNEO Trial

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Alectinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Histologically or cytologically confirmed adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology. Documented ALK-positive disease according to an FDA-approved and CE-marked test. Locally advanced NSCLC in stage III according to the 8th American Joint Committee on Cancer TNM edition, defined potentially resectable (any T with N2, T4N0-1). Documentation that the patient is a candidate for surgical resection of their lung cancer after multidisciplinary discussion. Patients must be treatment-naive for NSCLC and eligible to receive treatment with Alectinib. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with CT scan. Brain magnetic resonance imaging (MRI) or CT scan showing no evidence of metastatic disease. Positron emission tomography (PET)-computed tomography (CT) showing radiographic stage III lung cancer (mediastinal staging biopsy is allowed but not required). Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1. Ability to swallow oral medications. Adequate haematological function defined by white blood cell (WBC) count ≥ 2.500/mm3 with absolute neutrophil count (ANC) ≥ 1.500/mm3, platelet count ≥ 100.000/mm3 and haemoglobin ≥ 9 g/dL. Adequate hepatic function defined by a total bilirubin ≤ 1.5 x the upper limit of normal (ULN) range (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL), serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 if liver function test elevations are due to liver metastases). Adequate renal function defined by a serum creatinine ≤ 1.5 x ULN or an estimated creatinine clearance of ≥ 30 mL/minute for patients with creatinine levels above institutional limits (if using the Cockcroft-Gault formula). Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before trial inclusion date, and otherwise noted in other inclusion/exclusion criteria. Female patients with childbearing potential should be using adequate contraceptive measures and should not be breastfeeding during the study and for 90 days following the last dose of Alectinib. They and must have a negative serum pregnancy test within 7 days prior to the first dose of study drug. Female patients must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments; Women under 50 years old would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment with LH and FSH levels in the post-menopausal range for the institution; Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception for at least 14 days prior to administration of the first dose of study treatment, during the study, and for 90 days following the last dose of Alectinib. Ability to comply with protocol requirements. Ability to provide written informed consent. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that the patient may withdraw consent at any time without prejudice to future medical care. Exclusion Criteria: Prior treatment with any systemic anti-cancer therapy for locally advanced NSCLC including chemotherapy, biologic therapy, including ALK-TKI, immunotherapy or any investigational drug. Non-resectable stage III and stage IV disease with distant metastases (including malignant pleural effusion) identified on PET-CT scan or biopsy. Any concurrent and/or active malignancy that has required treatment within 2 years of the first dose of study drug. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol; or known active infection including hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV); screening for chronic conditions is not required; patients with HBV with negative HBV viral load on appropriate antiviral therapy will be permitted, if able to continue appropriate antiviral therapy throughout treatment period. Any severe infection, including COVID-19, within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infections. History of organ transplant. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of Alectinib. Any of the following cardiac criteria: Mean resting corrected QT interval (QTc)>470 msec, obtained from 3 electrocardiograms (ECGs) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250msec, symptomatic bradycardia <45 beats/minute. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval. Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry. History of hypersensitivity to active or inactive excipients of Alectinib or drugs with a similar chemical structure or class to Alectinib. This includes, but is not limited to, patients with galactose intolerance, a congenital lactase deficiency or glucose-galactose malabsorption. Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment with Alectinib except for oral corticosteroids up to 20 mg of prednisolone equivalent per day. Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site). Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.

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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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alectinib<br>The treatment will be administrated as neoadjuvant 8 weeks before surgery. After surgical intervention the treatment will be administered up to 96 weeks. Treatment will be discontinued in case of unacceptable toxicity or disease progression. | Drug: Alectinib<br>* 600 mg p.o. (four 150 mg capsules) twice daily with food (within 30 minutes after a meal, in the morning and evening).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathological Response (MPR) | Percentage of residual viable tumor cells histologically detected in the resected primary tumor and all resected lymph nodes after surgery ≤10%. Evaluation by Blinded Independent Pathology Reviewer (BIPR). | From the treatment start until surgery - 12 weeks period (8 weeks of neoadjuvant therapy; surgery should be done within 2-4 weeks afterwards. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response | The absence of residual viable tumor cells in all surgical specimens (resected primary tumor and all resected lymph nodes) as evaluated by BIPR. | From the treatment start until surgery - 12 weeks period (8 weeks of neoadjuvant therapy; surgery should be done within 2-4 weeks afterwards. | 
| Objective response | Complete Response (CR) or a Partial Responses (PR) based on the Investigator's assessment and measured according to standard RECIST criteria v1.1 | Pre-surgical radiological evaluation (after 8 weeks of neoadjuvant therapy start) | 
| Event-free survival (EFS) | The length of time after the trial inclusion the patient remains free of recurrence/progression or death, whatever the cause. | From the trial inclusion date to either the date of disease recurrence/progression or the date of death, monitored up to 3 years after surgery. | 
| Disease-free survival (DFS) | The length of time after surgical resection the patient remains free of recurrence/progression or death, whatever the cause. | From the date of surgical resection to either the date of disease recurrence or the date of death monitored up to 3 years after surgery. | 
| Overall survival (OS) | The length of time after the trial inclusion the patient remains alive | From the date of trial inclusion to the date of death monitored up to 3 years after surgery. | 
| Adverse Events (AE) | Untoward medical events occurring after trial inclusion. Adverse Events are defined and graded according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0. Adverse event of special interest are cases of potential drug-induced liver, suspected transmission of an infectious agent by the study treatment, Interstitial Lung Disease. Serious adverse events is any AE occurring at any dose that results in death; is life-threatening (i.e., in the opinion of the Investigator, the subject is at immediate risk of death from the AE); requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay); results in persistent or significant disability/incapacity (a substantial disruption of the subject's ability to conduct normal life functions); is a congenital anomaly/birth defect; constitutes an important medical event. | From the date of the trial inclusion until 30 days (90 days in case of AE serious/special interest) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first | 
| Tissue and cell-free (plasma) biomarkers | Characterization of Anaplastic Lymphoma Kinase fusion partner on DNA extracted from tissue biopsy and on cell-free nucleic acid (cfNA) (both cfDNA and cfRNA) extracted from plasma sample. | From the time of diagnosis up to 3 years after surgery | 

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