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JOURNAL ONKOLOGIE – STUDIE

Personalized Vaccine With SOC Chemo Followed by Nivo in Pancreatic Cancer

Rekrutierend

NCT-Nummer:
NCT04627246

Studienbeginn:
September 2020

Letztes Update:
13.11.2020

Wirkstoff:
Autologous Dendritic Cell Vaccine Loaded with Personalized Peptides (PEP-DC vaccine)

Indikation (Clinical Trials):
Adenocarcinoma

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Centre Hospitalier Universitaire Vaudois

Collaborator:
-

Kontakt

Studienlocations (1 von 1)

Studien-Informationen

Detailed Description:

This is a single center, single arm, phase Ib trial to evaluate the feasibility, safety,

immunogenicity, and efficacy of subcutaneous dendritic cell (DC) vaccine loaded with

personalized peptides [PEP-DC vaccine] in combination with standard of care adjuvant

chemotherapy (gemcitabine and capecitabine), followed by the antibody nivolumab in patients

with non-metastatic surgically resected pancreatic adenocarcinoma.

All patients will have previously undergone collection of resected advanced pancreatic tumor

tissue under a different research protocol with a separate informed consent. After

registration, all patients will receive standard of care chemotherapy consisting of

intravenous gemcitabine, and oral capecitabine for eight 21-day cycles. Additionally, all

eligible patients will undergo apheresis during the last week of cycle 3 of standard of care

chemotherapy to collect peripheral blood mononuclear cells (PBMCs) for dendritic cell vaccine

production. All patients will receive at least six PEP-DC vaccinations starting concomitant

with the 5th cycle of chemotherapy. Vaccine will be administered subcutaneously every 3

weeks, on day 9 (the day after last gemcitabine infusion) of each 21-day cycle, and

thereafter every four weeks starting from the second nivolumab administration. Nivolumab

intravenous administration will start three weeks after the last cycle of chemotherapy and

will be given as a flat dose every 2 weeks during the vaccination period until the last

vaccine dose or at least 8 weeks after the end of the last chemotherapy cycle if vaccination

stops earlier.

Regular physical examination, radiological evaluation and blood testing for safety parameters

will be performed according to the schedule during treatment.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Signed Informed Consent Form

- Histologically confirmed resected adenocarcinoma of the pancreas (T1-T4, N 0-1,

minimum 2cm - American Joint Committee on Cancer (AJCC) 8th edition).

- Mixed adenocarcinoma tumors are eligible provided the predominant invasive

component of the tumor is adenocarcinoma

- Both patients who received or did not receive neo-adjuvant chemotherapy are

eligible.

- No distant metastasis

- Appropriate amount of tumoral tissue was collected from the cytoreductive surgery and

allowed the identification of top 10 personalized peptides (PEP) for preparation of

PEP-DC vaccine

- Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 2

- Absence of any psychological, familial, sociological or geographical condition

potentially hampering compliance with the study protocol

- Adequate hematologic and end-organ function, defined by the following laboratory

results obtained within 21 days prior registration

- Adequate serology defined by the following laboratory results:

- Negative test for human immunodeficiency viruses (HIV)

- Patients with active or chronic hepatitis B (defined as having a positive

hepatitis B surface antigen [HBsAg] test at pre-screening) are not eligible.

- Patients with past/resolved hepatitis B virus (HBV) infection (defined as having

a negative hepatitis B surface antigen (HBsAg) test and a positive antibody to

hepatitis B core antigen (anti-HBc) antibody test) are eligible, if hepatitis B

virus deoxyribonucleic acid (HBV DNA) test is negative.

- Hepatitis B virus deoxyribonucleic acid (HBV DNA) must be obtained in patients

with positive hepatitis B core antibody prior start of study treatment.

