This study has been transitioned to CTIS with ID 2024-514598-23-00 check the CTIS register for the current data. This is an open-label, non-randomized, multicentre phase II study with an initial safety-run in. During the safety run-in phase, we will…
ID
Source
Brief title
Condition
- Exocrine pancreas conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety run-in phase endpoint. The primary endpoint for this part of the study
is safety. Safety is defined as maximum of 6 out of 20 patients experiencing a
grade 3/4/5 events related to the IMM-101 vaccination or SBRT before, during
and after IMM-101 and SBRT. These will be considered significant events for
this endpoint. Safety will be evaluated at completion of the 6 injections.
Phase II endpoint The primary endpoint is efficacy and will be calculated for
the overall study. Efficacy is defined as 1-year progression free survival
(PFS). Progression-free survival will be calculated from the start of
FOLFIRINOX (PFS 1) to the date of progressive disease of the primary tumour or
locoregional recurrence, progression of previously treated lungs and/or liver
metastasis, the occurrence of new metastases or death. Efficacy is defined as
an increase of 12 to 24% in patients which received at least 8 cycles of
FOLFIRINOX (standard cohort) and of 5 to 15% in 1-year progression-free
survival in patients with less than 8 cycles (expansion cohort), will be the
main endpoint.
Secondary outcome
Secondary endpoints are PFS calculated from the start of the first IMM-101
injection (PFS 2), overall survival (from start FOLFIRINOX and IMM-101 untill
death (OS1 and OS2)), quality of Life, the effects of IMM -101 administered
with SBRT on circulating immune cells and tumour markers CA 19-9, CEA and
radiological response (as determined by RECIST and iRECIST).
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. 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
This study has been transitioned to CTIS with ID 2024-514598-23-00 check the CTIS register for the current data.
This is an open-label, non-randomized, multicentre phase II study with an
initial safety-run in. During the safety run-in phase, we will investigate the
safety of combining IMM-101 administration with SBRT in 20 patients with
limited metastatic disease in the liver and/or lung. If deemed safe, we will
continue inclusion in the second phase of the study with an additional 80
patients in order to evaluate the efficacy of combining IMM-101 treatment with
SBRT based on a 100% improvement of progression free survival.
The primary objective of the safety run-in is to determine safety of IMM-101
combined with SBRT in patients with limited metastatic disease from PDAC. When
this combination is found to be safe, the second phase of the study will be
initiated, the primary objective of the phase II is to investigate the
potential efficacy of IMM-101 combined with SBRT. Secondary objectives are
biochemical immune response, the effect on tumour markers, radiological tumour
response and quality of life.
Study design
An open-label, non-randomized with an initial safety run-in followed by a phase
II multicentre study looking at the efficacy of IMM-101 administered with SBRT.
Intervention
Six intradermal injections of IMM-101 (a vaccine adjuvant containing
Heat-Killed Whole Cell Mycobacterium obuense) beginning 2 weeks prior to
stereotactic body radiation therapy of all metastatic lesions. If present, SBRT
will also be given on the primary tumour or on the local regional recurrence
determined under strict conditions by the radiologist. Between the third and
fourth injection of IMM-101 there will be a four-week break. Administration of
IMM-101 will be performed at week -2, 0,2,4,8,10 and 12. This treatment starts
4 weeks after FOLFIRINOX for both groups.
Thereafter, IMM-101 will be given at a 4-week interval for up to 12 months
(weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56) or until the patient
shows (clinical) progression, dies or withdraws from the study.
Study burden and risks
Patients will initially receive six intradermal injections with IMM-101 during
a 12- week period, followed by a monthly IMM-101 for up to 12 months. In
addition, they will undergo additional blood collections in order to determine
tumour- specific immune and tumour marker responses. These blood collections
can cause bruising or slight short-term discomfort. In previously performed
trials, IMM-101 administration proved to be safe showing a low toxicity
profile. The main adverse reactions were limited to local skin reactions, so we
do not expect any major side-effects of this treatment in our patient
population. However, treatment with IMM-101 and SBRT on liver and/or lung
metastases has not been investigated yet. Therefore, we will first include a
limited number of patients (n=20) in the safety run-in, in order to establish
the safety of IMM-101 administration before and during SBRT. Once the safety
profile is established, we will enrol additional patients (n=80) in the
subsequent second phase II of the trial.
Before FOLFIRINOX, and as part of the standard of care, all patients will
undergo a CPTC-02 biopsy from one metastatic lesion in order to diagnose and
confirm metastatic PDAC. The biopsy sample will also be used for Whole Genome
Sequencing.
For SBRT, tumour tracking is enabled by the Synchrony® Respiratory Tracking
System and requires the placement of radio- opaque markers in or near the
tumour (fiducials). Fiducials are 3 mm gold objects frontloaded in a 19 Gauge
FNA needle and pushed with the stylet through the entire length of the needle.
Fiducials are consecutively placed in or close to every lesion in the liver
(determined by the principal investigator) under endoscopic ultrasound or CT
guidance. Complications of this procedure is 2% in consecutive series. In the
lungs endovascular placement will be used to place fiducial markers.The success
rate of endovascular coil rate is 99,8% with 10% of patients developing gr 1
complications: mild haemoptysis or small asymptomatic pulmonary infarction or
haemorrhage. Since metastatic pancreatic cancer is a deadly disease with an
extremely poor survival rate, we find that the above-mentioned risks and burden
outweigh the potential benefit for patients participating in this trial.
's-Gravendijkwal 230
Rotterdam 3015 CE
NL
's-Gravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
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 (eGFR >= 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 FOLFIRINOX 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
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-514598-23-00 |
| EudraCT | EUCTR2020-003945-13-NL |
| CCMO | NL74985.078.20 |