Patient case: 57-year-old female with Pancreatic adenocarcinoma. Genetic variant: RB1, TP53, KRAS. Other conditions: None.

Clinical trial: A Pilot Study of OncoSil™ Given to Patients With Pancreatic Cancer Treated With Gemcitabine +/- Nab-paclitaxel.

Summary: The purpose of this research study is to investigate the safety of an active implantable (radiological) medical device OncoSil™, when implanted into patients with pancreatic cancer, who are already receiving standard chemotherapy. OncoSil™, is an experimental treatment. This means that it is not an approved treatment for pancreatic cancer anywhere in the world at this time.
  OncoSil™, carries the active treatment "radioactive Phosphorous (32P)" inside inactive silicon particles. These particles are tiny, and range in size from 28 to 32 micrometres, which is smaller than the width of a human hair (which typically range in width from 40 to 120 micrometres). Once implanted, the OncoSil™, microparticles will stay in the tumour permanently.
  The purpose of OncoSil™, is to deliver the action of 32P directly into a targeted tumor to destroy cancer cells. The number of these tiny microparticles inserted into the target tumor will range from 120 thousand to 2 million, depending on the dose needed for the size of the tumor.
  Patients will be taking part in a single arm open label research study - which means that everyone in the research study will receive the investigational treatment OncoSil™, plus their prescribed standard chemotherapy regimen which will be either; Gemcitabine or gemcitabine + nab-paclitaxel (Abraxane).
  Participation in this research study involves a Screening Period, a Treatment Follow Up Period and a Long Term follow up period. At the first screening visit, every patient will be asked to sign a consent form to agree to the study procedures, before any assessments are performed for the study.
  The Screening period will require attendance at 2 visits over a 2 week period, the Treatment Follow Up period will require attendance at assessment visits at the research study center; weekly for the first 12 weeks, the next visit will occur at week 16, then every 8 weeks after that until the End of Study (EOS) visit which will be scheduled once a patient's disease has progressed.
  The total number of visits patients will need to attend will depend on how long it takes for their disease to progress.
  The following assessments will be performed at all of the research study visits; Weight, current medications, , Quality of Life questionnaires, pain evaluation, Karnofsky performance status, blood sample, (Eastern Cooperative Oncology Group (ECOG) performance status, adverse events.
  The following assessments or procedures will take place at some of the study visits ( 1 or more): Informed consent, medical history, height, physical exam, Vital signs (blood pressure, heart rate, body temperature), tumor marker blood test, clotting factor blood test, pregnancy test, CT (computed tomography) scan - every 8 weeks, Bremsstrahlung Scan (2 only) The implantation of OncoSil™ will be completed in the endoscopy suite of the hospital. Implantation will only occur once during the treatment period, and once implanted, the device cannot be removed.
  A procedure called endoscopic ultrasound will be used to implant the microparticles. Endoscopic ultrasound is a standard procedure performed by a trained doctor. An endoscopic ultrasound involves a long flexible, fibre optic tube being passed from the mouth, down the oesophagus (food tube or gullet) and close to the pancreas while the patient is sedated. This allows the specialist doctor to view the pancreas and enables them to implant the OncoSil microparticles via a fine needle directly into the target tumor. The implantation procedure will be recorded and photographs taken of the target tumor and inside the stomach. The recording and photographic images will be identified only by the patient's research study identification number.
  After the procedure, there will be a 4 hour observation period to ensure that the patient is feeling fine and safe to go home.
  After the patients target tumor shows progression on imaging, their will be an end of study visit and then the Long Term follow up period will be conducted. The Long Term Follow up does not require the patient to return to the research study site, it is done via telephone contact from the site with the patient or review of the patient's medical records by site staff every 8 weeks for a maximum of up to 30 months.

