Pembrolizumab Plus Chemotherapy in 1st Line Treatment of Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This is an open-label, phase 2 study of Pembrolizumab in combination with chemotherapy in chemotherapy-naïve advanced pancreatic cancer

Detailed Description
-----------------
In unresectable advanced pancreatic cancer, palliative chemotherapy (mainly Gemcitabine/nab-Paclitaxel or FOLFIRINOX) is the mainstay of treatment. Regardless of the choice of first-line therapy, more than half of the patients with advanced/metastatic disease will progress within six months and will not survive more than one year. Immune cells (IC) are a significant part of the pancreatic tumor-associated stroma and play a fundamental part in maintaining a non-immunogenic and immuno-suppressive environment. IO (Immuno-Oncology drug) monotherapy is not effective in advanced pancreatic cancer; therefore, we need more active combination regimens including IO/IO or IO/chemotherapy, etc. Furthermore, we need biomarker study to uncover which population is an optimal target for this IO-based treatment strategy. Based on these rationale, we plan to conduct an open-label, phase 2 study to explore biomarkers and evaluate the safety and efficacy of the pembrolizumab/chemotherapy combination in an advanced pancreatic cancer primary environment.

Official Title
-----------------
Biomarker-oriented Study of Pembrolizumab in Combination With Chemotherapy in Chemotherapy -naïve Advanced Pancreatic Cancer

Conditions
-----------------
Pancreatic Cancer, Chemotherapy Effect

Intervention / Treatment
-----------------
* Drug: Gemcitabine
* Drug: Nab-paclitaxel
* Drug: Pembrolizumab
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Irinotecan
* Drug: 5FU


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male/female participants who are at least 18 years of age on the day of signing informed consent Histologically confirmed diagnosis of unresectable, recurrent, or metastatic pancreatic cancer Not pregnant, not breasfeeding, and agree to use proper contraception, Chemotherapy-naïve for advanced pancreatic cancer (previous adjuvant chemotherapy is allowed) Have measurable disease based on RECIST 1.1. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Have adequate organ function Haemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3) Platelet count ≥ 100 x 109/L (>75,000 per mm3) Serum creatinine CL>30 mL/min by the Cockcroft-Gault formula or serum creatinine ≤1.5 × ULN Serum bilirubin ≤ 1.5 x ULN AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN unless liver metastases are present, in which case it must be ≤ 5x ULN International normalized ratio (INR) or Prothrombin time (PT), activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy Exclusion Criteria: A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks Has received prior radiotherapy within 2 weeks of start of study treatment. Has received a live vaccine within 30 days prior to the first dose of study drug. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Has known active CNS metastases and/or carcinomatous meningitis. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Has active autoimmune disease that has required systemic treatment in the past 2 years Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Has an active infection requiring systemic therapy. Has a known history of Human Immunodeficiency Virus (HIV). Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Has a known history of active TB (Bacillus Tuberculosis). Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine/Nab-paclitaxel<br>Gemcitabine/Nab-paclitaxel + pembrolizumab | Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2 iv D1, 8, 15 (every 4 weeks)<br>Drug: Nab-paclitaxel<br>* Nab-paclitaxel 125 mg/m2 iv D1, 8, 15 (every 4 weeks)<br>Drug: Pembrolizumab<br>* Pembrolizumab ( 200 ) mg iv D1 (every 3 weeks)<br>|
| Experimental: FOLFIRINOX<br>FOLFIRINOX + pembrolizumab | Drug: Pembrolizumab<br>* Pembrolizumab ( 200 ) mg iv D1 (every 3 weeks)<br>Drug: Oxaliplatin<br>* Oxaliplatin 65 mg/m2 iv over 2 hours D1 (every 2 weeks)<br>Drug: Leucovorin<br>* Leucovorin 400 mg/m2 iv D1 (every 2 weeks)<br>Drug: Irinotecan<br>* Irinotecan 140 mg/m2 iv over 1.5 hours D1 (every 2 weeks)<br>Drug: 5FU<br>* 5-FU 2400 mg/m2 iv over 46 hours D1 (every 2 weeks)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The percentage of patients whose optimal response achieves CR or PR between the initial response assessment and the time between treatment termination or intermediate dropout due to any cause | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Time from enroll until disease progression or death | 8 weeks | 
| Duration of response | Time from enroll untill disease progression or death in patients whose optimal response achieves CR or PR | 8 weeks | 
| Disease control rate | The percentage of patients who have achieved complete response, partial response and stable disease | 8 weeks | 
| Overall survival | Time from enroll until death from any cause | 8 weeks | 
| Immune-related response | RECIST 1.1, ir response | 8 weeks |