Combined S-1 With DC+CIK As Maintenance Therapy For Advanced Pancreatic Ductal Adenocarcinoma

Phase II Randomized Controlled Trial Of Dendritic Cell + Cytokine-Induced Killer Cell Immunotherapy With S-1 Versus S-1 Alone As Maintenance Therapy For Advanced Pancreatic Ductal Adenocarcinoma Patients

The goal of this randomized phase 2 controlled clinical trial is to study safety, efficacy of S-1 combined DC+CIK maintenance therapy compared with S-1 alone in improving clinical benefit rate (CBR) among advanced PDAC patients. The main objectives aim to be achieved through this study are :

1. To evaluate the safety of DC+CIK combined immunotherapy when administered with the chemotherapy S-1 as maintenance therapy following first-line chemotherapy regime to advanced pancreatic ductal adenocarcinoma patients.
2. To demonstrate the superiority of of DC+CIK combined immunotherapy in improving clinical benefit rate (CBR) of advanced pancreatic ductal adenocarcinoma patients when administered with the chemotherapy S-1 as maintenance therapy following first-line chemotherapy regime.
3. To investigate the ability of S-1 combined DC+CIK maintenance therapy in reducing pancreatic ductal adenocarcinoma patients' circulating cancer stem cells (CSCs).

In this study, subjects who achieve at least stable disease or partial response will be randomized in ratio of 1:1 into treatment group: DC-CIK plus S1 (27 patients) and control group: S-1 alone (27 patients). For treatment group, they will be infused with DC first, followed by CIK immune cells on day 1. DC+CIK immunotherapy will be repeated for another 2 times (day 8 and 15) as one cycle. All patients are left to rest for a week (start from day 21) prior to receive another 3 times of infusion (day 28, 35 and 42) if condition allowed. Additional third cycle can be performed on those who tolerate well with no toxicity or respond very well. Patients from treatment group will be assessed for their eligibility to receive booster dose on following conditions: 1) tumour achieves partial response or stable disease and 2) ECOG-PS performance status of 0-2 and 3) doesn't exhibit grade 1 and 2 toxicities to improve tumour control.

Additionally, S-1 will be given twice daily after meals for 2 weeks as first cycle along with DC+CIK. Next second cycle of S-1 will be given after 7-days (1 week) rest. The cycles will be repeated every 21 days until disease progression, unacceptable toxic effects, or withdrawal with consent. Dose of S-1 will be determined according to the body surface area.

Meanwhile, patients from control group will receive S-1 alone as maintenance therapy twice daily after meals for 14 days (2 weeks) as one cycle. The next cycle of S-1 will be given after 7-days rest. The cycles will be repeated every 21 days until disease progression, unacceptable toxic effects, or withdrawal with consent.

This trial is designed as randomized phase 2 controlled clinical trial.

Subjects who fulfill following inclusion criteria will be admitted to this phase 2 trial and will be excluded if they fulfill any one of the exclusion criteria. All patients must have undergone first-line of chemotherapy (either modified FOLFIRINOX or gemcitabine-based) for at least 3 months and achieved at least stable disease. The inclusion criteria are as follow: 1) histologically and cytologically confirmed advanced pancreatic ductal adenocarcinoma according to AJCC (American Joint Committee on Cancer) TNM system; 2) have undergone first-line of chemotherapy (modified FOLFIRINOX or gemcitabine-based) for at least 3 months and achieved at least stable disease; 3) Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0-2; 4) age above 18 ages and 5) life expectancy more than three months. Meanwhile, the exclusion criteria are 1) pregnant and lactating women; 2) concomitant beta-adrenergic drug blockers medication; 3) active infection; 4) current enrollment in another clinical study with an investigational agent and 5) patients who undergo pancreas or metastatic site radiotherapy need to be recovered from the toxicities.

Next, patients who achieve at least stable disease will be checked for peripheral blood mononuclear cells (PBMC) adequacy, hematoprofiling using full blood count (FBC) and their baseline status. This is followed by leukapheresis once all conditions satisfied and met. Apheretic products will be sent to local sponsor-contracted laboratory prior for incubation of patients' immune cells with PDAC antigens under specific medium.