Detailed description: Detailed Description
  Clinical Investigation Plan Rationale This clinical investigation will determine the safety and efficacy of the OncoSil™ investigational device when implanted directly into pancreatic tumors using endoscopic ultrasound guidance (EUS) in patients with unresectable locally advanced pancreatic cancer (LAPC)1. OncoSil™ is a brachytherapy device that implants a pre-determined tumouricidal dose of the beta radiation emitting isotope (Phosphorus-32), directly into cancerous tissue. The implanted activity will be equivalent to an absorbed intended average dose of 100 Gray (100 Gy) (±20%). The dose of 100 Gy proposed in the present ONC01P03 study has been selected as it has shown to be safe and well tolerated in a previous pancreatic clinical trial DB2-201 that encompassed the largest pool of patients to date.
  OncoSil™ is a locally-directed therapy that is expected to be used in combination with systemic chemotherapy in this patient group in line with accepted clinical practice. The previous studies of OncoSil™ in pancreatic cancer were conducted with gemcitabine which at the time was standard of care, having been shown to be superior to 5- fluorouracil (5-FU). Recently, regimens consisting of combinations of agents have shown greater efficacy in advanced pancreatic cancer compared with gemcitabine alone. The combination of gemcitabine and nab-paclitaxel was superior to gemcitabine in a Phase III study, demonstrating a statistically significant survival advantage (median overall survival 8.5 vs 6.7 months; p<0.001). This study was in patients with overt metastatic disease at presentation. This regimen has not been studied in prospective randomized controlled studies in LAPC. The regimen is being used in patients with good performance status (ECOG 0-1) and favourable co-morbidity profile and the recent American Society of Clinical Oncology (ASCO) Clinical Practice Guideline has recommended that it is reasonable to consider this combination in LAPC on the basis of extrapolation from the data obtained in the metastatic setting. Therefore this study aims to assess the safety of OncoSil™ when used in combination with a contemporary chemotherapy regimen.
  Given the patient specificity of chemotherapy administration it is not practical to standardize chemotherapy regimens across all patients.
  Gemcitabine and Gemcitabine+nab-paclitaxel are chemotherapeutics, and as such are injected by infusion. These chemotherapeutics work to destroy fast dividing cells in an indiscriminate systemic fashion. OncoSil™ is a brachytherapy device that implants a pre-determined dose of beta radiation emitting isotope directly into cancerous tissue. The beta particles emitted by OncoSil™ travel a short distance in tissue causing direct damage to cancer cell DNA, which renders them incapable of further cell division and proliferation. Through this mechanism OncoSil™ is able to stop cancer cells from multiplying and ultimately shrink tumor masses when the cells eventually die. Therefore, the OncoSil™ device is intended for local treatment of cancerous pancreatic cells when it is implanted intratumourally.
  Following enrolment, safety will be measured by laboratory parameters once a week through to week 12, then 4 weeks later at week 16 and then every 8 weeks thereafter until the end of study (EOS) visit.
  Adverse events will be assessed throughout the duration of the study. Pain will be assessed via Numerical Rating Scale (NRS) and European Organization for Research and Treatment of Cancer Pancreatic Cancer Quality of Life Questionnaire (EORTC QLQ PAN-26). NRS will be assessed at each visit and EORTC QLQ PAN-26 will be assessed at screening and visit 1, then every 4 weeks until week 16, then 8 weekly until study participants reach documented progression of disease criteria for both local progression free survival (LPFS) and progression free survival (PFS).
  Response will be assessed by 3-dimensional computed tomography (CT) scanning every 8 weeks after visit 1. CT scans performed at 8 week intervals, is in line with standard radiological guidelines. Study participants will be managed by their local medical team according to clinical assessment based on clinical examination, tumor markers and radiological scans.
  Clinical Investigation Plan (CIP) Design: This will be a prospective, interventional, open label, single arm safety study with each site following a common protocol. Twenty study participants will be enrolled at up to 5 sites in the United States of America where recruitment will be competitive.
