Intensified Chemo-immuno-radiotherapy With Durvalumab for Stage III Non-Small Cell Lung Cancers

Study Overview
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Brief Summary
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This is a phase II study that will assess if Durvalumab (MEDI4736) used as induction chemo-immunotherapy followed by concurrent chemo-immuno-radiotherapy and consolidation immunotherapy may improve oncologic outcomes compared with standard of care chemoradiation followed by durvalumab (as in the PACIFIC trial) with a reasonable safety profile.

Detailed Description
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Prospective, non-randomized, open label, single arm, multi-institutional, phase 2 study, including patients with stage III non-small cell lung cancer able to receive concurrent chemoradiation. Eligible patients will then receive treatment as follows: Induction chemo-immunotherapy Two 21-day cycles of carboplatin, paclitaxel and durvalumab will be given BEFORE concurrent chemo-immuno-radiotherapy. Thereafter, patients without progressive disease (or patients with disease progression that is still locally advanced and can be safely encompassed within tolerable radiation fields) will receive concurrent chemo-immuno-radiotherapy, as follows: Concurrent chemo-immuno-radiotherapy Concurrent carboplatin, paclitaxel, and durvalumab with radiation therapy, initiated preferably 3-5 weeks after the last dose of induction chemo-immunotherapy. Thereafter, patients without progressive disease will receive consolidation immunotherapy, as follows: Consolidation immunotherapy Twelve 28-day cycles of durvalumab will be given, initiated preferably within one week following concurrent chemo-immuno-radiotherapy.

Official Title
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Intensified Chemo-immuno-radiotherapy With Durvalumab (MEDI4736) for Stage III Non-Small Cell Lung Cancers (NSCLCs): a Brazilian Single Arm Phase II Study (PACIFIC BRAZIL)

Conditions
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Lung Neoplasms

Intervention / Treatment
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* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Histologically or cytologically confirmed non-small cell lung cancer. Stage III according to the American Joint Committee on Cancer (AJCC) Staging Manual, 8th edition. No prior systemic therapy, radiation therapy, or surgery for the current cancer. Age ≥ 18 years at time of study entry Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Body weight >30kg Pre- or post-bronchodilator forced expiratory volume 1 ≥ 1.2 litres/second or ≥ 50% of predicted value Adequate normal organ and marrow function EXCLUSION CRITERIA Patients whose radiation treatment is likely to encompass a volume of whole lung receiving ≥ 20 Gy in total of more than 35% of lung volume. Patients whose radiation treatment is likely to deliver a cardiac dose V50 > 25% Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients Participation in another clinical study with an investigational product with anti-neoplastic activity during the last 3 weeks prior to treatment initiation Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study History of allogenic organ transplantation. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 antibodies Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational product. Prior radiation therapy to the region of the study cancer that would result in overlap of radiation therapy fields. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of the investigational product. Active or prior documented autoimmune or inflammatory disorders Uncontrolled intercurrent illness History of another primary malignancy Known active infection including tuberculosis , hepatitis B, hepatitis C, or human immunodeficiency virus.

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
Interventional Model Description: Prospective single-arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DURVALUMAB (MEDI4736) + carboplatin-paclitaxel<br>Induction chemo-immunotherapy phase: Two cycles of Paclitaxel 200 mg/m2, Carboplatin AUC 6 and Durvalumab 1500 mg intravenously every 21 days. Concurrent chemo-immuno-radiotherapy phase: Radiation therapy concomitantly with: paclitaxel 50 mg/m2 intravenously every 7 days (+/- 3 days) until completion of radiation therapy, carboplatin AUC 2 intravenously every 7 days (+/- 3 days) until completion of radiation therapy and durvalumab 1500 mg intravenously every 21 days (+/- 6 days) for a maximum of 2 doses. Concurrent chemo-immuno-radiotherapy: Durvalumab 1500 mg intravenously every 28 days (+/- 7 days) for a maximum of 12 doses | Drug: Durvalumab<br>* Intensified chemo-immuno-radiotherapy with durvalumab in combination with carboplatin, paclitaxel and radiation<br>* Other names: Paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12 months Progression-Free Survival | Proportion of patients who are alive and progression-free 12 months after cycle 1, day 1 of induction treatment, estimated by the Kaplan-Maier method and using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Tumor scans will be performed at baseline, after the induction and concomitant phases and 3, 6, 9, and 12 months after the last dose of radiation therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from cycle 1, day 1 of induction treatment until death due to any cause. | OS will be evaluated until month 24 after C1D1. | 
| Overall response rate to induction treatment | The proportion of patients with at least one tumor scan of complete response (CR) or partial response (PR) using RECIST v1.1. | Tumor scans will be performed at baseline, after the induction and concomitant phases and 3, 6, 9, and 12 months after the last dose of radiation therapy. | 
| Patterns of Failure | Rate of disease failure in local, regional and distant sites | Tumor scans will be performed at baseline, after the induction and concomitant phases and 3, 6, 9, and 12 months after the last dose of radiation therapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage III Non-Small Cell Lung Cancer, Unresectable Non-Small Cell Lung Cancer, Durvalumab, MEDI4736