A Clinical Trial of Durvalumab (MEDI4736) as 1st Line Therapy in Advanced Non-small Cell Lung Cancer Patients

Study Overview
=================
Brief Summary
-----------------
This is a single-arm phase II clinical trial evaluating the safety and efficacy of the PD-L1 inhibitor durvalumab as first-line therapy in 47 patients with advanced NSCLC and ECOG Performance Status 2 (PS2).

Detailed Description
-----------------
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 50 mg/mL for intravenous (IV) administration. Durvalumab will be administered at 1500 mg (fixed dose) every 4 weeks until disease progression, death, unacceptable toxicity or withdrawal of consent for a maximum of 12 months of therapy.

Official Title
-----------------
A Phase II Clinical Trial Evaluating the Safety and Efficacy of Durvalumab (MEDI4736) as 1st Line Therapy in Advanced Non-small Cell Lung Cancer (NSCLC) Patients With Eastern Cooperative Oncology Group (ECOG) Performance Status of 2

Conditions
-----------------
Non-Small Cell Lung Cancer NSCLC

Intervention / Treatment
-----------------
* Drug: durvalumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent Patients must have histologically or cytologically confirmed Stage IIIB or IV (American Joint Committee on Cancer, 7th edition; AJCC 7) non-small cell lung cancer. Patients must have measurable disease. Patients must have not have received any prior therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) for the treatment of stage IV NSCLC. Age ≥ 18 years at time of study entry. ECOG performance status of 2. Life expectancy of greater than 12 weeks. Tissue available (archived or fresh tumor biopsy) for the PD-L1 assay. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (> 1500 per mm^3) Hemoglobin ≥ 9.0 g/dL Platelet count ≥ 100 x 10^9/L (>100,000 per mm^3) Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN unless liver metastases are present, in which case it must be ≤ 5x ULN Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula Female subjects must either be of non-reproductive potential OR must have a negative serum pregnancy test upon study entry. The effects of durvalumab on the developing human fetus are unknown. For this reason and because immunomodulatory agents are potentially teratogenic, sexually active women of child-bearing potential and men must agree to use adequate contraception (2 methods of effective contraception from screening) from screening, for the duration of study participation, and for at least 90 days following the last infusion of durvalumab. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Exclusion Criteria: Involvement in the planning and/or conduct of the study; previous enrollment in the present study. Participation in another clinical study with an investigational product for cancer during the last 12 months. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids in excess of prednisone 10 mg/d or equivalent. Sensitizing mutations in EGFR or rearrangements in ALK or ROS1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab. Mean QT interval corrected for heart rate (QTc) ≥ 470 ms. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids . Patients may be on systemic corticosteroids provided the dose does not exceed prednisone 10 mg/d or equivalent for 1 week prior to study drug administration. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). History of primary immunodeficiency. History of allogeneic organ transplant. Uncontrolled intercurrent illness. Known history of previous clinical diagnosis of tuberculosis. History of leptomeningeal carcinomatosis. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. Subjects with uncontrolled seizures. Pregnant women; breastfeeding should be discontinued. Prior history of radiation pneumonitis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: durvalumab<br>1500 mg of durvalumab will be administered intravenously (IV) on day 1 of every 28 day cycle. | Drug: durvalumab<br>* A human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against programmed cell death ligand 1 (PD-L1)<br>* Other names: MEDI4736;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Median length of time from the start of treatment from start of treatment to death from any cause. | Up to 30 months | 
| Overall Survival (OS12) | Number of patients alive at 12 months post start of treatment. | At 12 months | 
| Overall Survival (OS24) | Number of patients alive at 24 months post start of treatment. | At 24 months | 
| Treatment-related Adverse Events ≥ Grade 3 | Number of participants with ≥ Grade 3 adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 that are at least possibly related to study treatment. | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Median duration of time from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.0 Progressive Disease (PD) for target lesions: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions:Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | Up to 30 months | 
| Progression-Free Survival (PFS) at 12 Months | Number of patients without progressive disease or death at 12 months from start of treatment. Per RECIST v1.0 Progressive Disease (PD) for target lesions: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | At 12 months | 
| Progression-Free Survival (PFS) at 24 Months | Number of patients without progressive disease or death at 24 months from start of treatment Per RECIST v1.0 Progressive Disease (PD) for target lesions: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions:Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | At 24 months | 
| Progression-Free Survival (PFS) by PD-L1 Expression at 12 Months | Number of patients of know PD-L1 status without progressive disease or death at 12 months from start of treatment. Per RECIST v1.0 Progressive Disease (PD) for target lesions: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | At 12 months | 
| Progression-Free Survival (PFS) by PD-L1 Expression Status at 24 Months | Number of patients of know PD-L1 status without progressive disease or death at 24 months from start of treatment Per RECIST v1.0 Progressive Disease (PD) for target lesions: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions:Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | At 24 months | 
| Overall Survival by PD-L1 Expression Status at 12 Months | Number of patients with know PD-L1 status that are alive at 12 months post start of treatment. | At 12 months | 
| Overall Survival by PD-L1 Expression Status at 24 Months | Number of patients with know PD-L1 status that are alive at 24 months post start of treatment. | At 24 months | 