  Enrolment is estimated to take 6-12 months to complete. Each consented study participant is to be followed until documented progression of disease criteria is met for both LPFS and PFS (marking this as the end of the treatment follow-up period and EOS). From the EOS or discontinuation visit, 8 weekly medical record review will be used to monitor for possible device or late radiation related adverse events, and oncology treatments/procedures administered for up to 12 months post OncoSil™ implantation. Overall survival will also be conducted via the 8 weekly telephone contact and medical record reviews until study participant death, or until 104 weeks post the last study participant enrolled. No scheduled study participant study on-site visits are required for these follow-up reviews.
  All study participants will receive an OncoSil™ intratumoural implantation into a pancreatic tumor via injection under Endoscopic Ultrasound Guidance (EUS), at an average absorbed dose of 100Gy (±20%).
  Twenty study participants will receive OncoSil™ plus either Gemcitabine or Gemcitabine+nab-paclitaxel chemotherapy treatment. The chemotherapy agents will be administered per local approved prescribing standards. Once 10 study participants have been enrolled all using one of the chemotherapy options (e.g. Gemcitabine), all remaining study participants needed to meet the study total of 20 must only be enrolled if they will be prescribed the remaining chemotherapy option (i.e. gemcitabine +nab-paclitaxel) A medical review of all safety events will occur regularly throughout the investigation.
  Treatment Design: The study has been chosen as open-label which is typical for oncology studies of this type, and reflects the fact that a sham endoscopy procedure poses a risk to study participants due to requiring sedation with no procedure performed.
  The order of OncoSil™ will be required to be made 28 calendar days before the implantation date. OncoSil™ implantation is to occur during the fourth (4th) week of the first chemotherapy cycle. For this to occur, the chemotherapy regimen must commence at a minimum of 7 and a maximum of 14 days post enrolment.
  Study Aim: To further investigate the safety of the active implantable (radiological) medical device, OncoSil™ when implanted intratumourally using EUS guidance in study participants with unresectable, locally advanced pancreatic cancer. Study participants will receive either Gemcitabine or gemcitabine+nab-paclitaxel chemotherapy plus OncoSil™. The following endpoints will be assessed Permissible Medications/Treatments Medication for supportive therapy and existing medical conditions is permitted as determined by the treating physician.
  Prohibited Medications/Treatments With exception of Gemcitabine and gemcitabine+ nab-paclitaxel, any anti-cancer therapy including cytotoxic, biological/immunotherapy or radiotherapy is not permitted after the study participant has been screened and found eligible for the study, until the study participant reaches documented progression of disease criteria for both LPFS and PFS. Thereafter, study participants may be treated at the investigator's discretion. However, since the combination of standard radiotherapy and OncoSil™ has not been investigated, additional radiotherapy is not recommended following OncoSil™ treatment.
  Study participants should not receive any other investigational products (e.g. drugs, devices), or investigational therapies, during the study or within 30 days of screening or five half-lives of screening, whichever is longer.
  The investigator should instruct the study participant to notify the study site about any new medications (including over-the-counter products and herbal remedies) he/she takes after enrolment. All medications and significant non-drug therapies (including physical therapy and blood transfusions) administered after implantation with the study device must be documented in the electronic case report form (eCRF).
  Termination of the study:
  The study may be stopped if, in the judgment of the OncoSil Medical study physician and or SRC, study participants are placed at undue risk because of clinically significant findings that:
  -  Meet individual stopping criteria or are otherwise considered significant
  -  Are assessed as causally related to study device
  -  Are not considered to be consistent with continuation of the study Regardless of the reason for termination, all data available for the study participant at the time of termination of follow-up must be recorded in the eCRF. All reasons for discontinuation of treatment must be documented. In terminating the study, the Sponsor will ensure that adequate consideration is given to the protection of the study participants' interests.
