Trial of Antigen Pulsed Dendritic Cells (APDC) in Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
This trial is to compare the efficacy and safety of modified FOLFOX6 [mFOLFOX6, a specific chemotherapy regimen of Oxaliplatin ,5-Fluorouracil and Leucovorin] chemotherapy plus Antigen Pulsed Dendritic Cells (APDC，a kind of autologous tumor lysates pulsed human dendritic cells vaccine) with modified chemotherapy alone in patients with metastatic colorectal cancer.

Detailed Description
-----------------
Metastatic colorectal cancer (CRC) patients will be randomly assigned (3:1) to receive either modified FOLFOX6 [mFOLFOX6] chemotherapy combined with Antigen Pulsed Dendritic Cells (Arm APDC + Chemotherapy), or chemotherapy alone (Arm Chemotherapy). Each patient recruited in the study will receive maximum 12 cycles of (14 days/cycle) mFOLFOX6 chemotherapy. Patients in Arm APDC + Chemotherapy will receive APDC vaccination in addition to chemotherapy in the cycle 1-3 and 7-9, and in cycle 4-6 and 10-12 receive only chemotherapy. APDC + Chemotherapy or Chemotherapy will be stopped in case of disease progression, intolerable toxicities, or patient withdrawal with the consent. After 12 cycles, patients in Arm APDC + Chemotherapy will receive 5-Fluorouracil treatment plus every 3 months APDC therapy and patients in Arm Chemotherapy will receive only 5-Fluorouracil treatment. PFS, ORR and OS will be assessed, and toxicity and immunologic effects will be monitored.

Official Title
-----------------
Phase III Trial of Antigen Pulsed Dendritic Cells (APDC) Combined With Chemotherapy in Metastatic Colorectal Cancer

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Biological: APDC + Chemotherapy
* Drug: Chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed adenocarcinoma of the colorectum with metastatic lesions and received no previous therapy for metastatic lesions; Be able to undergo surgical resection to obtain at least 1cm3 tumor tissues; The patients are from 18-75 years old regardless of gender; An estimated life expectancy of more than 6 months with ECOG≤2; Adequate hepatic, renal, and bone marrow functions: neutrophilic granulocyte≥1.5×109/L, Hb(hemoglobin)≥90g/L, PLT(platelets)≥100×109/L, serum Cr(creatinine)≤1.5-time upper normal limit, serum TBIL(total bilirubin)≤1.5-time upper normal limit, both serum ALT and AST(alanine aminotransferase and aspartate aminotransferase)≤2.5-time upper normal limit, hepatic metastases CRC patients' serum ALT/AST≤5-time upper normal limit; At least one measurable lesion after surgical resection (According to the standard of RECIST1.1 version: Response Evaluation Criteria in Solid Tumors 1.1 version); Written informed consent. Exclusion Criteria: Severe (ie, active) heart disease, such as coronary heart disease symptoms, the New York Heart Association (NYHA) II-class or more serious congestive heart failure or severe arrhythmia requiring medication intervention, or history of myocardial infarction within the last 12 months; severe pulmonary dysfunction; peripheral neuropathy; unstable hypertension; Metastases lesions> 50% of liver volume; Autoimmune diseases, organ transplantation requiring immunosuppressive therapy and patients requiring long-term systemic corticosteroid therapy; History of other malignant diseases (except cured basal cell carcinoma and cervical carcinoma in situ) in the last 5 years; Pregnant or lactating women (women at childbearing age in the baseline pregnancy test positive or pregnancy test not examined. Menopausal women have menopause at least 12 months); Acute or chronic infectious diseases in active phase; severe uncontrolled infection, or other serious uncontrolled concomitant diseases; Definite history of allergy or allergic constitutions; Chemotherapy, radiotherapy or immunotherapy within four weeks; Administration of other investigational drugs or procedures within four weeks.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APDC + Chemotherapy<br>Patients in Arm APDC + Chemotherapy will receive APDC combined with chemotherapy. | Biological: APDC + Chemotherapy<br>* Patients in Arm APDC+Chemotherapy receive maximum 12 cycles (14days/cycle) mFOLFOX6 chemotherapy. Each cycle chemotherapy consist of Oxaliplatin at 85mg/ m2 infused for 2 hours only on day 1,and Leucovorin at 400 mg/m2 was administered intravenously for 2 hours, followed by continuous intravenous administration of 5-Fluorouracil at 400 mg/m2 (2.4g/m2 for 46 hours).On day 8 of cycle1-3 and 7-9, patients also receive APDC vaccine infusion in 100ml saline. After 12 cycles, patients in Arm APDC+chemotherapy will receive 5-Fluorouracil /Leucovorin (Leucovorin at 400 mg/m2/day administered intravenously for 2 hours, intravenous bolus of 5-Fluorouracil at 400 mg/m2 , followed by continuous intravenous administration of 5-Fluorouracil at 1200 mg/m2/d for 2 days, repeated every 2 weeks) plus APDC therapy (once every 3 months). Treatments will continue unless disease progression, intolerable toxicity or patients withdrawal).<br>|
| Active Comparator: Chemotherapy<br>Patients in Arm Chemotherapy will receive chemotherapy only. | Drug: Chemotherapy<br>* Patients in Arm Chemotherapy receive maximum 12cycles (14days/cycle) mFOLFOX6 chemotherapy. Each cycle chemotherapy consist of Oxaliplatin at 85mg/ m2 infused for 2 hours only on day 1, and Leucovorin at 400 mg/m2 was administered intravenously for 2 hours, followed by continuous intravenous administration of 5-Fluorouracil at 400 mg/m2 (2.4g/m2 for 46 hours). After 12 cycles, patients in Arm chemotherapy will receive only 5-Fluorouracil /Leucovorin (Leucovorin at 400 mg/m2/day administered intravenously for 2 hours, intravenous bolus of 5-Fluorouracil at 400 mg/m2 , followed by continuous intravenous administration of 5-Fluorouracil at 1200 mg/m2/d for 2 days, repeated every 2 weeks). Treatments will continue unless disease progression, intolerable toxicity or patients withdrawal).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival, PFS | Time from the randomization date to the start of disease progression (progression assessed by investigator using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1 guidelines) for metastatic colorectal cancer subjects. | Up to approximately six years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response | From randomisation to occurrence of objective response( complete regression (CR) and partial regression (PR) need to be confirmed 28 days after the occurrence) | Up to approximately six years | 
| Overall Survival, OS | From randomisation to the time of death of any cause. | Up to approximately six years | 
| Clinical benefit Rate | From randomisation to confirmation of objective response | Up to approximately six years | 
| Quality of Life | From randomisation to the end of all treatments (according to the EORTC QLQ-C30: European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-C30) | Up to approximately six months | 
| Adverse Events | From randomisation to the end of follow-up | Up to approximately six years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Colorectal Cancer, Tumor Therapeutic Vaccine, Dendritic Cell