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Trial registered on ANZCTR


Registration number
ACTRN12620001286932
Ethics application status
Approved
Date submitted
24/08/2020
Date registered
27/11/2020
Date last updated
27/11/2020
Date data sharing statement initially provided
27/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the effect of a virus-based immunotherapy as a pre-surgical treatment for prostate cancer
Scientific title
Neoadjuvant Study of the effect of Intratumoural and Intravenous Pexastimogene Devacirepvec (Pexa-Vec) on CD8-based anti-tumour response in Prostate Cancer Prior to Radical Prostatectomy
Secondary ID [1] 302060 0
Nil
Universal Trial Number (UTN)
Trial acronym
IMPROVE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 318660 0
Condition category
Condition code
Cancer 316679 316679 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: MRI-guided intratumoural (IT) Pexastimogene Devacirepvec (Pexa-Vec) (1x109 PFU) x 1 dose (Day 1). Radical prostatectomy will be performed 29-43 days following the IT injection. The MRI-guided injection will be performed by a specialised radiologist with previous experience and training in this procedure. Overall study duration for participants in this arm is 119-133 days.
Arm 2: MRI-guided intratumoural Pexastimogene Devacirepvec (Pexa-Vec) (1x109 PFU) x 2 doses (Day 1, 15). Radical prostatectomy will be performed 43-57 days after the first IT injection. The MRI-guided injection will be performed by a specialised radiologist with previous experience and training in this procedure. Overall study duration for participants in this arm is 133 - 147 days.
Arm 3: Systemic intravenous (IV) infusion Pexastimogene Devacirepvec (Pexa-Vec) (1x109 PFU) x 2 doses (Day 1, 8). The IV infusion will be performed by a medical oncologist and clinical research coordinator. Radical prostatectomy will be performed 36-50 days after the first IV infusion. Overall study duration for participants in this arm is 126-140 days.
For all arms of the study adherence to the intervention will be monitored by the Data and Safety Monitoring Committee and central medical review of source documents. Laboratory tests and clinical reviews will be performed 7 days after each treatment.
Intervention code [1] 318362 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324804 0
Composite primary outcome - evaluate the effect of neoadjuvant treatment with Intratumoural (IT) Pexa-Vec oncolytic virus on CD8-based anti-tumour response in prostate cancer.
Defined as the proportion patients with a greater than or equal to 30% increase in the proportion of CD8+ (and/or CD45RO+) T-cells in the radical prostatectomy specimen compared to that of the baseline prostate biopsy.
Timepoint [1] 324804 0
Composite primary outcome 1 assessed:
1) During the Treatment Phase - Fresh tumour biopsy at screening for cohorts 1 and 2 patients only prior to the first IT injection.
-Fresh tumour Biopsy collected in cohort 2 patients only at the time of the second IT injection.
2) At time of surgery 29 – 57 days after the completion of Pexa-Vec treatment.
Primary outcome [2] 324805 0
Composite primary outcome - evaluate the effect of neoadjuvant treatment with intravenous Pexa-Vec oncolytic virus on CD8-based anti-tumour response in prostate cancer.
Defined as the proportion patients with a greater than or equal to 30% increase in the proportion of CD8+ (and/or CD45RO+) T-cells in the radical prostatectomy specimen compared to that of the baseline prostate biopsy.
Timepoint [2] 324805 0
Composite primary outcome 2 assessed:
1) At time of surgery 36 – 50 days after the completion of Pexa-Vec treatment.
Primary outcome [3] 324806 0
To assess the safety and tolerability of neoadjuvant treatment with IT and IV Pexa-Vec oncolytic virus in patients undergoing radical prostatectomy.