  Visit schedule and assessments: Study visits will occur at Screening 1, Screening 2/Enrolment, Day 0 and then at weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, then 4 weeks later at week 16 then every 8 weeks until PD criteria is met for both LPFS and PFS. Study participants, who are discontinued for any reason, should be scheduled for an End of Study (EOS) visit as soon as possible, at which time all of the assessments listed for the 'End of Study' visit will be performed.
  Study participants are to be seen for all visits on the designated day with an allowed visit window of ± 3 days for weeks 2 to 16 (visits 2 to 14), and a window of ± 7 days for CT scans and visits/reviews post 16 weeks (V14). The date of commencement of chemotherapy by default becomes Visit 1. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans are performed during the screening period and at week 12. There is ± 7 day window for performance of these scans. Bremsstrahlung Imaging will be performed at the Week 4 and Week 5 visits.
  The following assessments may be performed at one, some or all of the study visits:
  -  Confirmation of written Informed Consent
  -  EORTC QLQ-C30 QoL Questionnaire
  -  EORTC QLQ-PAN26 Questionnaire
  -  ECOG and Karnofsky Performance Status
  -  NRS (Numerical Rating Scale)
  -  Demographics and Medical History
  -  Confirmation of cancer related symptoms
  -  Concomitant medication
  -  Prior neoplastic therapy
  -  Adverse Events
  -  Vital signs
  -  Body weight and height
  -  Physical examination
  -  Pregnancy test
  -  Laboratory Examinations
  -  Carbohydrate Antigen (CA) 19-9 & carcinoembryonic antigen (CEA)
  -  Prothrombin Time (PT), Partial Thromboplastin Time (PTT)
  -  CT scans of the thorax/abdomen/pelvis. Read by the Central Reading Center (CRC)
  -  RECIST 1.1 evaluation
  -  Confirmation of meeting all the inclusion criteria and none of the exclusion criteria
  -  Blood sampling for radioactivity before OncoSil™ implantation - Analysed by the Central Laboratory (CL)
  -  OncoSil™ Implantation via Endoscopic Ultrasound (EUS) Guidance (8 hour fasting required for EUS procedure)
  -  OncoSil™ Implant Recording and Photography
  -  Bremsstrahlung Imaging
  -  Blood sampling for radioactivity post OncoSil™ implantation - Analysed by the CL
  -  Urine sampling for radioactivity after OncoSil™ implantation - Analysed by the CL.
  Then, 8 weekly medical record review will be used to monitor possible deice or late radiation related adverse events, and oncology treatments/procedures administered for up to 12 months post OncoSil™ implantation.
  Overall survival will also be conducted via the 8 weekly medical record reviews until study participant death, or until 104 weeks post the last study participant enrolled.
  Gemcitabine or gemcitabine+nab-paclitaxel chemotherapy will be dosed per standard of care (SoC) schedules concurrently with these visits.
  Females of child-bearing potential should use reliable methods of contraception from the time of screening and for 12 months after implantation of the study device.
  Male study participants should be asked to use barrier contraceptives (i.e., by use of condoms) during sex with all partners during the study and for a period of 12 months following the implantation of the study device.
  Device Description:
  OncoSil™, is comprised of OncoSil Phosphorous-32 Microparticles (hereafter Microparticles) and OncoSil Diluent (hereafter Diluent). OncoSil™ is an active implantable (radiological) medical device intended for use in brachytherapy, where cancer is treated by the insertion of radioactive implants directly into the cancerous tissue. OncoSil™ has been designed to be injected directly into, and to deliver an average absorbed dose of 100 Gy to the target treatment tumor. In therapeutic use 98% of the radiation is delivered within 81 days. OncoSil™ is supplied sterile and is intended for single-patient single-use.
  The Diluent has been designed to perform as a carrier to facilitate implantation of the Microparticles into the target treatment tumor. Prior to study participant administration, OncoSil™ is prepared by the treating facility's radio-pharmacist. The Microparticles and Diluent are combined in accordance with a pre-defined suspension preparation protocol. The resulting suspension has a pre-determined total activity required to deliver an average absorbed dose of 100 Gy to the target treatment tumor. Following preparation, the Microparticles are intratumourally implanted into a pancreatic tumor via injection under endoscopic ultrasound guidance.