- Patients with active hepatitis C are not eligible. Patients positive for

hepatitis C virus (HCV) antibody are eligible only if Polymerase Chain Reaction

(PCR) is negative for hepatitis C virus ribonucleic acid (HCV RNA)

- No measurable tumor lesion according to radiologic criteria (New Response Evaluation

Criteria in Solid Tumours 1.1 (RECIST 1.1))

- Recovery from any toxic effects of prior neo-adjuvant therapy to less than Grade 1 per

the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03

except for toxicities described below, as long as they do not put at risk the

patient's condition and do not require systemic immunosuppressive steroids at any

dose, including but not limited to:

- Fatigue

- Alopecia

- Skin disorders

- Stable neuropathy

- Endocrinopathies requiring replacement treatment

Note: For other medical conditions, or for any other toxicity with a higher grade but

controlled by adequate treatment, prior discussion and agreement with the principal

investigator is mandatory.

Note: Patients may have undergone surgical procedures within the past 3 weeks, as long as

all toxicities have recovered to grade 1 or less.

- For women of childbearing potential (sexually mature women who have not undergone a

hysterectomy, have not been naturally post-menopausal for at least 12 consecutive

months or have a serum follicle-stimulating hormone (FSH) less than 40 milli

international unit per milliliter (mIU/ml):

1. Agreement to follow instructions for methods of contraception for the couple from

screening until 6 months after last vaccine dose, or last chemotherapy treatment,

or last nivolumab treatment

2. Women of childbearing potentia must have a negative urine pregnancy test within 7

days, before registration. A positive urine test must be confirmed by a serum

pregnancy test.

- For men and their female partners: agreement to follow instructions for methods of

contraception for the couple from screening until 7 months after last vaccine dose, or

last chemotherapy treatment, or last nivolumab treatment.

- Patient is able to undergo leukapheresis

Exclusion Criteria:

- Pregnant or breast-feeding women

- Other malignancy within 2 years prior study enrollment, except for those treated with

surgical intervention as curative intent. Patients with a predicted 5-year

recurrence-free survival rate equal or more than 95% can be included at the

investigator's discretion.

- Current, recent (within 4 weeks prior registration), or planned participation in an

experimental drug study.

- Past history with cardiac problem:

- New York Heart Association Class II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior

registration. History of stroke or transient ischemic attack within 6 months

prior registration.

- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or

recent peripheral arterial thrombosis) within 6 months prior registration.

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of

therapeutic anticoagulation).

- Known hypersensitivity to any component of the study treatment

- History of autoimmune disease, including but not limited to myasthenia gravis,

myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,

inflammatory bowel disease, vascular thrombosis associated with antiphospholipid

syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,

multiple sclerosis, vasculitis, or glomerulonephritis.

The following exceptions are considered:

- Patients with a history of autoimmune-related hypothyroidism on a stable dose of

thyroid replacement hormone are eligible for this study.

- Patients with controlled Type I diabetes mellitus on a stable insulin regimen are

eligible

- Psoriasis not requiring systemic treatment.

- Vitiligo.

- Other conditions not expected to recur in the absence of an external trigger, are

permitted to enroll after agreement with the principal investigator.

- Severe infections within 8 weeks prior registration including but not limited to

hospitalization for complications of infection, bacteremia, or severe pneumonia or

signs or symptoms of infection requiring oral or intravenous antibiotics within 8

weeks prior registration.

- Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic

obstructive pulmonary disease exacerbation or for dental extraction) are eligible.

- Administration of a live, attenuated vaccine within 8 weeks before registration

- Influenza vaccination should be given during influenza season only (approximately

October to March). Patients must not receive live, attenuated influenza vaccine within

4 weeks prior registration or at any time during the study.

- Dihydropyrimidine dehydrogenase deficiency

- Any other diseases, metabolic dysfunction, physical examination finding, or

clinical laboratory finding giving reasonable suspicion of a disease or condition

that contraindicates the use of an investigational drug or that may affect the

interpretation of the results or render the patient at high risk from treatment

complications.

- Any serious or uncontrolled medical disorder or active infection that, in the

opinion of the investigator, may impair the ability of the subject to receive

protocol therapy and comply with study visits and procedures.

