PD-L1 PET Imaging During Neoadjuvant (Chemo)Radiotherapy in Esophageal and Rectal Cancer

Study Overview
=================
Brief Summary
-----------------
The overall aim of this pilot study is to prospectively monitor programmed death-ligand 1 (PD-L1) expression dynamics in vivo, during neoadjuvant chemoradiotherapy (CRT) or short-course preoperative radiotherapy (SCPRT) in rectal and esophageal cancer by a positron emission tomography (PET) imaging approach.

Official Title
-----------------
Programmed Death-ligand 1 Positron Emission Tomography Imaging During Neoadjuvant (Chemo)radiothErapy in Esophageal and Rectal Cancer (PETNEC): a Prospective Non-randomized Open-label Single-center Pilot Study

Conditions
-----------------
Rectal Cancer Stage, Oesophageal Cancer

Intervention / Treatment
-----------------
* Radiation: CRT
* Radiation: SCPRT
* Radiation: CROSS Protocol
* Diagnostic Test: PD-L1 PET


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years of age and older All sexes Histologically confirmed carcinoma of the rectum or oesophagus (squamous cell carcinoma and adenocarcinoma, including oesophago-gastric junction cancers) Medical need for a neoadjuvant CRT/SCPRT Suitable to withstand the course of neoadjuvant CRT/SCPRT Written informed consent form (ICF) for participation in the study Exclusion Criteria: Metastatic disease, which is considered incurable by local therapies (expect for oligometastatic disease with a curative intend) Previous surgery of the tumor other than biopsy Pregnancy, breastfeeding or expectancy to conceive Prior therapy with anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 or any other agent directed against co-inhibitory T cell receptors or has previously participated in clinical studies with immunotherapy Disagreement of participants with reproductive potential to use contraception throughout the study period and for up to 180 days after the last dose of study therapy Hepatitis B or C Human immunodeficiency virus (HIV) Immunodeficiency Allogeneic tissue or solid organ transplantation Autoimmune disease that has required systemic therapy in the past 2 years with modifying agents, steroids or immunosuppressive drugs Active non-infectious pneumonitis Active infection requiring systemic therapy Systemic steroids or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment Diagnosed and/or treated additional malignancy within 5 years of randomization, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin and/or curatively-resected in situ cervical and/or breast cancers Treatment with botanical preparations (i.e. herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment Participants with serious or uncontrolled medical disorders Uncontrolled or significant cardiovascular disease (myocardial infarction, uncontrolled angina, any history of clinically significant arrhythmias, QTc prolongation in males > 450 ms and > 470 ms in females, participants with history of myocarditis) Allergies and adverse drug reaction (history of allergy or hypersensitivity to study drug components, contraindications to any of the study drugs of the chemotherapy regimen) Other exclusion criteria: Prisoners or participants who are involuntarily incarcerated, participants who are compulsorily detained for treatment of either a psychiatric or physical (i.e. infectious disease) illness

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

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

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

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

Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Neoadjuvant Chemoradiotherapy (CRT)<br> | Radiation: CRT<br>* 50 Gy in 2 Gy fractions over 25 working days + capecitabine 1650 mg/m2/d PO<br>Diagnostic Test: PD-L1 PET<br>* 10 mg atezolizumab IV followed by 37 MBq 89Zr-atezolizumab IV. PET imaging will be done before neoadjuvant CRT/SCPRT (day 0) and between day 10-14 during CRT/SCPRT.<br>|
| Other: Short-course preoperative radiotherapy (SCPRT)<br> | Radiation: SCPRT<br>* 25 Gy in 5 Gy fractions over 5 working days<br>Diagnostic Test: PD-L1 PET<br>* 10 mg atezolizumab IV followed by 37 MBq 89Zr-atezolizumab IV. PET imaging will be done before neoadjuvant CRT/SCPRT (day 0) and between day 10-14 during CRT/SCPRT.<br>|
| Other: Neoadjuvant Chemoradiotherapy (CROSS protocol)<br> | Radiation: CROSS Protocol<br>* 41.4 Gy in 1.8 Gy fractions over 23 working days + carboplatin AUC of 2 mg/ml/min + paclitaxel 50 mg/m2 IV Q1W<br>Diagnostic Test: PD-L1 PET<br>* 10 mg atezolizumab IV followed by 37 MBq 89Zr-atezolizumab IV. PET imaging will be done before neoadjuvant CRT/SCPRT (day 0) and between day 10-14 during CRT/SCPRT.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intratumoral changes of PD-L1 expression during neoadjuvant CRT/SCPRT | Intratumoral PD-L1 expression dynamics induced by neoadjuvant CRT/SCPRT will be assessed by 89Zr-atezolizumab PET imaging (day 0 and between day 10-14). | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic therapy response | Radiographic therapy response will be determined by magnetic resonance imaging-assessed tumor regression grade (mrTRG) for rectal cancer and PET response criteria in solid tumors (PERCIST) for esophageal cancer. | 12 weeks | 
| Pathological therapy response | Pathological therapy response will be determined according to the latest American Joint Committee on Cancer/International Union Against Cancer-Tumor Node Metastasis (AJCC/UICC-TNM) staging and tumor regression grade (TRG). | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rectal Cancer, Oesophageal Cancer, Chemoradiotherapy, Short-course preoperative radiotherapy, PD-L1 PET, 89Zr-atezolizumab