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Trial registered on ANZCTR


Registration number
ACTRN12616001021460
Ethics application status
Approved
Date submitted
23/07/2016
Date registered
2/08/2016
Date last updated
16/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Sodium Valproate/Metformin Combination therapy for prostate cancer
Scientific title
A Phase I trial of Sodium Valproate/MetformIn Combination as neoadjuvant therapy for ProstatE canceR
Secondary ID [1] 289745 0
None
Universal Trial Number (UTN)
U1111-1185-6959
Trial acronym
VIPER 1 trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate cancer 299592 0
Condition category
Condition code
Cancer 299561 299561 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Combination of sodium valproate and metformin will be administered as oral tablets.
Three dose levels of the drugs are planned. First level – a fixed dose of Met and VPA at 500 mg twice daily will be given to the participants. If no dose limiting toxicity is seen in this cohort I (N=3), after the 4 weeks of drug administration, participants will be next dosed at level 2 dosing where the starting dose is 500 mg twice daily for both drugs. In this cohort II (N=3), Met dose alone will be increased to 1000 mg twice daily from week 2 onwards while VPA dose will be maintained at 500 mg twice daily. If no dose limiting toxicity is seen in this cohort II, subjects will be dosed at next dose level. Subjects in this cohort III (N=6) will have both the drug doses increased from the starting dose of 500 mg twice daily to 1000 mg twice daily sequentially. Dose escalation will not proceed beyond the 1000 mg twice daily schedule. Participants in cohort I will receive 4 weeks on Met and VPA 500mg each twice daily; cohort II week 1 Met and VPA 500mg each twice daily then Met 1000mg and VPA 500mg twice daily from week 2 -4; cohort III week 1 Met and VPA 500mg each twice daily then Met 1000mg and VPA 500mg twice daily from week 2; then Met 1000 mg and VPA 1000 mg twice daily week 3-4. All study drugs will be ceased at least 48 hours but no more than 7 days prior to surgery. Participants will be requested to return any left over tablets.
Intervention code [1] 295383 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299037 0
To evaluate the safety of the combination of Metformin and VPA in men undergoing radical prostatectomy for prostate cancer.
Safety will be assessed using the common toxicity critieria (NCI-CTC v1.0) as well as physical examination and blood tests for organ function.
Timepoint [1] 299037 0
At the end of 4 weeks of commencement of study drug therapy
Secondary outcome [1] 325938 0
To evaluate PSA response using serum assay
Timepoint [1] 325938 0
Immediately prior to and 4 weeks of study treatment
Secondary outcome [2] 325969 0
Incidence of positive surgical margins will be assessed by examination of the surgical specimen post radical prostatectomy
Timepoint [2] 325969 0
Following radical prostatectomy
Secondary outcome [3] 326222 0
To evaluate Ki 67 response using immunohistochemistry in the biopsy specimen
Timepoint [3] 326222 0
Ki 67 at the end of 4 weeks of study drug therapy will be compared with the baseline
Secondary outcome [4] 326223 0
Incidence of pathological response as assessed by examination of the surgical specimen post radical prostatectomy
Timepoint [4] 326223 0
Following radical prostatectomy'

Eligibility
Key inclusion criteria
1 Patients must have histologically confirmed localized or locally advanced prostate cancer – Clinical stage T1c or T2 with high-grade disease (Gleason's 8-10) on initial biopsy, or clinical stage T2b-T2c with Gleason's grade >/= 7 and PSA > 10ng/ml.
2 Must be planned for radical prostatectomy within the next 6-8 weeks
3 No documented metastatic disease on CT or Bone scans. Prostate specific Membrane antigen (PSMA) PET scans allowed – but, not mandatory for establishing non-mestastatic disease
4 Age >18 years.
5 ECOG performance status <1
6 Life expectancy of greater than 12 months
7 Patients must have normal organ and marrow function
8 Not planned for Androgen deprivation therapy
9 Ability to understand and the willingness to sign a written informed consent document.
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1 Patients who have had chemotherapy or radiotherapy or metformin or sodium valproate
2 Patients may not be receiving any other investigational agents.
3 Patients with known metastases
4 History of allergic reactions attributed to compounds of similar chemical composition to the agents used in study.
5 Patients receiving any medications or substances that are inhibitors or inducers of CYP450 3A4 are ineligible. Lists including medications and substances known or with the potential to interact with CYP450 3A4 isoenzymes are provided in product information of the study drugs.
6 Past history of pancreatitis, extensive bowel resection, known urea cycle disorders or porphyria
7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
8 Patients with diabetes or known epilepsy

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
Who is / are masked / blinded?



Intervention assignment
Other design features
This study is a single arm Phase I trial evaluating the safety and tolerability of the combination of Metformin and VPA in men with non-metastatic prostate cancer who are planned to undergo radical prostatectomy.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Sample size for this study is as per any other Phase I trial with 3+3 design. A total of 12 subjects with 3 each in dosing level I and II while 6 in the dosing Level III is the expected sample size. If maximum tolerated dose (MTD) occurs at a lower dose than the expected 1000 mg twice daily each of MET and VPA, 6 other subjects will be evaluated at the same dose level where MTD occurred. No formal power calculation was performed

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 6241 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 6242 0
Repatriation Hospital - Daw Park
Recruitment postcode(s) [1] 13663 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 294126 0
Charities/Societies/Foundations
Name [1] 294126 0
The Repat Foundation: Road Home Grant
Country [1] 294126 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
Flinders Drive, Bedford Park, South Australia - 5042
Country
Australia
Secondary sponsor category [1] 292958 0
None
Name [1] 292958 0
Address [1] 292958 0
Country [1] 292958 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295532 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 295532 0
Ethics committee country [1] 295532 0
Date submitted for ethics approval [1] 295532 0
23/07/2016
Approval date [1] 295532 0
13/09/2016
Ethics approval number [1] 295532 0
282.16

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67650 0
Dr Ganessan Kichenadasse
Address 67650 0
Flinders Medical Centre/Flinders University
1 Flinders Drive,
Bedford Park,
South Australia - 5042
Country 67650 0
Australia
Phone 67650 0
+61 8 8204 6151
Fax 67650 0
Email 67650 0
Ganessan.Kichenadasse@flinders.edu.au
Contact person for public queries
Name 67651 0
Kelly Mead
Address 67651 0
Flinders Medical Centre/Flinders University
1 Flinders Drive,
Bedford Park,
South Australia - 5042
Country 67651 0
Australia
Phone 67651 0
+ 61 8 8204 6151
Fax 67651 0
Email 67651 0
Kelly.Mead@sa.gov.au
Contact person for scientific queries
Name 67652 0
Ganessan Kichenadasse
Address 67652 0
Flinders Medical Centre/Flinders University
1 Flinders Drive,
Bedford Park,
South Australia - 5042
Country 67652 0
Australia
Phone 67652 0
+61 8 8204 6151
Fax 67652 0
Email 67652 0
Ganessan.Kichenadasse@flinders.edu.au

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseThe combination of metformin and valproic acid induces synergistic apoptosis of prostate cancer cells via p53 activation and the intrinsic pathway.2017https://dx.doi.org/10.1158/1538-7445.AM2017-1062
N.B. These documents automatically identified may not have been verified by the study sponsor.