- Patients who have received prior treatment with anti-programmed cell death 1

(PD1), anti-programmed death ligand 1 (PD-L1) or anti-cytotoxic

T-lymphocyte-associated protein 4 (CTLA-4) may be enrolled, provided at least 5

half-lives have elapsed from the last dose to the first dose of nivolumab and

there was no history of severe immune-mediated adverse effects from such therapy

(National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events

(CTCAE) Grade 3 and 4).

- Treatment with systemic immunostimulatory agents (including but not limited to

interferon-alpha, interleukin-2) for any reason within 4 weeks or five half-lives

of the drug, whichever is shorter, prior to registration.

- Treatment with systemic immunosuppressive medications (including but not limited

to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate,

thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior

registration.

- Patients who are receiving acute, low-dose, systemic immunosuppressant medications

(e.g., an one-time dose of dexamethasone for nausea) or physiologic replacement doses

(i.e., prednisone 5-7.5 mg/day, or other) for adrenal insufficiency may be enrolled in

the study.

- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is

allowed.

- Treatment with Granulocyte colony-stimulating factor within 4 weeks prior

registration.

Studien-Rationale

Primary outcome:

1. Number of cases for which vaccine is produced (Time Frame - 3 years after study activation):
Feasibility will be assessed measuring the number of cases, in which vaccine is produced successfully (defined as production and quality control release of at least 6 PEP-DC vaccines for a patient) among the enrolled patients and number of patients who receive at least one dose of vaccine

2. Assessment of adverse events (Time Frame - 3 years after study activation):
Collection of adverse events and serious adverse events, treatment limiting toxicities and assessment of immunogenicity

Secondary outcome:

1. Relapse free survival (Time Frame - 8 years):
Time from enrolment (registration) date until one of the following events: a. patients disease-free at inclusion, until first date of documented progression, b. patients with non-measurable lesions at inclusion, until first date of documented progression, c. death

2. Overall survival (Time Frame - 8 years):
Time from enrolment (registration) date to date of death due to any cause, or last patient contact. For living patients, the date of most recent clinic visit or a phone or email contact will be employed to document the overall survival time.

3. Gene analysis of immunological response (Time Frame - 8 years):
The assessment of the interactions between tumor cells and the immune system within the tumor microenvironment will be performed by gene expression quantification using with multiplex gene expression profiling.

4. Cell analysis of immunological response (Time Frame - 8 years):
The assessment of the interactions between tumor cells and the immune system within the tumor microenvironment will be performed by cell quantification using with multi-parametric single-cell cytometry and single cell RNA sequencing analysis

5. Evaluation of tumor marker carbohydrate antigene 19-9 (CA19-9) or carcinoembryonic antigen (CEA) kinetics (Time Frame - 8 years):
Measurement of tumoral markers by blood analysis

6. Correlation between immune-related adverse events and relapse-free survival (Time Frame - 8 years):
Number of immune-related adverse events using the CTCAE v.4.03 correlated with relapse-free survival (time in months)

Geprüfte Regime

  • Autologous Dendritic Cell Vaccine Loaded with Personalized Peptides (PEP-DC vaccine):
    SOC: gemcitabine intravenously, on days 1 and 8 of each 21-day cycle, and capecitabine orally for 14 days of a 21-day cycle. Total: 8 cycles. PEP-DC vaccine: At least 6 vaccinations starting with the 5th cycle of chemotherapy. Vaccine will be administered subcutaneously every 3 weeks, on day 9 (the day after last gemcitabine infusion) of each 21-day cycle (cycle 5, 6, 7 and 8), and thereafter every 4 weeks starting from the second nivolumab administration. Nivolumab: it will be administered intravenously, starting 3 weeks after the last chemotherapy cycle and will be given as a flat dose of 240mg every 2 weeks during the vaccination period until the last vaccine dose or at least for 8 weeks after the end of last chemotherapy cycle if vaccination stops earlier. Afterwards, it will be given as a maintenance therapy without vaccine at 480 mg (flat dose) every 4 weeks until appearance of new lesions or unacceptable toxicity for a maximum of 2 years.

Quelle: ClinicalTrials.gov


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