Th-1 Dendritic Cell Immunotherapy Plus Standard Chemotherapy for Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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This is a phase 1, first in man, dose escalation study for safety and feasibility for administration of 3 doses of DC vaccine for pancreatic adenocarcinoma.

Detailed Description
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The primary objective of this phase 1, first in man trial is to determine the safety, toxicity, and feasibility of delivering autologous dendritic cells (DCs) loaded with pancreatic adenocarcinoma lysate plus mRNA to pancreatic cancer patients as adjuvant therapy following completion of standard chemotherapy. Patients will first complete standard treatment for pancreatic adenocarcinoma which is surgically resectable or potentially resectable and then within 3 months of finishing standard treatment, they will have three doses of the dendritic cell vaccine by perinodal injection using ultrasound (US) or computed-tomography (CT) guidance.

Official Title
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Phase I Study of Th-1 Dendritic Cell Immunotherapy in Combination With Standard Chemotherapy for the Adjuvant Treatment of Pancreatic Adenocarcinoma (DECIST)

Conditions
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Pancreatic Adenocarcinoma, Pancreatic Cancer

Intervention / Treatment
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* Biological: Autologous DC vaccine


Participation Criteria
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Eligibility Criteria
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Step 1 Inclusion Criteria: Provision of signed and dated informed consent form for Step 1 Male or female, aged 18 years and older Diagnosed with adenocarcinoma of the pancreas deemed to be potentially resectable and who are deemed to be good candidates for adjuvant and/or neoadjuvant chemotherapy. This may include patients whose tumors are deemed suitable for upfront resection as well as patients whose tumors are deemed borderline resectable and thus undergo neoadjuvant therapy prior to resection. Note: women of child-bearing potential must be on birth control for 30 days prior to first vaccination; it is recommended to discuss this requirement with subjects at Step 1. Step 1 Exclusion Criteria: Unresectable or metastatic (stage IV) pancreatic cancer. Patients with known HIV and a positive viral load. Patients with active HBV and HCV infection. Those who are Hepatitis B sAb positive as well as those who are Hepatitis C Ab positive but Hepatitis C RNA viral load negative will not be excluded. Patients with any active autoimmune disease or immune deficiency or previous Guillain-Barre syndrome. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g. patient with psoriatic arthritis are excluded) are eligible provided all of the following conditions are met: rash must cover < 10% of body surface area; disease is well controlled at baseline and requires only low-potency topical corticosteroids; no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. Step 2 Inclusion Criteria: Provision of signed and dated informed consent form for Step 2 Must have completed standard neo-adjuvant and/or adjuvant chemotherapy and surgery, as deemed by Investigator. Must have completed standard care within 3 months of step 2 registration. Must have adequate tissue obtained from surgery, as determined and confirmed by Dr. Decker. Adequate kidney, liver, bone marrow function, and immune function, as follows, within 28 days prior to step 2 registration: Hemoglobin greater than/equal to 8 gm/dL; Absolute neutrophil count (ANC) greater than/equal to 1,500 cells/mm3; Platelet count greater than/equal to 75,000/mm3; Total bilirubin less than/equal to 1.5 times upper limit of normal (ULN); Aspartate transaminase AST (SGOT) and alanine aminotransferase ALT (SGPT) less than/equal to 2.5 times the ULN; TSH range between 0.4-4.0 mIU/L; RF less than/equal to 15 IU/ml. Negative Hepatitis B and C serology. Positive HBs Ab indicating immunity is not exclusionary. Those who are Hepatitis B sAb positive as well as those who are Hepatitis C Ab positive but Hepatitis C RNA viral load negative will not be excluded. ECOG performance status less than/equal to 2 For women of child bearing potential (WOCBP): At the time or (or prior to) registration to Step 2, use of highly effective contraception must be discussed with participant. NOTE: Patient must agree to start contraception at least 30 days before first vaccination and continue for at least 12 weeks after his/her last vaccination. WOCBP must have a negative serum pregnancy within 28 days of registration to step 2. