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Trial registered on ANZCTR
Registration number
ACTRN12623000223639
Ethics application status
Approved
Date submitted
16/02/2023
Date registered
2/03/2023
Date last updated
25/04/2024
Date data sharing statement initially provided
2/03/2023
Type of registration
Prospectively registered
Titles & IDs
Public title
A safety and early efficacy study of LSTA1 in combination with durvalumab, gemcitabine and nab-paclitaxel, as first-line treatment in locally advanced pancreatic ductal adenocarcinoma (PDAC)
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Scientific title
A Phase 1 single-blind study evaluating LSTA1 in combination with durvalumab, gemcitabine and nab-paclitaxel as a first-line treatment in locally advanced pancreatic ductal adenocarcinoma (PDAC)
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Secondary ID [1]
308990
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Nil known
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Universal Trial Number (UTN)
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Trial acronym
iLSTA
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Cancer
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Condition category
Condition code
Cancer
325998
325998
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0
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Pancreatic
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Cohort 2:
Gemcitabine (1,000mg/m2 over 30 minutes +/- 3 minutes; intravenously; Day 1 (D1), Day 8 (D8), Day 15 (D15) of every 28 day cycle) + Nab-Paclitaxel (125mg/m2 over 30 minutes +/- 3 minutes; intravenously; D1, D8, D15 of every 28 day cycle) + LSTA1 (3.2mg/kg over 1 minute +/-30 seconds; intravenously; D1, Day 2 (D2), D8, D15, Day 16 (D16) of every 28 day cycle) + Placebo Durvalumab (750mg over 60 minutes +/- 6 minutes; intravenously; D1, D15 of every 28 day cycle). All 4 drugs will be administered for a total of 6 cycles or until disease progression or unacceptable adverse event.
Cohort 3:
Gemcitabine (1,000mg/m2 over 30 minutes +/- 3 minutes; intravenously; D1, D8, D15 of every 28 day cycle) + Nab-paclitaxel (125mg/m2 over 30 minutes +/- 3 minutes; intravenously; D1, D8, D15 of every 28 day cycle) + LSTA1 (3.2mg/kg over 1 minute +/-30 seconds; intravenously; D1, D2, D8, D15, D16 of every 28 day cycle) + Durvalumab (750mg over 60 minutes +/- 6 minutes; intravenously; D1, D15 of every 28 day cycle). All 4 drugs will be administered for a total of 6 cycles or until disease progression or unacceptable adverse event.
Placebo Durvalumab will be an infusion of 0.9% sodium chloride in place of active durvalumab.
Patients will attend clinic visits on D1, D2, D8, D15, D16 and D22 of each cycle prior to receiving treatment. Safety bloods will be collected on Day 1, D8, D16 and D22 and will be reviewed prior to drug administration.
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Intervention code [1]
325432
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Treatment: Drugs
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Comparator / control treatment
Cohort 1: Control Group
Gemcitabine (1,000mg/m2 over 30 minutes +/- 3 minutes; intravenously; D1, D8, D15 of every 28 day cycle) + Nab-paclitaxel (125mg/m2 over 30 minutes +/- 3 minutes; intravenously; D1, D8, D15 of every 28 day cycle) + Placebo LSTA1 (3.2mg/kg over 1 minute +/-30 seconds; intravenously; D1, D2, D8, D15, D16 of every 28 day cycle) + Placebo Durvalumab (750mg over 60 minutes +/- 6 minutes; intravenously; D1, D15 of every 28 day cycle). All 4 drugs will be administered for a total of 6 cycles or until disease progression or unacceptable adverse event.
Placebo LSTA1 and Placebo Durvalumab will be an infusion of 0.9% sodium chloride in place of active LSTA1 and durvalumab.
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Control group
Active
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Outcomes
Primary outcome [1]
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To determine the safety and tolerability of the addition of LSTA1 when added to the combination of durvalumab, gemcitabine, and nab-paclitaxel in subjects with locally advanced pancreatic ductal adenocarcinomas.