  The Microparticles have been designed to deliver a localised distribution of beta radiation within the target treatment tumor and to remain there permanently following implantation.
  Note: OncoSil™ does not incorporate any material or ingredient derived from medicinal, human, animal or recombinant origin.
  Intended Use / Indications for Use
  -  OncoSil™ is intended for intratumoural implantation into a pancreatic tumor via injection under endoscopic ultrasound guidance.
  -  OncoSil™ is indicated for the treatment of patients with advanced unresectable pancreatic cancer, in combination with standard of care chemotherapy.
  OncoSil Medical can only authorise a shipment of the OncoSil™ System to a site once:
  1. The license for the study centre to receive and hold 32P has been verified by OncoSil Medical.
  2. A training visit has been conducted in which relevant individuals permitted to work as an Authorised Dispenser (AD) and Authorised User (AU), investigators, study coordinators and surgical/procedural personnel etc. have completed the training and experience requirement set out by OncoSil Medical. In addition, the AD and AU must undergo additional training to obtain accreditation to handle, dispense and or implant OncoSil™.
  Authorised Dispenser (AD is the person preparing the OncoSil™ suspension (i.e. Radiopharmacist, Nuclear Medicine Personnel) and must successfully complete additional training on the OncoSil™ device as described below.
  Authorised Dispenser (AD): The AD attends the OncoSil Medical Training Programme and performs at least one cold dose (i.e. Microparticles are not radioactive) dilution which is supervised in the physical presence of an OncoSil Medical representative (Authorised Trainer). This training will be documented on the training log and a copy provided to OncoSil Medical.
  This training allows the Authorised Dispenser (AD) to:
  1. Order the OncoSil™ System calibration dose to perform a calibration procedure.
  2. Once the calibration dose has been successfully completed, the site will be able to order the OncoSil™ System study participant dose, to be used during the Authorised Users (AUs) supervised EUS implantation procedure of the first study participant at the respective study centre (refer to below) Authorised User (AU)
  -  Definition of Authorised User (AU) is the physician physically depressing the syringe containing OncoSil™ during the implantation procedure and must have successfully completed additional training on the OncoSil™ device as outlined below:
  -  Authorised User (AU): In order to become a fully accredited Authorised User, the AU attends the OncoSil Medical Training Programme and must perform their first study participant implantation in the physical presence of an OncoSil Medical representative (Authorised Trainer).
  Once the completed training log has been provided to OncoSil Medical, the AD and AU will each receive an accreditation certificate to document that they are authorised to order and handle the OncoSil™ System.
  Note: In some cases the AD and the AU may be the same person, however, they will be required to complete both training programmes in order to be accredited in both roles.
  All personnel must be trained by OncoSil Medical, or an Authorised Representative. Supplemental training may be required if significant revisions are made to existing procedures by the company. Upon site activation, once a study participant has been deemed eligible by a study investigator and enrolled into the study, the investigator will notify the Authorised Dispenser (Nuclear Medicine Personnel/ Radio-pharmacist) for device ordering.
  An order of the OncoSil™ System is then placed with OncoSil Medical, and the study participant is booked in for an EUS procedure (allowing 28 calendar days from time of order to receipt of the OncoSil™ System).
  Implantation Strategy for OncoSil™ The pancreatic target tumor volume will be determined from the screening/baseline CT scan i.e. the last measurement taken prior to implantation that meets the requirements of the protocol.
  The target tumor volume will be measured independently by the CRC who will provide an Adobe pdf file of the baseline target tumor volume to the Principal Investigator. This document must be stored in the study participant file.
  The baseline target tumor volume will be used to determine the OncoSil™ Volume to be Implanted (VTBI).