All subjects in this trial have been diagnosed with advanced stage of PDAC and being treated with standard chemo: modified FOLFIRINOX or gemcitabine-based regime for at least 3 months. Once the DC+CIK infusion bags are ready to be manufactured, those who achieve at least stable disease or partial response will be randomized in ratio of 1:1 into treatment group: DC-CIK plus S1 (27 patients) and control group: S-1 alone (27 patients).

For treatment group, DC+CIK infusion bag will be administrated right after 17 days patients discharged. Patients will be infused with DC first, followed by CIK immune cells on day 1. DC+CIK immunotherapy will be repeated for another 2 times (day 8 and 15) as one cycle. All patients are left to rest for a week (start from day 21) prior to receive another 3 times of infusion (day 28, 35 and 42) if condition allowed. DC+CIK immunotherapy will be offered as two cycles for every patient in treatment group.

Additional third cycle can be performed on those who tolerate well with no toxicity or respond very well. Patients from treatment group will be assessed for their eligibility to receive booster dose on following conditions: 1) tumour achieves partial response or stable disease and 2) ECOG-PS performance status of 0-2 and 3) doesn't exhibit grade 1 and 2 toxicities to improve tumour control.

Additionally, S-1 will be given twice daily after meals for 2 weeks as first cycle along with DC+CIK. Next second cycle of S-1 will be given after 7-days (1 week) rest. The cycles will be repeated every 21 days until disease progression, unacceptable toxic effects, or withdrawal with consent. Dose of S-1 will be determined according to the body surface area.

Meanwhile, patients from control group will receive S-1 alone as maintenance therapy twice daily after meals for 14 days (2 weeks) as one cycle. The next cycle of S-1 will be given after 7-days rest. The cycles will be repeated every 21 days until disease progression, unacceptable toxic effects, or withdrawal with consent.

All patients will be followed up for clinical effects of S-1 combined maintenance therapy translated by tumour best overall response towards the treatment, either complete response (CR), partial response (PR), stable disease (SD) outcomes or progression disease (PD) and level of prognostic biomarkers. Besides, all patients will undergo baseline CT/MRI scan within 4 weeks of patient randomization and before immunotherapy being initiated. This is followed by reassessment CT/MRI scan at the end of 8th weeks starting from date of first treatment, and after S-1 combined DC+CIK immunotherapy completed. All patients will be followed-up regularly to monitor disease progression using reassessment CT/MRI scan at eight weeks interval until first PD observed (Timeframe = 12 months).

Patients' blood will be taken before maintenance treatment initiated and after maintenance treatment completed to evaluate serum cytokine concentration changes and level of circulating cancer stem cells (CSCs). Furthermore, blood will also be taken after each cycle of DC+CIK immunotherapy completed to evaluate baseline peripheral immune profile. Serum CA19-9 concentrations will be monitored every 4 weeks using blood test after first cycle of DC+CIK treatment completed.

Two endoscopic-ultrasound (EUS) guided biopsy pancreatic specimens (optional) will be collected from treatment group patients before maintenance treatment given and after completion of second cycle DC+CIK immunotherapy to quantify tumour-infiltrating lymphocytes (TILs), apoptotic protein expressed on tumour cells and apoptotic cells.

Finally, patients will be monitored for side effects, toxicities and response toward treatment weekly starting on day 7th onward after initial DC+CIK administration. All dated events occurring any time after informed consent will be obtained until 7 days (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.

Inclusion Criteria:

1. Histologically and cytologically confirmed advanced pancreatic ductal adenocarcinoma according to AJCC (American Joint Committee on Cancer) TNM system;
2. Have undergone first-line of chemotherapy (modified FOLFIRINOX or gemcitabine-based) for at least 3 months and achieved at least stable disease;
3. Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0-2;
4. Age above 18 ages
5. Life expectancy more than three months.

Exclusion Criteria:

1. Pregnant and lactating women
2. Concomitant beta-adrenergic drug blockers medication
3. Active infection
4. Current enrollment in another clinical study with an investigational agent
5. Patients who undergo radiotherapy to pancreas or metastatic site need to be recovered from the toxicities