Safety and tolerability will be tested by performing weekly blood tests (haematology and chemistry) and 8 weekly disease assessment (CT CAP and RECIST 1.1). Patients will be well informed of potential safety issues through the patient informed consent form. The study will utilise CTCAE V5.0 when assessing any adverse events experienced by the patient. The patients will also be reviewed by a trained and delegated study coordinator as well as the treating oncologist or trained sub-investigator at each clinic visit.
Toxicities to be monitored:
- Neutropenia (monitored with weekly blood tests)
- Thrombocytopenia (monitored with weekly blood tests)
- Febrile neutropenia (monitored with weekly blood tests and vital sign collection)
- Peripheral neuropathy (monitored through patient reporting of symptoms and weekly physical exams)
- Cutaneous toxicity (monitored through patient reporting of symptoms and weekly physical exams)
- Gastrointestinal toxicity (mucositis, diarrhoea) (monitored through patient reporting of symptoms and weekly physical exams)
- Myelotoxicity (monitored through patient reporting of symptoms and weekly physical exams)
- Sepsis (monitored through patient reporting of symptoms, weekly physical exams and weekly blood tests)
- Hepatotoxity (monitored with weekly blood tests)
- Thrombotic microangiopathy (monitored through patient reporting of symptoms and weekly blood tests)
- Pulmonary toxicity (monitored through patient reporting of symptoms, weekly physical exams and 8-weekly scans)
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Assessment method [1]
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Timepoint [1]
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All adverse events and dose limiting toxicities will be summarized descriptively and assessed continuously from first dose through until 30 days after the last dose of trial drug or until resolution of AEs/toxicity. Patients will then be monitored by their treating oncologist for 5 years as standard of care.
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Secondary outcome [1]
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1. The disease control rate (DCR) (complete response (CR) + partial response (PR) + stable disease (SD)) at 16-weeks.
This will be assessed using CT CAP imaging, RECIST 1.1 assessment, blood tests and tumour markers at baseline and every 8 weeks thereafter. Blood tests are at NATA accredited laboratories using standard measurements and all images are assessed by RECIST 1.1
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Assessment method [1]
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Timepoint [1]
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1. Response assessments will be determined by performing 8-weekly imaging and Recist 1.1 at the 16-week time point, post-first dose.
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Secondary outcome [2]
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2. The best overall response rate (ORR) (CR+PR) at 16-weeks.
This will be assessed using CT CAP imaging, RECIST 1.1 assessment, blood tests and tumour markers at baseline and every 8 weeks thereafter. Blood tests are at NATA accredited laboratories using standard measurements and all images are assessed by RECIST 1.1
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Assessment method [2]
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Timepoint [2]
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2. Best overall response will be determined by reviewing each of the 8-weekly imaging and Recist 1.1 results at the 16-week time point, post-first dose..
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Secondary outcome [3]
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3. Median progression-free survival (mPFS) and median progression-free survival (mPFS) at 6 months (mPFS 6 mo.).
Standard of care is to review of patients by the treating oncologist with blood tests, tumour markers and imaging every 3 months until either progression / recurrence or the patients achieves 5 years of disease free state. Blood tests are at NATA accredited laboratories using standard measurements and all images are assessed by RECIST1.1
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Assessment method [3]
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Timepoint [3]
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3. Average PFS amongst the participants at the end of the study as well as 6 month time point, post-first dose. As per standard of care practice, patients will continue to be monitored for 5 years by their treating oncologist.
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Secondary outcome [4]
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4. Median overall survival (mOS) and median overall survival 6 months (mPFS 6 mo.).
Standard of care is to review of patients by the treating oncologist with blood tests, tumour markers and imaging every 3 months until either progression / recurrence or the patients achieves 5 years of disease free state. Blood tests are at NATA accredited laboratories using standard measurements and all images are assessed by RECIST 1.1
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Assessment method [4]
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Timepoint [4]
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4. Average OS amongst the participants at the end of the study as well as 6 month time point, post-first dose. As per standard of care practice, patients will continue to be monitored for 5 years by their treating oncologist.
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Secondary outcome [5]
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5. Duration of response for responding patients with measurable disease at baseline.