  A single dose is implanted into the body of the tumor using the final suspension of OncoSil™ with a radioactive concentration of 6.6 megabecquerel (MBq) per mL (the radioactivity concentration required, with an Implanted Volume/Tumor Volume (IV/TV) of 8%, to deliver 100 Gy to the tumor mass).
  Implantation of OncoSil™ is performed using a disposable 22 gauge EUS-fine needle aspiration (FNA) needle, loaded through the biopsy channel of the echoendoscope and slowly advanced through the gastric wall or duodenal wall into the target pancreatic tumor (avoiding vessels and avoiding damage to surrounding organs) using ultrasound guidance.
  The position of the needle tip within a tumor will be identified by endoscopic ultrasound localisation prior to injection. In this way the Endoscopist will need to determine that the needle is placed intratumourally. The required amount of OncoSil™ is then implanted within the tumor by the Authorised User.
  Radiological Dose Administered:
  An assessment has been conducted of the absorbed dose measured in Gray, (the average radiation energy imparted to a medium, where 1 Gy = 1 J/kg) that is likely to be administered during implantation into a tumor in the pancreas.
  The average absorbed dose that any treated tumor will receive is 100Gy (±20%). Only one tumor will be treated per study participant.
  Treatable tumors will be between ≥ 2.0 cm in the shortest diameter and ≤ 6 cm in the longest diameter and a minimum tumor volume of 14.0 cc as assessed by the CRC.
  Decay/Disposal of Study Device and Components Supplies During the study, all used / remaining investigational devices must be decayed and/or destroyed at the treatment facility that received the study device shipment and in accordance with local regulations. A device deficiency of the OncoSil™ System should be notified to OncoSil Medical or designee. Written instructions provided by OncoSil Medical should be followed when reporting a device deficiency of the OncoSil™ System.
  Post OncoSil™ Implant Study participant Observation Following implantation, it is recommended that study participants are observed for four hours (with regular observations of consciousness and vital signs as clinically indicated) and if stable and pain-free they can be discharged the same day. An overnight stay is optional and is at the discretion of the investigator.
  Evaluation and Documentation of Adverse Events (AE) and Device Deficiencies Investigators are required to evaluate and document all AEs and Device Deficiencies observed in study participants.
  To ensure study participant safety, every AE, (regardless of suspected causality), occurring during the following periods outlined below must be reported to OncoSil Medical from learning of its occurrence.
  From the date of signed informed consent until the study participant has stopped study participation and must also be followed for no shorter period than:
  -  28 days post last chemotherapy administered
  -  120 days post OncoSil™ implantation
  For all observed or reported AEs, investigators should assess and document the details in the study participant's medical records/source documents. The general procedure for investigators reporting any adverse event is as follows:
  -  Report the event via the eCRF system as soon as possible but no later than the timeframes outlined in the International Standard Good Clinical Practice (ISO14155:2011) guidelines.
  -  Complete all sections of the Adverse Event eCRF
  -  Each unique event/diagnosis must be documented separately
  -  Documented pre-existing conditions are not considered to be reportable AEs unless there is a change in the nature or severity of the condition
  -  The Adverse Event information must be documented in the study participant's source documents, reviewed and approved by the Investigator.
  The Safety Review Committee (SRC) will comprise of Medical and Radiation Oncologists, Nuclear Medicine Physician, the OncoSil Chief Medical Officer, and the Coordinating Principal Investigator for the study. Additional ad hoc members may be invited to participate in meetings depending on the safety findings and required scope of expertise. The SRC will meet to review the safety profile of the study (all adverse events) on an on-going basis. Particular Attention will be paid to potential sub-acute/late effects of radiation, such as gastrointestinal haemorrhages, bowel ulceration, enteritis, perforations, fistula and stricture that could occur.
