FOLFIRINOX Versus OncoSil™ in Addition to FOLFIRINOX in Patients With Locally Advanced Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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The purpose of the study is to assess the safety and efficacy of OncoSil™ when given in addition to standard FOLFIRINOX chemotherapy for treatment of Locally Advanced Pancreatic Cancer

Detailed Description
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Patients with Locally Advanced Pancreatic Cancer who have not received prior treatment to their pancreatic cancer will be informed about the study and the potential risks and benefits. After providing informed consent patients will undergo a 3 week screening period to confirm eligibility for the study. Patients who meet all eligibility criteria will be randomised 1:1 to either the control arm of up to 12 cycles of standard of care FOLFIRINOX chemotherapy or implantation of OncoSil™ in addition to the same FOLFIRINOX chemotherapy regimen. Patients will be followed for side side effects and palliative benefits during 4-8 weekly study visits and the objective efficacy of the treatment will be assessed by CT scans every 8 weeks. Quality of Life will be measured on various time-points using questionnaires.

Official Title
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An Open-label, Multi-centre, Randomized Study of TaRgeted Intratumoural Placement of P-32 (OncoSil™) in Addition to FOLFIRINOX Chemotherapy vs FOLFIRINOX Alone in Patients With Unresectable Locally Advanced Pancreatic Adenocarcinoma.

Conditions
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Locally Advanced Pancreatic Cancer