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during study participation and for an additional 12 weeks following discontinuations of last vaccination. Patient must agree to not donate blood for up to 90 days after last vaccination. Step 2 Exclusion Criteria: Use of nonstandard adjuvant chemotherapy regimen, as determined by the Investigator. Female patients who are pregnant, breast feeding, or of childbearing potential without a negative pregnancy test within 28 days of registration to Step 2 (or decline contraception requirements as outlined above). Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Patients unwilling or unable to comply with the protocol or provide informed consent. Any severe or uncontrolled medical condition or other condition that could affect participation in this study (in the opinion of the investigator), including but not limited to: hyper/hypothyroidism, active systemic autoimmune disorders, untreated viral hepatitis or autoimmune hepatitis. Treatment with a systemic steroid or with any systemic immunosuppressive agent within 7 days of step 2 registration.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-arm, open-label study where all subjects will receive the DC vaccine. The amount of cells in the vaccine will vary based on the cohort determination and dose escalation schema. Six arms are specified to allow differentiation of the cohorts and their respective dose levels.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous DC Vaccine Cohort 1<br>Vaccine made from autologous dendritic cells loaded with tumor cell lysate and RNA. Subject will get 3 doses of DC vaccine (one every 14 days) and be monitored (vital signs every 30 minutes) for 2 hours after each dose. During treatment, subjects get weekly peg-interferon a-2a at 180 mcg/week on the first day of vaccination up through 14 days after last vaccination. DC Vaccine dose evaluated in Cohort 1: st vaccine - 0.5 million cells nd vaccine - 1 million cells rd vaccine - 2 million cells At each dose level, the 1st subject should get all 3 vaccinations before the 2nd and 3rd subjects at that level receive their 1st vaccination. The 3rd subject can begin vaccination regardless of the time since the 2nd subject began vaccinations. All 3 subjects in cohort should get all 3 vaccinations before any subjects are treated in the next higher cohort. Because of this, the study may not progress to every dose level before MTD is found. | Biological: Autologous DC vaccine<br>* Autologous DC vaccine given as 3 doses every 14 days. Dosage is cohort-dependent.<br>|
| Experimental: Autologous DC Vaccine Cohort 2<br>Vaccine made from autologous dendritic cells loaded with tumor cell lysate and RNA. Subject will get 3 doses of DC vaccine (one every 14 days) and be monitored (vital signs every 30 minutes) for 2 hours after each dose. During treatment, subjects get weekly peg-interferon a-2a at 180 mcg/week on the first day of vaccination up through 14 days after last vaccination. DC Vaccine dose evaluated in Cohort 2: st vaccine - 1 million cells nd vaccine - 2 million cells rd vaccine - 4 million cells At each dose level, the 1st subject should get all 3 vaccinations before the 2nd and 3rd subjects at that level receive their 1st vaccination. The 3rd subject can begin vaccination regardless of the time since the 2nd subject began vaccinations. All 3 subjects in cohort should get all 3 vaccinations before any subjects are treated in the next higher cohort. Because of this, the study may not progress to every dose level before MTD is found. | Biological: Autologous DC vaccine<br>* Autologous DC vaccine given as 3 doses every 14 days. Dosage is cohort-dependent.<br>|
| Experimental: Autologous DC Vaccine Cohort 3<br>Vaccine made from autologous dendritic cells loaded with tumor cell lysate and RNA. Subject will get 3 doses of DC vaccine (one every 14 days) and be monitored (vital signs every 30 minutes) for 2 hours after each dose. During treatment, subjects get weekly peg-interferon a-2a at 180 mcg/week on the first day of vaccination up through 14 days after last vaccination. DC Vaccine dose evaluated in Cohort 3: st vaccine - 2 million cells nd vaccine - 4 million cells rd vaccine - 8 million cells At each dose level, the 1st subject should get all 3 vaccinations before the 2nd and 3rd subjects at that level receive their 1st vaccination. The 3rd subject can begin vaccination regardless of the time since the 2nd subject began vaccinations. All 3 subjects in cohort should get all 3 vaccinations before any subjects are treated in the next higher cohort. Because of this, the study may not progress to every dose level before MTD is found. | Biological: Autologous DC vaccine<br>* Autologous DC vaccine given as 3 doses every 14 days. Dosage is cohort-dependent.<br>|