This will be assessed using CT CAP imaging, RECIST 1.1 assessment, blood tests and tumour markers at baseline and every 8 weeks thereafter. Blood tests are at NATA accredited laboratories using standard measurements and all images are assessed by RECIST 1.1
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Assessment method [5]
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Timepoint [5]
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5. Measured from the first timepoint where an objective response is determined until the last timepoint the patient is found to have an objective response. As per standard of care practice, patients will continue to be monitored for 5 years by their treating oncologist.
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Secondary outcome [6]
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6. To determine levels of immune cell infiltration in tumour biopsies (pre-treatment and on-treatment at 12 weeks) in each cohort
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Assessment method [6]
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Timepoint [6]
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6. Change in tumour infiltrating lymphocyte (TIL) score as measured by H&E TIL count according to Salgado criteria from pre-surgical biopsy to resected tumour specimen.
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Eligibility
Key inclusion criteria
1. Have histologically confirmed locally advanced pancreatic ductal adenocarcinoma
2. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent must be obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
3. Age > 18 years at time of study entry, age > 20 years for Japanese patients.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Have either adequate archival tissue from prior biopsy for biomarker evaluation or willingness to undergo biopsy before treatment starts and willing to have biopsy during treatment at 12 weeks (if appropriate)
6. Have a negative serum pregnancy test (if a premenopausal female subject). Men and women of child-bearing potential must be willing to use effective contraceptive methods during the study, Section 9.1.5.
7. Adequate normal organ and marrow function as defined below:
a. Haemoglobin greater than or equal to 9.0 g/dL
b. Absolute neutrophil count (ANC) greater than or equal to 1.5 × 10^9 /L
c. Platelet count greater than or equal to 100 × 10^9/L
d. Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN).
e. AST (SGOT)/ALT (SGPT) less than or equal to 3 x institutional upper limit of normal.
f. Measured creatinine clearance (CL) >60ml/min/1.73 m2 or calculated creatinine Cl >40mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
8. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
9. Must have a life expectancy of at least 12 weeks
10. Have no clinically significant abnormalities on urinalysis.
11. Have acceptable coagulation status:
a. Prothrombin time (PT) within normal limits
b. Partial Thromboplastin Time (PTT) within normal limits
12. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumour assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomisation.
Must be eligible for treatment with nab-paclitaxel and gemcitabine
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Have received any prior chemotherapy, immunotherapy, or any other investigational agents for the treatment of pancreatic cancer
2. Concurrent enrolment in another clinical study, unless it is an observational (non- interventional) clinical study or during the follow-up period of an interventional study
3. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
4. History of allogenic organ transplantation.
5. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
6. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
7. History of another primary malignancy
8. History of leptomeningeal carcinomatosis
9. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) greater than or equal to 470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) Regardless of whether this criteria stays or not, all patients should have a baseline ECG
10. History of active primary immunodeficiency
11. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HbsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HbsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
12. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies.
13. Known to have active tuberculosis
14. Have a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on baseline chest CT scan.
15. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
16. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
This study will enroll 30 participants randomised 4:1:1 in favour of the cohort 3 study intervention.
Data will be presented in a tabular form with mean and standard deviation or median with lowest and highest values and/or 95% confidence interval values. Analysis of the primary endpoint will be on a full population set basis.
Due to primary safety endpoint and small sample size this study will not be powered towards defined statistical significance.
The full analysis set will include all subjects who are randomised.
The safety population includes all subjects who took at least one dose of any trial medication.
