Stereotactic Radiotherapy + Anti PD-1 Therapy in Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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Stereotactic Radiotherapy + Anti PD-1 Therapy in Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma

Detailed Description
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Phase I/II, multicentre, open label, with no control arm clinical trial of 4-weeks stereotactic radiotherapy followed by nivolumab 3 mg/kg every two weeks in adults with locally advanced pancreatic cancer who does not progress during 4 cycles of standard chemotherapy FOLFIRINOX

Official Title
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Stereotactic Radiotherapy + Anti PD-1 Therapy in Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma

Conditions
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Locally Advanced Unresectable Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Nivolumab
* Radiation: Stereotactic radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged ≥18 years Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 Locally advanced, unresectable, histologically confirmed primary adenocarcinoma of pancreas with no progression during induction chemotherapy (4 cycles of FOLFIRINOX - not a part of trial). Within screening period tumor tissue must be available and sent to the central pathological reviewer in order to confirm the diagnosis. Measurable (one target lesion is sufficient) disease as per RECIST 1.1 criteria Laboratory values: Aspartate aminotransferase (AST) ≤ 3x ULN (upper limit of normal) Alanine transaminase (ALT) ≤ 3x ULN Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome who must have a total bilirubin ≤ 3x ULN) Creatinine: Serum creatinine ≤ 1.5 ULN or creatinine clearance > 50ml/min (using Cockcroft/Gault formula) White blood cells ≥ 2000 /ul Neutrophils ≥ 1500 /ul Platelets ≥ 100x 103 /ul Hemoglobin ≥ 9.0 g/l Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and who is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, females under age of 55 years must have serum follicle stimulating hormone (FSH) level > 40mIU/ml to confirm menopause. Exclusion Criteria: Other histology then primary pancreatic adenocarcinoma Resectable disease Distant metastases Progressive disease during induction chemotherapy (4 cycles of FOLFIRINOX) Other previous treatment of the disease except induction chemotherapy (4 cycles of FOLFIRINOX) ECOG performance score of 2 or more Previous therapy of malignant disease in 5 years and less before inclusion to the trial (except skin epithelial tumors) Previous radiotherapy in abdominal region Previous immunological treatment (anti-CTLA-4, anti-PD1 or anti-PD-L1) Active, known or suspected serious autoimmune disease Major surgery less than 28 days prior to the first dose of study treatment Treatment of any investigational medicinal product within 4 weeks before this trial enrolment Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency synrome (AIDS) Prisoners or subjects who are involuntarily incarcerated Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness

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: Arm 1<br>4-weeks stereotactic radiotherapy followed by nivolumab 3 mg/kg every two weeks | Drug: Nivolumab<br>* Nivolumab 3 mg/kg intravenously every two weeks untill disease progression or unacceptable toxicity<br>* Other names: Opdivo;Radiation: Stereotactic radiotherapy<br>* The prescribed dose will be 32 Gy in four fractions in four weeks (8 Gy per one fraction).<br>* Other names: Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - incidence of treatment-related adverse events | Measured by the incidence of adverse events (AEs), serious adverse events (SAEs), deaths | Through study completion, an average of 4 years | 
| Safety - incidence of laboratory abnormalities | Biochemistry - Na (mmol/l), K (mmol/l), Cl (mmol/l), Ca (mmol/l), Ca ionized (mmol/l), Mg (mmol/l), P (mmol/l), urea (mmol/l), creatinine (µmol/l), LDH (µkat/l), AST(µkat/l), ALT(µkat/l), ALP(µkat/l), GMT(µkat/l), total bilirubin (µmol/l), conjuged bilirubin (µmol/l), total protein (g/l), albumin (g/l), fasting glucose (mmol/l), amylase (µkat/l), C-reactive protein (mg/l), endocrine panel - TSH (mU/l), Free T3 (pmol/l), Free T4 (pmol/l), hematology - complete blood count (CBC): hemoglobin (g/l), hematocrit (ratio), white blood cells (WBC) (10E9/l), red blood cells (10E12/l), platelets (10E9/l) including differential (all 10E9/l), coagulation - APTT (ratio), PT (ratio) | Through study completion, an average of 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | To evaluate progression free survival (median of progression free survival and 1-, 2-year progression free survival) | Through study completion, an average of 4 years | 
| Overall survival | To evaluate overall survival (median of overall survival and 1-, 2-year overall survival) | Through study completion, an average of 4 years | 
| Relationship of laboratory markers and progression | To evaluate the relationship of laboratory markers (PD-L1 expression, tumor infiltrating lymphocytes presence, neopterin level) to progression status and time related progress of biomarkers (CEA, CA19-9) | Through study completion, an average of 4 years | 
| patient's capacity to fulfill the activities of daily living and quality of life | Assess by questionnaire European Organisation for Research and Treatment of Cancer (EORTC) Quality of life questionnaire (QLQ-C30) questionnaire. The EORTC QLQ-C30 comprises 30 items (i.e. single questions), 24 of which are aggregated into 9 multi-item scales, that is, 5 functioning scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain and nausea/vomiting) and one global health status scale. The remaining 6 single-item (dyspnoea, appetite loss, sleep disturbance, constipation, diarrhoea and the financial impact) scales assess symptoms.All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). | Through study completion, an average of 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stereotactic radiotherapy, Nivolumab, Anti PD-1, Pancreatic cancer, Pancreatic Adenocarcinoma