| Experimental: Autologous DC Vaccine Cohort 4<br>Vaccine made from autologous dendritic cells loaded with tumor cell lysate and RNA. Subject will get 3 doses of DC vaccine (one every 14 days) and be monitored (vital signs every 30 minutes) for 2 hours after each dose. During treatment, subjects get weekly peg-interferon a-2a at 180 mcg/week on the first day of vaccination up through 14 days after last vaccination. DC Vaccine dose evaluated in Cohort 4: st vaccine - 6 million cells nd vaccine - 6 million cells rd vaccine - 6 million cells At each dose level, the 1st subject should get all 3 vaccinations before the 2nd and 3rd subjects at that level receive their 1st vaccination. The 3rd subject can begin vaccination regardless of the time since the 2nd subject began vaccinations. All 3 subjects in cohort should get all 3 vaccinations before any subjects are treated in the next higher cohort. Because of this, the study may not progress to every dose level before MTD is found. | Biological: Autologous DC vaccine<br>* Autologous DC vaccine given as 3 doses every 14 days. Dosage is cohort-dependent.<br>|
| Experimental: Autologous DC Vaccine Cohort 5<br>Vaccine made from autologous dendritic cells loaded with tumor cell lysate and RNA. Subject will get 3 doses of DC vaccine (one every 14 days) and be monitored (vital signs every 30 minutes) for 2 hours after each dose. During treatment, subjects get weekly peg-interferon a-2a at 180 mcg/week on the first day of vaccination up through 14 days after last vaccination. DC Vaccine dose evaluated in Cohort 5: st vaccine - 7 million cells nd vaccine - 7 million cells rd vaccine - 7 million cells At each dose level, the 1st subject should get all 3 vaccinations before the 2nd and 3rd subjects at that level receive their 1st vaccination. The 3rd subject can begin vaccination regardless of the time since the 2nd subject began vaccinations. All 3 subjects in cohort should get all 3 vaccinations before any subjects are treated in the next higher cohort. Because of this, the study may not progress to every dose level before MTD is found. | Biological: Autologous DC vaccine<br>* Autologous DC vaccine given as 3 doses every 14 days. Dosage is cohort-dependent.<br>|
| Experimental: Autologous DC Vaccine Cohort 6<br>Vaccine made from autologous dendritic cells loaded with tumor cell lysate and RNA. Subject will get 3 doses of DC vaccine (one every 14 days) and be monitored (vital signs every 30 minutes) for 2 hours after each dose. During treatment, subjects get weekly peg-interferon a-2a at 180 mcg/week on the first day of vaccination up through 14 days after last vaccination. DC Vaccine dose evaluated in Cohort 6: st vaccine - 8 million cells nd vaccine - 8 million cells rd vaccine - 8 million cells At each dose level, the 1st subject should get all 3 vaccinations before the 2nd and 3rd subjects at that level receive their 1st vaccination. The 3rd subject can begin vaccination regardless of the time since the 2nd subject began vaccinations. All 3 subjects in cohort should get all 3 vaccinations before any subjects are treated in the next higher cohort. Because of this, the study may not progress to every dose level before MTD is found. | Biological: Autologous DC vaccine<br>* Autologous DC vaccine given as 3 doses every 14 days. Dosage is cohort-dependent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of DC Vaccine | Maximum tolerated dose of dendritic cell vaccine following completion of surgery and standard adjuvant chemotherapy, as determined by BOIN design. DLTs were defined as shown in the subsequent Primary Outcome Measure. | From treatment start until 6 weeks after. | 
| Number of participants who experienced Dose Limiting Toxicities (DLTs) | A DLT is defined as any non-hematologic toxicity of grade 3 or 4 by the Common Terminology Criteria for Adverse Events Version 5.x (CTCAE 5.x) that was probably or definitely DC-vaccine related. Certain grade 4 hematologic toxicities that are probably or definitely DC-vaccine related are also considered DLTs. | From treatment start until 6 weeks after. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recurrence | Measurement of time from resection surgery to recurrence of pancreatic adenocarcinoma. | From surgery until recurrence or up to 3 years after surgery, whichever comes first. | 
| Overall Survival | Measurement of time from resection surgery to death. | From surgery until death or up to 3 years after surgery, whichever comes first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Adjuvant therapy