Intervention / Treatment
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* Drug: FOLFIRINOX chemotherapy
* Device: OncoSil™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven adenocarcinoma of the pancreas. Unresectable locally advanced pancreatic adenocarcinoma according to NCCN 2021 guidelines.Staging and unresectability must be confirmed by central review of the baseline CT scan. Pancreatic target tumour diameter of < 7.0 cm (longest axis), as qualified by the central reading centre. Karnofsky Performance Status ≥ 70 ≥ 18 years of age at screening. Considered fit to commence first-line standard FOLFIRINOX chemotherapy: i) Adequate renal function: serum creatinine less than 1.5 x upper limit of normal (ULN). ii) Adequate liver function: serum liver transaminases ≤ 3 x ULN and serum bilirubin ≤ 1.5 x ULN*. *For study participants with recent biliary obstruction treated by drainage (e.g. stent), serum bilirubin of > 1.5 x ULN will be accepted for study entry provided that serial levels demonstrate clear improvement. In addition, chemotherapy should not be commenced until serum bilirubin is ≤ 1.5 x ULN. iii) Adequate bone marrow function: white blood cells (WBCs) ≥ 3,000/mm3, absolute neutrophil count (ANC) ≥ 1,500/mm3, haemoglobin ≥ 9 g/dL, and platelets ≥ 100,000/mm3 iv) UGT1A1 polymorphism and DPD deficiency test performed and dose reductions applied as per local institutional practice. Provide signed Informed Consent. Willing and able to complete study procedures within the study timelines. Life expectancy of at least 3 months at the time of screening as judged by the investigator. Treated with or eligible to commence prophylactic treatment with a proton-pump inhibitor prior to implantation, and to continue to receive treatment for at least 6 months post implantation. Not pregnant, and if of childbearing potential, agrees to use adequate birth control (hormonal or barrier method of birth control or abstinence) prior to study entry and during the study and agrees not to donate sperm or ova, for the duration of the study and 12 months post implantation of the investigational device. Exclusion Criteria: Evidence of distant metastases, based on review of baseline CT scan. More than one pancreatic tumour lesion. Any prior radiotherapy or chemotherapy for pancreatic cancer. Pregnant or lactating. In the opinion of the investigator, EUS-directed implantation posing undue study subject risk. This includes: i) where previous EUS-FNA was considered technically too difficult to perform; ii) imaging demonstrates multiple collateral vessels surrounding or adjacent to the target tumour within the pancreas; iii) presence (or significant risk) of varices near to the target tumour. Note: The feasibility of implantation of the target tumour and assessment of risk can be repeated at any time between Screening Visit 1 and the implantation date. If any of the above risk features becomes apparent following subject screening and/or enrolment prior to and including at the time of OncoSil™ treatment, the patient should remain in the study but the implantation should be deferred or cancelled. History of malignancy, treated or untreated, within the past five years whether or not there is evidence of local recurrence or metastases, with the exception of basal cell carcinoma of the skin and cervical carcinoma in situ. Evidence of radiographic invasion into stomach or duodenum (if not certain, confirmation must be obtained prior to enrolment). A known history of hypersensitivity to silicon or phosphorous, or any of the OncoSil™ components. Any other health condition that would preclude participation in the study in the judgment of the investigator.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FOLFIRINOX Chemotherapy<br>Subjects in Arm A will receive up to 12 cycles of Standard Of Care FOLFIRINOX chemotherapy | Drug: FOLFIRINOX chemotherapy<br>* Standard Of Care Chemotherapy regimen for treatment of Locally Advanced Pancreatic cancer<br>* Other names: Folinic Acid, 5-FU, Oxaliplatin, Irinotecan;|
| Experimental: OncoSil™ in addition to FOLFIRINOX Chemotherapy<br>Subjects in Arm B will be implanted with the OncoSil™ device in addition to up to 12 cycles of Standard Of Care FOLFIRINOX chemotherapy | Drug: FOLFIRINOX chemotherapy<br>* Standard Of Care Chemotherapy regimen for treatment of Locally Advanced Pancreatic cancer<br>* Other names: Folinic Acid, 5-FU, Oxaliplatin, Irinotecan;Device: OncoSil™<br>* Implantation of OncoSil 32P microparticles into the Pancreatic Tumour under EUS guidance<br>* Other names: Phosphorous-32 microparticles;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | The primary analysis for safety of OncoSil™ is defined by the Adverse Event profile | Through study completion, an average of 18 months | 
| Local Disease Control Rate (LDCR) at 16 Weeks | The LDCR at Week 16 will be summarised as a count and proportion of subjects with Local Disease Control at 16 Weeks | 16 weeks after initiation of FOLFOX chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Progression Free Survival (LPFS), within the pancreas | Local Progression Free Survival (LPFS) is defined as the time from enrolment to the date of the radiological scan used to determine local tumour progression or date of death from any cause, whichever comes first. | From date of enrolment until the date of first documented local progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| Progression Free Survival | Progression free survival (PFS) is defined as the time from enrolment to the date of tumour progression or of recurrence (in case of complete response (CR) or resection of the primary pancreatic tumour), or death from any cause, whichever comes first. | From date of enrolment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| Time to symptomatic progression | Time to symptomatic progression is defined as the time between enrolment and worsening of cancer related symptoms as measured by the symptoms domains of QLQ-C30/PAN26 | From date of enrolment until the date of symptomatic progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| Clinical Benefit Response | Clinical Benefit Response is a composite endpoint consisting of weight, Performance Status and pain score and will be derived at 4 weekly intervals.The frequency and percentage of subjects with a clinical benefit response will be summarised | From date of enrolment until the date of first documented local progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| CA 19-9 response | CA 19-19 response will be defined as ≥ 50% decline from baseline and ≥ 90% decline from baseline and return to normal range respectively. Subgroups will be created for study subjects with CA 19-9 > ULN at baseline. | From date of enrolment until the date of first documented local progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| Overall Survival | Overall survival (OS) is the time from enrolment to the date of death from any cause. | Through study completion, an average of 18 months | 
| Patient Reported Outcomes | EQ-5D, EORTC QLQ-C30 and PAN26 will be analyses per their validated methodology | Through study completion, an average of 18 months | 
| Pain Scores | NRS and QLC-PAN26 | From date of enrolment until the date of first documented local progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| Weight loss | weight will be assessed at all applicable study visits | From date of enrolment until the date of first documented local progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| Tumour response | RECIST 1.1 per central review | From date of enrolment until the date of first documented local progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient | 
| Surgical resection rate | assessment of rate of secondary R0/R1 resection | Through study completion, an average of 18 months | 
| Target Tumour Volumetric Change | A central reading centre will analyse all CT scans to measure target tumour volume changes from baseline. | From date of enrolment until the date of first documented local progression or date of death from any cause, whichever came first, assessed up to 7 months after last enrolled patient |