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Recruitment
Recruitment status
Recruiting
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Date of first participant enrolment
Anticipated
31/03/2023
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Actual
3/04/2023
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Date of last participant enrolment
Anticipated
31/12/2024
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Actual
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Date of last data collection
Anticipated
31/12/2026
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Actual
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Sample size
Target
30
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Accrual to date
17
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Final
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Recruitment in Australia
Recruitment state(s)
WA
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Recruitment hospital [1]
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St John of God Hospital, Subiaco - Subiaco
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Recruitment postcode(s) [1]
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6008 - Subiaco
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Funding & Sponsors
Funding source category [1]
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Charities/Societies/Foundations
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Name [1]
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Warpnine Incorporated
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Address [1]
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35 Davenport Road. Booragoon, WA 6154
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Country [1]
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Australia
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Primary sponsor type
Charities/Societies/Foundations
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Name
Warpnine Incorporated
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Address
35 Davenport Road. Booragoon, WA 6154
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
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Address [1]
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Country [1]
314919
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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St John of God HREC
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Ethics committee address [1]
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Level 1, 556 Wellington Street, Perth WA 6000
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Ethics committee country [1]
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Australia
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Date submitted for ethics approval [1]
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13/01/2023
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Approval date [1]
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14/02/2023
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Ethics approval number [1]
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1949
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Summary
Brief summary
This study aims to assess the safety and tolerability of a new cancer treatment drug, LSTA1, in combination with durvalumab, gemcitabine and nab-paclitaxel, as first-line treatment for patients with locally advanced pancreatic ductal adenocarcinoma (PDAC). Who is it for? You may be eligible for this study if you are aged 18 years or older (or aged 20 or older if Japanese), you have been diagnosed with locally advanced pancreatic ductal adenocarcinoma and you have not yet started treatment for your cancer. You will also need to meet certain health criteria prior to being eligible for this study. Study details Participants who choose to enrol in this study will be randomly allocated by chance (similar to flipping a coin) to one of 3 treatment groups. Participants allocated to the first treatment group will receive gemcitabine, nab-paclitaxel and two placebo treatments. Participants allocated to the second treatment group will receive gemcitabine, nab-paclitaxel, LSTA1 and one placebo treatment. Participants allocated to the third treatment group will receive gemcitabine, nab-paclitaxel, LSTA1 and durvalumab treatments. All treatments will be administered on set days of a 28-day treatment cycle. Participants will continue to receive their allocated treatments every 28 days unless they experience any serious side effects, they have disease progression or such a time that their health deteriorates to the point where the treatment is no longer practicable . During treatment, participants will be asked to undergo blood tests, imaging and a biopsy to determine how the treatment is affecting their cancer. It is hoped this research will determine whether adding the new cancer treatment drug, LSTA1 and immunotherapy to currently used cancer treatment drugs is safe and whether it has any effect on cancer cells. If this study finds that LSTA1 is safe to use in combination with the current cancer treatment drugs, it may be expanded to a larger study to further assess the effect of LSTA1 on cancer cells for patients with locally advanced pancreatic ductal adenocarcinoma. Thus far, we have not been able to get immunotherapy to engage with pancreatic cancer cells. Early studies, however, indicate that LSTA1 changes the tumour environment to make the immune cells work more effectively. This mechanism decreases immunosuppressive Tregs (Regulatory T cells (Tregs) which are a specialised subpopulation of T cells that act to suppress immune response against the tumour) and increases the percentage of cancer-fighting CD8+ T cells within the tumour. (CD8+T cells can mount a response against pathogens by secreting cytokines and can defend against tumours by directly killing transformed cells.)
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Trial website
https://www.warpnine.org.au/ourprojectsandimpact
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Andrew Dean
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Address
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St John of God Subiaco Hospital. Suite C202, 12 Salvado Road, Subiaco WA 6008
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Country
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Australia
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Phone
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+61 8 9438 8554
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Fax
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Email
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adean@wamo.net.au
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Contact person for public queries
Name
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Meg Croucher
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Address
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Warpnine Incorporated: 35 Davenport Road, Booragoon, WA 6154
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Country
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Australia
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Phone
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+61 406 818 810
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Fax
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Email
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meg@warpnine.org.au
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Contact person for scientific queries
Name
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Meg Croucher
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Address
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Warpnine Incorporated: 35 Davenport Road, Booragoon, WA 6154
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Country
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Australia
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Phone
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+61 406 818 810
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Fax
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Email
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meg@warpnine.org.au
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification.
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When will data be available (start and end dates)?
Immediately following publication, no end date
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Available to whom?
Case-by-case basis at the discretion of Primary Sponsor
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Available for what types of analyses?
Any purpose
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How or where can data be obtained?
Access subject to approvals by Principal Investigator: adean@wamo.net.au
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
No additional documents have been identified.
Download to PDF