Defined as the proportion of patients who develop one of the following during the treatment and follow up periods:
- Dose-limiting toxicity (DLS) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5).
DLS is defined as one of the following toxicities occurring during the first 28 days following the initial Pexa-Vec oncolytic virus injection in cohort 1 and 28 days after the second Pexa-Vec oncolytic virus IT injection/IV infusion in cohort 2 and 3:
• Grade 4 hematological toxicity lasting greater than or equal to 7 days except:
- Grade 4 lymphopaenia without clinically relevant sequelae
- Grade 4 thrombocytopaenia not associated with a clinically significant bleeding event
• All Grade 3 and Grade 4 non-haematologic toxicity that represent a 2-grade increase
over baseline except:
- Grade 3 flu-like symptoms (specifically fatigue, malaise, headache, and myalgia)
lasting <14 days
- Grade 3–4 fever lasting <3 days
- Grade 3 hypotension lasting <24 hours
- Grade 3 nausea, vomiting and diarrhea lasting <7days
- Grade 3 hypothyroidism responsive to hormone therapy
- Grade 3 hyponatraemia without clinical significance
- Grade 3–4 non-haematologic toxicity without clinical significance (e.g., transient,
asymptomatic elevation of amylase or lipase)
• Any Grade 3 or Grade 4 non-haematologic laboratory value if:
- The abnormality leads to hospitalization and requires active intervention
• Grade 3 or greater cardiac toxicity that does not decrease to a Grade 1 event 72 hours
after initiation of maximal supportive care
• Grade 3 and Grade 4 thrombocytopenia with clinically-significant bleeding associated
with Pexa-Vec
• Grade greater than or equal to 3 febrile neutropenia
a. If Grade 3, the event must (in the judgement of the Investigator) be clinically
significant and require intervention (e.g. G-CSF, antibiotic therapy) for resolution of
the event
• Grade 5 toxicity
Assessed using blood tests, physical examination and self reporting.

- Surgical complication of interest
Surgical complications will be assessed according to the Clavien-Dindo classification. A SCOI will be defined as one of the following events occurring at the time surgery or during the following 30 days following surgery:
• Inability to complete radical prostatectomy
• Rectal injury
• Ureteric injury
• Significant blood loss requiring blood transfusion
• Any surgical difficulty or complication which in the opinion of the operating surgeon
may be related to prior PEXA-Vec treatment

- Adverse event
Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5).

- Serious adverse event
Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5).
Timepoint [3] 324806 0
DLS - Assessment during the Treatment Phase - day 1, 2, 8, 9, 15, 16 and 22 and during surgery, 14 days, 30 days and 90 days post surgery.

SCOI - Assessed during surgery, 14 days, 30 days and 90 days post surgery.
Secondary outcome [1] 385789 0
To assess changes within the tumour microenvironment in radical prostatectomy specimens following treatment with IT or IV Pexa-Vec. Assessed by histological examination of fresh and stained prostate specimens following treatment with IT or IV Pexa-Vec.
Timepoint [1] 385789 0
1) During the Treatment Phase - Fresh tumour biopsy at screening for cohorts 1 and 2 patients
only prior to the first IT injection.
-Fresh tumour Biopsy collected in cohort 2 patients only at the
time of the second IT injection.
2) At time of surgery in all cohorts 29 – 57 days after the completion of Pexa-Vec treatment

Eligibility
Key inclusion criteria
1. Patient has provided written informed consent
2. Patients with histologically confirmed prostate adenocarcinoma
3. Age greater than or equal to 18 years
4. Suitable for radical prostatectomy in the opinion of the treating surgeon, following results of all screening investigations, including PSMA PET/CT scan
5. Disease detectable on MRI
6. Patient has adequate organ function within 7 days prior to registration as defined as:
White blood cell count (WCC) greater than or equal to 2 x 109/L
Absolute neutrophil count (ANC) greater than or equal to 1 x 109/L
Haemoglobin greater than or equal to 90 g/L
Platelet count greater than or equal to 100 x 109/L
Activated partial thromboplastin time (aPTT) less than or equal to 1.5 ULN
International Normalized Ratio (INR) less than or equal to 1.5 ULN
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x ULN unless liver metastases are present, in which case it must be less than or equal to 5 x ULN
Serum sodium 130-150mmol/L
Serum potassium 3.0-5.5mmol/L
Serum Corrected Calcium 2.0-2.9 mmol/L
Serum Creatinine less than or equal to 1.5 ULN or estimated glomerular filtration rate greater than 30mL/min/1.73m2
Oxygen saturation (SaO2) by pulse oximetry greater than 90% at rest
7. For patients who are sexually active with partners of childbearing potential: willing to use double barrier contraception method for at least 6 weeks after each treatment of Pexa-Vec
8. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations during both the treatment and follow-up phases
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior anti-cancer therapy for prostate cancer
2. High volume metastatic disease on imaging including PSMA PET/CT as defined by
one or more of the following criteria:
a. The presence of visceral metastases
b. greater than or equal to 4 bone lesions, including greater than or equal to 1 beyond the vertebral bodies and pelvis
3. Low-risk prostate cancer as defined by all of the following criteria
a. PSA < 20ng/ml
b. Gleason score 3+4=7 or equal to or less than 6
c. Clinor equal toical stage < T2c

