Alectinib Followed by Concomitant Consolidation Radiation Therapy in Advanced NSCLC With ALK-rearrangement (A-SAB)

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn evaluate the safety and efficacy of the addition of radiation therapy to all tumour lesions, to first line medical treatment with alectinib in non-small cell lung cancer harbouring ALK-rearrangements. The main aims of the trial are to evaluate: if the treatment combination is safe if the treatment combination can inhibit progression Participants who have responded to 1st line alectinib will be treated with consolidation radiation therapy to all remaining tumour lesions while continuing on alectinib until disease progression, unacceptable toxicity or another discontinuation criterion is met.

Detailed Description
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This is phase I/II study to evaluate the feasibility (phase I) and progression free survival (phase II) in patients with advanced NSCLC with ALK-rearrangement receiving consolidation radiation therapy (RT) to all known macroscopic tumour lesions present after 2-3 months of treatment with alectinib and then continuing with alectinib. Eligible patients are those with an ALK-rearranged stage III (non-surgical/non-radiochemotherapy candidates) OR stage IV NSCLC who, after a 2-3-month-induction period of alectinib show stable disease/partial response to systemic therapy. When entering the trial, all known tumour lesions are treated with SBRT/RT/SRS with concomitant alectinib followed by continuation alectinib until disease progression, unacceptable toxicity or another discontinuation criterion is met.

Official Title
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A-SAB - Alectinib Followed by Concomitant Consolidation SBRT/Hypofractionated Radiation Therapy/SRS in Advanced NSCLC With ALK-rearrangement

Conditions
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Radiotherapy Side Effect, Non-small Cell Lung Cancer, ALK Gene Mutation

Intervention / Treatment
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* Radiation: SBRT/SRS/radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmed NSCLC: Stage IV NSCLC OR Stage III NSCLC not suitable for surgery or radiochemotherapy OR Recurrent NSCLC after previous surgery (not amendable for curative multimodal therapy) ALK-rearrangement Adequate organ function to tolerate alectinib and clinical tolerance to alectinib Stable disease (SD) or partial response (PR) after 2-3 months induction treatment with alectinib Maximum 5 tumour lesions +/- thoracic lymph nodes active on an 18F-FDG-PET scan post induction treatment with alectinib All active tumour lesions amendable to RT under the following conditions: All metastases possible to treat with Extracranial metastases: SBRT of at least 7 Gy x 5 (corresponding to 50 Gy EQD2 using alfa/beta 10Gy) Intracranial metastases: SRS or f-SRS The primary tumour and/or lymph nodes and/or pulmonary metastases amendable to SBRT (≥ 7Gy x 5, see above) or moderately hypofractionated RT of 3 Gy x 15 (corresponding to 49 Gy EQD2 using alfa/beta 10Gy) Adequate organ function to tolerate SBRT/RT: Fulfilment of dose constraints to adequate organs at risk ECOG performance status (PS) 0-2 FEV1 ≥1 litre (only applicable for lung targets) Age ≥ 20 years Measurable lesions according to RECIST v 1.1 Signed written informed consent Exclusion Criteria: Leptomeningeal carcinosis (on MRI or in cerebrospinal fluid (CSF)) Persistent malignant pleural effusion, malignant pericardial effusion or malignant ascites after induction treatment PD after 2-3-month-induction treatment with alectinib Previous TKI, chemotherapy or immunotherapy (previous adjuvant chemotherapy for early stage NSCLC is allowed) for metastatic NSCLC Previous RT for NSCLC (any stage) Previous RT for any other cancer within the last 3 years possibly interfering with the planned RT within this study Life expectancy of less than 6 months Inability to understand given information or undergo study procedures according to protocol. Has evidence or a past medical history of interstitial lung disease or active, non-infectious pneumonitis or known pulmonary fibrosis. Pregnant or breast-feeding. Patients must agree to use safe contraception during and for 3 months after study treatment.

Ages Eligible for Study
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Minimum Age: 20 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
Interventional Model Description: Single arm, multicenter, phase I/II study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy + alectinib<br>All patients receive consolidation radiation therapy to all active tumour lesions after induction treatment with alectinib. | Radiation: SBRT/SRS/radiation therapy<br>* Consolidation radiation therapy (SBRT/SRS/moderately hypofractionated radiation therapy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity (safety) | No and percentage of patients suffering grade 3-5 toxicity attributed to RT and within 6 months post RT). | 6 months post radiation therapy | 
| Progression free survival (PFS) | PFS-rate at 12 months (KM-estimated method). Successrate is 12-month-PFS-rate of 85%. Median PFS will also be measured | PFS rate at 12 months after initiation of alectinib | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | OS-rate at 1-, 2-, 3- and 5 years post initiation of alectinib using the KM-method. Median OS will also be measured. | 5 years | 
| Progression free survival II | (Time between the date of initiation of alectinib and the date of documented 2nd tumour progression or death, from whatever reason.) PFS II rate at 1-, 2-, 3- and 5 years (KM-method) will be measured. | 5 years | 
| Time to treatment failure | Time between the date of initiation of alectinib and the date of documented progressive disease, unacceptable toxicity related to SBRT, toxicity attributed to alectinib leading to interruption of the treatment or death. (Time between the date of initiation of alectinib and the date of documented 2nd tumour progression or death, from whatever reason.) TTF-rate at 1-, 2-, 3- and 5 years (KM-method). | 3 years | 
| Time to next therapy | Time between the date of initiation of alectinib and the date of next therapy. (Time between the date of initiation of alectinib and the date of documented 2nd tumour progression or death, from whatever reason.) Rate at 1-, 2-, 3- and 5 years (KM-method). | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stereotactic body radiation therapy, SBRT, Radiotherapy, Non-small Cell Lung Cancer, ALK-rearrangement