  The SRC will meet initially, after the first five (5) study participants have been implanted with OncoSil™ and also once these study participants have completed the first eight (8) weeks of follow-up post implant. The SRC will continue to meet to review the safety profile of the study after every additional five (5) study participants have been implanted with OncoSil™ until enrolment has completed. Then the committee will subsequently meet every four (4) months until the completion of all study participants follow up.
  Any one of the following conditions will pause the study.
  -  One implant with missed target tumor (determined by Bremsstrahlung imaging)
  -  A subject with evidence of radioactivity in the blood >1% of the activity of the injected dose at any time point
  -  One Serious Adverse Device Effect, requiring hospitalisation
  -  A study participant death (related to the device) within 4 weeks of OncoSil™ implant The results and recommendations of the SRC will be minuted. The composition and activities of the committee are described within the SRC charter and Safety Management Plan - which are separate documents.
  Risks associated with OncoSil™ and or implantation procedure
  The following adverse events, considered to have a causal relationship with OncoSil™ or procedure, were recorded during previous clinical studies:
  -  Procedure-related pain
  -  Abdominal pain and discomfort
  -  Lethargy
  -  Fever
  -  Nausea and vomiting
  -  Abnormal liver function tests There may also be unforeseen risks to the study participant, embryo or fetus if the study participant fathers a child, or becomes pregnant. The study participant should not father a child, become pregnant, or breast-feed a baby within twelve months of receiving an implantation. In addition, an effective, hormonal or barrier method of birth control or abstinence method of birth control must be used post-implantation for the entire duration of the study (and for not less than twelve months after implantation).
  Although not experienced by any of the patients previously dosed with OncoSil™, there are potential sub-acute/late effects of radiation, such as gastrointestinal haemorrhages, bowel ulceration, enteritis, perforations, fistula and stricture that could occur.
  All risks individually and cumulatively, considered versus the benefit, have been taken into account. Residual risks are low and acceptable when balanced against the clinical benefit associated with use of the device. The overall risk assessment for OncoSil™ has therefore been assessed as being acceptable.
  In addition to the risks listed in the above section, there may be further risks to the study participants, the nature of which are unknown.
  STATISTICAL ANALYSES Populations for Analysis The intention-to-treat (ITT) population will consist of all enrolled study participants.
  The Safety population will consist of all study participants who received an implantation of OncoSil™.
  Study participant Demographics/Other Baseline Characteristics All study participants' demographic and other baseline characteristics will be summarised descriptively for the ITT and Safety populations.
  Overall Survival An analysis of overall survival will be conducted once 52 weeks post the last possible enrolled study participant has completed and then a final analysis 104 weeks post the last possible enrolled study participant. Because these analyses are not pivotal there will be no adjustment to p-values for the multiple tests.
  Statistics Methods The demographic and baseline characteristics will be summarised as mean, standard deviation, minimum, median, and maximum for continuous variables, and as frequencies and percentages for categorical variables.
  The time to event efficacy variables such as local progression free survival (LPFS), will be summarized as sample size, number of events, median time to the event, and 95% confidence interval for the median. The distribution of each time to event variable will be estimated for each treatment with the Kaplan-Meier curve.
  Training of Study Site Personnel The clinical investigation shall not commence until the required approval/s are obtained. With written acknowledgement from OncoSil Medical, any additional requirements imposed by a local Ethics Committee and/or Regulatory Authority shall be followed.
  Only Investigators/Co-Investigators, named on the study delegation log, trained by the sponsor or delegate, and who meet local licensing requirements will perform the implantation procedure. OncoSil™ will be prepared by designated personnel licensed to handle radioactive products and who have completed the OncoSil Medical Training. All site investigation personnel will receive and document training prior to commencing participation in the investigation.
  Before the first study participant is entered into the study, an OncoSil Medical representative will review and discuss the requirements of the Clinical Investigation Plan and related documents with the investigational staff and also train them in any study specific procedures and the eCRF system utilised.
  The Principal Investigator will ensure that appropriate training relevant to the study is given to all of these staff, and that any new information relevant to the performance of this study is provided to and reviewed by, the staff involved.