4. Known immunodeficiency due to underlying illness (e.g., human immunodeficiency
virus [HIV] / acquired immune deficiency syndrome [AIDS]) and/or long-term
immune-suppressive medication including high-dose corticosteroids (defined as >10
mg/day prednisone or equivalent)
5. Known myeloproliferative disorders requiring systemic therapy
6. History of severe inflammatory or exfoliative skin condition (e.g. eczema or ectopic
dermatitis) requiring systemic therapy
7. Tumour in location that would potentially result in significant clinical adverse effects if post-treatment tumour swelling were to occur
8. Tumour invading a major vascular structure or other key anatomical structure
9. Severe or unstable cardiovascular disease, including but not limited to significant
coronary artery disease (e.g., myocardial infarction or other coronary artery disease
requiring angioplasty or stenting) or congestive heart failure within the preceding 12
months
10. Inability to suspend treatment with anti-hypertensive medication (including but not
limited to: diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors,
aldosterone antagonists, etc.) for 48 hours prior to and 48 hours after all Pexa-Vec
treatments
11. Use of anti-viral medications
12. Use of anti-platelet, or anti-coagulation medication that cannot be safely suspended
prior to IT injections
13. Medical conditions that place the patient at risk should tachycardia, hypotension or
volume loading occur during or following treatment with Pexa-Vec
14. Experienced a severe systemic reaction or side-effect as a result of a previous
smallpox vaccination
15. Other medical condition or laboratory abnormality or active infection that in the
judgment of the Investigator may increase the risk associated with study participation
or may interfere with interpretation of study results and/or otherwise make the patient
inappropriate for entry into this study
16. Prior malignancy except for cancer from which the patient has been disease-free for 3
years, or the following: adequately treated basal or squamous cell skin cancer, in situ
carcinoma (including cervical, breast and superficial bladder cancer)
17. Prior or planned organ transplant
18. Use of interferon/pegylated interferon (PEG-IFN) or ribavirin that cannot be
discontinued within 14 days prior to any Pexa-Vec dose
19. Known active Hepatitis B or Hepatitis C
20. Patients must not receive live vaccines, other than Pexa-Vec, within 30 days of
planned start of Pexa-Vec, during the study, and for a minimum of 15 weeks after the
last dose of Pexa-Vec
21. Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural
effusions
22. Inability to avoid direct physical contact with household contacts who are at high risk if
exposed to Pexa-Vec. High risk patients include any of the following:
a. pregnant or breastfeeding women
b. children <12 months of age
c. immunocompromised individuals (e.g., organ transplant recipients, HIV-positive
individuals, or those receiving chronic immunosuppressive medication)
d. individuals with ongoing severe inflammatory skin condition requiring medical
treatment or history of severe eczema requiring medical treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Recruitment to each cohort will occur in a consecutive manner, with each cohort completing recruitment and ensuring safety, prior to commencement of recruitment to the next cohort. The first cohort to be evaluated will be cohort 1 and will follow a 3 + 3 + 4 recruitment strategy. Recruitment decisions will be made by the Safety Monitoring Committee.