| Overall Response Rate (ORR) | Percentage of patients with a Best Response of Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). Per RECIST v1.0, for target lesions: PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither PR nor PD (target lesions); persistence of 1 or more non-target lesions and/or the maintenance of tumor marker levels above normal limits. PD: at least a 20% increase in sum of diameters (target lesions), taking as reference the smallest sum on study (includes baseline sum if smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase of at least 5 mm. (includes appearance of one or more new lesions) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | Up to 30 months | 
| Overall Response Rate (ORR) in Patients With PD-L1 Expression Status = 0 | Percentage of patients with PD-L1 expression status = 0, with a Best Response of Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). Per RECIST v1.0 (target lesions): PR: ≥30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither PR nor PD (target lesions); persistence of 1 or more non-target lesions and/or the maintenance of tumor marker levels above normal limits. PD: ≥20% increase in sum of diameters (target lesions), taking as reference the smallest sum on study (includes baseline sum if smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase of at least 5 mm. (includes appearance of one or more new lesions) ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | Up to 30 months | 
| Overall Response Rate (ORR) in Patients With PD-L1 Expression Status = 0%<PD-L1<50%. | Percentage of patients with PD-L1 expression status=0%<PD-L1<50%, with a Best Response of Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). Per RECIST v1.0 (target lesions): PR: ≥30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither PR nor PD (target lesions); persistence of 1 or more non-target lesions and/or the maintenance of tumor marker levels above normal limits. PD: ≥20% increase in sum of diameters (target lesions), taking as reference the smallest sum on study (includes baseline sum if smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase of at least 5 mm. (includes appearance of one or more new lesions) ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | Up to 30 months | 
| Overall Response Rate (ORR) in Patients With PD-L1 Expression Status ≥50% | Percentage of patients with PD-L1 expression status ≥50%, with a Best Response of Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). Per RECIST v1.0 (target lesions): PR: ≥30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither PR nor PD (target lesions); persistence of 1 or more non-target lesions and/or the maintenance of tumor marker levels above normal limits. PD: ≥20% increase in sum of diameters (target lesions), taking as reference the smallest sum on study (includes baseline sum if smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase of at least 5 mm. (includes appearance of one or more new lesions) ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. | Up to 30 months | 
| Health Related Quality of Life (HRQL) - FACT-G | Patient self-administered 27-item questionnaire that measures health state in cancer patients in prior 7 days, including physical, social, emotional, and functional well-being. Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-108. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | At baseline | 
| Health Related Quality of Life (HRQL) - FACT-G | Patient self-administered 27-item questionnaire that measures health state in cancer patients in prior 7 days, including physical, social, emotional, and functional well-being. Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-108. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | Within first two treatment cycles, up to 56 days | 
| Health Related Quality of Life (HRQL) - FACT-G | Patient self-administered 27-item questionnaire that measures health state in cancer patients in prior 7 days, including physical, social, emotional, and functional well-being. Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-108. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | At 6 months | 
| Health Related Quality of Life (HRQL) - FACT-G | Patient self-administered 27-item questionnaire that measures health state in cancer patients in prior 7 days, including physical, social, emotional, and functional well-being. Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-108. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | At 12 months | 
| FACT Lung Cancer Subscale (LCS) | The FACT-LCS is the lung cancer subscale of the FACT-L. LCS includes the average symptom burden index (ASBI; based on 5 symptoms: anorexia, fatigue, cough, dyspnea, hemoptysis, and pain) and the 3-item global index (2-IGI; symptom distress, interference with activities, and health-related quality of life). Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-28. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | At baseline | 
| FACT Lung Cancer Subscale (LCS) | The FACT-LCS is the lung cancer subscale of the FACT-L. LCS includes the average symptom burden index (ASBI; based on 5 symptoms: anorexia, fatigue, cough, dyspnea, hemoptysis, and pain) and the 3-item global index (2-IGI; symptom distress, interference with activities, and health-related quality of life). Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-28. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | Within first two treatment cycles, up to 56 days | 
| FACT Lung Cancer Subscale (LCS) | The FACT-LCS is the lung cancer subscale of the FACT-L. LCS includes the average symptom burden index (ASBI; based on 5 symptoms: anorexia, fatigue, cough, dyspnea, hemoptysis, and pain) and the 3-item global index (2-IGI; symptom distress, interference with activities, and health-related quality of life). Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-28. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | At 6 months | 
| FACT Lung Cancer Subscale (LCS) | The FACT-LCS is the lung cancer subscale of the FACT-L. LCS includes the average symptom burden index (ASBI; based on 5 symptoms: anorexia, fatigue, cough, dyspnea, hemoptysis, and pain) and the 3-item global index (2-IGI; symptom distress, interference with activities, and health-related quality of life). Scoring: Five-point scale: 0 (not at all) to 4 (very much). Total score is from 0-28. Questions are phrased so that higher numbers indicate a better health state, leading to some items being reverse-scored. | At 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PD-L1 (programmed cell death ligand 1)