No registrations found.
ID
Source
Brief title
Health condition
limited metastatic pancreatic cancer
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main goal of the safety run-in is to determine the safety/toxicity profile of IMM-101 vaccination in combination with SBRT in patients with limited meta- or synchronous metastatic disease liver and/or lung metastatic disease from pancreatic cancer.
Secondary outcome
• Overall survival calculated from the start of FOLFIRINOX (OS1).
• Overall survival calculated from start of IMM-101 (OS2).
• Progression-free survival calculated from the start of IMM-101 (PFS 2) at 12-month to the date of progressive disease of the primary tumour, locoregional recurrence, progression of previously treated lungs and/or liver metastases, the occurrence of new metastases, or death. All included patients will be analysed for this endpoint.
• Quality of Life.
• Radiological response rate after IMM-101 and SBRT using RECIST criteria (version 1.1).
• Immunological effects: effect of IMM-101 and SBRT on circulating immune cells.
• Effect on tumour markers, CA19.9 and CEA.
Background summary
Approximately 40% to 50% of patients diagnosed with pancreatic cancer present with metastatic disease. In addition, 80% of patients with resected pancreatic ductal adenocarcinoma (PDAC) develop recurrent disease due to its aggressive nature and its tendency to develop early metastases. Around 25% of patients with recurrence develop liver only metastases. Lung-only recurrence is seen in 14,7% of the patients. All these patients including those who develop metastases after resection are currently treated with palliative chemotherapeutic drugs, regardless of their pattern of metastases. Median overall survival in these metastatic patients treated with FOLFIRINOX, the most effective chemotherapeutic regimen is shorter than 11 months with a 1-year progression free survival of 12%.
Patients with limited hepatic and/or pulmonary metastases could potentially benefit from additional multimodality treatment after standard palliative treatment. This treatment could be effective for patients with few metastases to limited organ sites, also known as oligometastatic disease [4]. Recently, a new definition of oligometastatic disease in PDAC was proposed, which includes anatomical and biological criteria. We define limited metastatic disease as ≤5 metastases in the liver and/or lungs with a total tumour size per organ of < 9 cm. The concept of limited metastatic disease creates extra treatment approaches for each patient’s individual metastatic state. The addition of Stereotactic Body Radiation (SBRT) with immunotherapy (IMM-101) after FOLFIRINOX will harness the immune system in a synergistic approach. SBRT can act as an in- situ vaccine, increasing the expression of cell surface receptors and tumour antigen presentation and can even produce anti-tumour cytotoxic T cell response. In addition, IMM-101 (suspension of heat-killed whole cell Mycobacterium obuense) activates and maturates antigen presenting cells. Especially dendritic cells can aid in the antigen processing and T-cell cross priming, processes that are deficient in the setting of metastatic pancreatic cancer. IMM-101 immunotherapy thereby has the potential to optimize the immunogenic anti-tumour effect of radiation therapy. The combination of boosting the immune responses with immunotherapy in the presence of an increased exposure to tumour antigen will provide sufficient induction of the immune system to counter further metastatic burden. We hypothesize that treatment of IMM-101 combined with SBRT in patients with limited metastatic hepatic or pulmonary disease of PDAC induces a durable local and systemic anti-tumour immune response to obtain disease control. This IMM-101 and SBRT protocol will start 4 weeks after standard chemotherapy treatment (FOLFIRINOX).
Study objective
The addition of Stereotactic Body Radiation (SBRT) with immunotherapy (IMM-101) after FOLFIRINOX will harness the immune system in a synergistic approach. SBRT can act as an in- situ vaccine, increasing the expression of cell surface receptors and tumour antigen presentation and can even produce anti-tumour cytotoxic T cell response. In addition, IMM-101 (suspension of heat-killed whole cell Mycobacterium obuense) activates and maturates antigen presenting cells. Especially dendritic cells can aid in the antigen processing and T-cell cross priming, processes that are deficient in the setting of metastatic pancreatic cancer. IMM-101 immunotherapy thereby has the potential to optimize the immunogenic anti-tumour effect of radiation therapy. The combination of boosting the immune responses with immunotherapy in the presence of an increased exposure to tumour antigen will provide sufficient induction of the immune system to counter further metastatic burden. We hypothesize that treatment of IMM-101 combined with SBRT in patients with limited metastatic hepatic or pulmonary disease of PDAC induces a durable local and systemic anti-tumour immune response to obtain disease control. This IMM-101 and SBRT protocol will start 4 weeks after standard chemotherapy treatment (FOLFIRINOX).
Study design
Week 0, 2,4,8,10,12,16,20,24,28, 32,36,40,44,48 and 52
Intervention
IMM-101 immunotherapy and stereotactic radiotherapy (SBRT)
Inclusion criteria
• Histologically confirmed metastatic pancreatic cancer, as indicated by a definite cytology/histology report.
• ≤5 hepatic and/or pulmonary metastases in total.
• The combined diameter of all liver metastases AND the primary tumour or local recurrence in the pancreas is <9 cm.
• The combined diameter of all pulmonary metastases is <9 cm.
• CA 19-9 < 1000 IU/mL after completion of chemotherapy.
• Age > 18 years and < 75 years.
• WHO performance status of 0-2
• Tumour volume of the primary tumour <7cmx7cmx7cm. Each diameter must not exceed 7 cm.
• Adequate renal function (Creatinine ≥ 30 ml/min).
• Adequate liver tests (bilirubin < 1.5 times normal; ALAT/ASAT < 5 times normal).
• Adequate bone marrow function (WBC > 3.0 x 109/L, platelets > 100 x 109/L and hemoglobin > 5.6 mmol/l).
• Effective contraceptive methods.
• Written informed consent.
• Patients who did not complete at least 8 cycles of chemotherapy due to severe toxicity, will be included in the expansion cohort.
Exclusion criteria
• Metastasis in other organs than the lung and liver.
• Histopathologically proven extra regional lymph node metastasis.
• Malignant ascites.
• Liver function insufficient to tolerate the prescribed dose of radiotherapy.*
• Child-Pugh Classification grade B/C.
• Lung function insufficient to tolerate the prescribed dose of radiotherapy.*
• Diffuse liver metastasis pattern on CT scan.
• Current or previous treatment with immunotherapeutic drugs.
• Second primary malignancy except in situ carcinoma of the cervix, adequately treated non-melanoma skin cancer, or other malignancy treated at least 5 years previously to diagnosis of pancreatic cancer and without evidence of recurrence.
• Pregnancy, breast feeding.
• An active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or other immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the planned first dose of the study. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
• History of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
• Active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Positive PCR test for presence of SARS-CoV-2 during screening stage.
• Live virus vaccine within 30 days of planned start of trial treatment.
• Use of herbal remedies, including traditional Chinese herbal products (e.g., mistletoe).
• Allergic reaction to M. obuense or had previously received IMM-101.
• Otherwise deemed unsuitable by the Investigator.
*To be determined by the treating radiologist.
Design
Recruitment
IPD sharing statement
Followed up by the following (possibly more current) registration
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL8819 |
| CCMO | NL74985.078.20 |
| OMON | NL-OMON54853 |