Dose Limiting Toxicities (DLTs) and Surgical Complications of Interest (SCOI) will be monitored over the first 28 days of treatment for DLTs and during the 30 days post-surgical period for SCOIs. After each group of patients within each cohort complete both observation periods, the SMC will meet and review the available safety and toxicity information to determine if recruitment of the next group of patients is to continue.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Co-primary endpoints will be reported using descriptive statistics. The incidence of adverse events, including serious adverse events will be calculated for each cohort.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17308 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 17309 0
Frankston Hospital - Frankston
Recruitment hospital [3] 17310 0
Southwest Health Care - Warrnambool - Warrnambool
Recruitment hospital [4] 17311 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [5] 17312 0
Western Hospital - Footscray - Footscray
Recruitment hospital [6] 17313 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 31034 0
3050 - Parkville
Recruitment postcode(s) [2] 31035 0
3199 - Frankston
Recruitment postcode(s) [3] 31036 0
3280 - Warrnambool
Recruitment postcode(s) [4] 31037 0
3084 - Heidelberg
Recruitment postcode(s) [5] 31038 0
3011 - Footscray
Recruitment postcode(s) [6] 31039 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 306494 0
Charities/Societies/Foundations
Name [1] 306494 0
Movember
Address [1] 306494 0
PO Box 60
East Melbourne
VIC 8002
Country [1] 306494 0
Australia
Funding source category [2] 306501 0
Government body
Name [2] 306501 0
Medical Research Future Fund
Address [2] 306501 0
Department of Health
GPO Box 9848
Canberra ACT 2601
Country [2] 306501 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
Grattan St Parkville Vic 3052
Country
Australia
Secondary sponsor category [1] 307020 0
None
Name [1] 307020 0
Address [1] 307020 0
Country [1] 307020 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306687 0
Melbourne Health HREC
Ethics committee address [1] 306687 0
Grattan St Parkville Vic 3052
Ethics committee country [1] 306687 0
Australia
Date submitted for ethics approval [1] 306687 0
10/06/2020
Approval date [1] 306687 0
16/09/2020
Ethics approval number [1] 306687 0

Summary
Brief summary
The purpose of this study is to learn whether injecting Pexa-Vec directly into the prostate cancer or into the blood stream is a safe and useful treatment for patients with prostate cancer, before they undergo standard surgery to remove the prostate gland.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, have been recently diagnosed with prostate cancer and you haven't received any previous cancer treatments, including surgery, androgen deprivation therapy, chemotherapy or radiotherapy.

Study details
Participants in this study will have a small sample of prostate tissue (biopsy) taken before they receive any treatment. The first 10 participants will have a single dose of Pexa-Vec modified viral treatment injected directly into their prostate gland while they are in an MRI scanner, at least 4 weeks prior to prostate removal surgery. The second 10 participants will have two doses of Pexa-Vec treatment injected directly into their prostrate gland while they are in an MRI scanner, the first dose will be 6 weeks prior to surgery and the second dose at least 4 weeks prior to surgery. The last 10 participants will have two doses of Pexa-Vec treatment injected into their blood stream, the first dose will be at least 5 weeks prior to surgery and the second dose at least 4 weeks prior to surgery.

All participants will undergo prostate removal surgery as scheduled by their doctor and will be asked to attend a series of follow-up appointments for up to 90 days after surgery to discuss their health and any complications they might have had.

It is hoped this research may be used to improve health outcomes for future patients with prostate cancer by determining whether Pexa-Vec is safe and effective at changing the appearance of tumour and immune cells, while possibly reducing tumour cell growth prior to prostate removal surgery.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104678 0
Dr Niall Corcoran
Address 104678 0
Royal Melbourne Hospital
Grattan Street
Parkville VIC 3052
Country 104678 0
Australia
Phone 104678 0
+61 3 9342 7000
Fax 104678 0
Email 104678 0
niallmcorcoran@gmail.com
Contact person for public queries
Name 104679 0
Dr Niall Corcoran
Address 104679 0
Royal Melbourne Hospital
Grattan Street
Parkville VIC 3052
Country 104679 0
Australia
Phone 104679 0
+61 3 9342 7000
Fax 104679 0
Email 104679 0
niallmcorcoran@gmail.com
Contact person for scientific queries
Name 104680 0
Dr Niall Corcoran
Address 104680 0
Royal Melbourne Hospital
Grattan Street
Parkville VIC 3052
Country 104680 0
Australia
Phone 104680 0
+61 3 9342 7000
Fax 104680 0
Email 104680 0
niallmcorcoran@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All data generated from this study will remain confidential and no published report will contains any reference to patient names or patient identifiers.
What supporting documents are/will be available?
No other documents available
Summary results
No Results