  Ethical Considerations It is mandatory that all considerations regarding the protection of human study participants be carried out in accordance with the CIP, Good Clinical Practices (GCP), ISO14155: 2011, the ethical principles that have their origin in the Declaration of Helsinki, and all applicable regulatory requirements. Before enrolment of any study participant into the study, the final study protocol, including the final version of the Informed Consent Form, is approved by the national regulatory authority or a notification to the national regulatory authority is done, according to local regulations.
  Informed Consent and Study participant Information Obtaining informed consent must be done according to the guidelines provided in the Declaration of Helsinki, ISO14155, and local regulations.
  OncoSil Medical Ltd will provide to Investigators an informed consent form that complies with the ISO14155 guidelines and regulatory requirements and is considered appropriate for this study.
  The Principal Investigator (according to applicable regulatory requirements) or a person designated by the Principal Investigator and under the Investigator's responsibility must comply with the terms of the informed consent process and must fully inform study participants of all pertinent aspects of the clinical study.
  Patient Confidentiality A report of the results of this study may be published or sent to the appropriate health authorities in any country in which the study device may ultimately be marketed, but the study participant's name will not be disclosed in these documents. The study participant's name may be disclosed to the Sponsor of the study, OncoSil Medical, or the governing health authorities or the regulatory authorities if they inspect the study records. Appropriate precautions will be taken to maintain confidentiality of medical records and personal information.

Eligibility: Inclusion Criteria:
  -  Histologically or cytologically proven adenocarcinoma of the pancreas
  -  Stage III unresectable locally advanced pancreatic carcinoma
  -  Pancreatic target tumor diameter of ≥ 2.0 cm (shortest axis) to ≤ 6.0 cm (longest axis) and a minimum tumor volume of 14.0 cc as qualified by the central reading center
  -  An ECOG Performance Status of 0 to 1 and Karnofsky Performance Status of 80 - 100
  -  Subjects ≥ 18 years of age at screening
  -  To commence first-line standard nab-paclitaxel and gemcitabine chemotherapy, or gemcitabine alone, (per standard of care according to the approved prescribing schedule), within 7 to 14 days post enrolment, with OncoSil™ implantation to occur during the fourth (4th) week of the first chemotherapy cycle
  -  Provide signed Informed Consent
  -  Willing and able to complete study procedures within the study timelines
  -  Adequate renal function: serum creatinine less than 1.5 x upper limit of normal (ULN)
  -  Adequate liver function: serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) ≤ 2 × ULN and serum bilirubin ≤ 1.5 × ULN unless Gilbert's syndrome has previously been confirmed for the subject
  -  A Prothrombin Time (PT) or Partial Thromboplastin Time (PTT) within normal range
  -  Adequate bone marrow function: white blood cells (WBCs) ≥ 3,000/mm3, absolute neutrophil count (ANC) ≥ 1,500/mm3, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000/mm3
  -  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 (refer to Section 7.3 Permissible and Prohibited Medications/Treatments)
  Exclusion Criteria:
  -  Evidence of distant metastases as determined by the central reading committee
  -  More than one primary lesion
  -  Any prior radiotherapy or chemotherapy for pancreatic cancer
  -  Use of other investigational agent at the time of screening, or within 30 days or five half-lives of screening 1, whichever is longer
  -  Pregnant or lactating
  -  In the opinion of the investigator, EUS directed implantation posing undue subject risk e.g. previous EUS-FNA was considered technically too difficult to perform, or imaging demonstrates multiple collateral vessels surrounding or adjacent to the target tumor
  -  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, duodenum or peritoneum (if not certain confirmation must be obtained prior to enrolment)
  -  A known allergy or history of hypersensitivity to silicon, phosphorous or any of the OncoSil™ components
  -  Any other health condition that would preclude participation in the study in the judgment of the principal investigator

Relevance to patient case: not relevant