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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
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Scientific title
A Phase I trial of Sodium Valproate/MetformIn Combination as neoadjuvant therapy for ProstatE canceR
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Secondary ID [1]
289745
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None
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Universal Trial Number (UTN)
U1111-1185-6959
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Trial acronym
VIPER 1 trial
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Prostate cancer
299592
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Condition category
Condition code
Cancer
299561
299561
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0
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Prostate
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
295383
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Treatment: Drugs
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Comparator / control treatment
No control group
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Control group
Uncontrolled
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Outcomes
Primary outcome [1]
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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.
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Assessment method [1]
299037
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Timepoint [1]
299037
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At the end of 4 weeks of commencement of study drug therapy
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Secondary outcome [1]
325938
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To evaluate PSA response using serum assay
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Assessment method [1]
325938
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Timepoint [1]
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Immediately prior to and 4 weeks of study treatment
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Secondary outcome [2]
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Incidence of positive surgical margins will be assessed by examination of the surgical specimen post radical prostatectomy
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Assessment method [2]
325969
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Timepoint [2]
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Following radical prostatectomy
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Secondary outcome [3]
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To evaluate Ki 67 response using immunohistochemistry in the biopsy specimen
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Assessment method [3]
326222
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Timepoint [3]
326222
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Ki 67 at the end of 4 weeks of study drug therapy will be compared with the baseline
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Secondary outcome [4]
326223
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Incidence of pathological response as assessed by examination of the surgical specimen post radical prostatectomy
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Assessment method [4]
326223
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Timepoint [4]
326223
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Following radical prostatectomy'
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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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Males
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Can healthy volunteers participate?
No
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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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
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Who is / are masked / blinded?
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Intervention assignment
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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.
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Phase
Phase 1
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Type of endpoint/s
Safety
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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
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/12/2016
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Actual
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
12
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
SA
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Recruitment hospital [1]
6241
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Flinders Medical Centre - Bedford Park
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Recruitment hospital [2]
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Repatriation Hospital - Daw Park
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Recruitment postcode(s) [1]
13663
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5042 - Bedford Park
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Funding & Sponsors
Funding source category [1]
294126
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Charities/Societies/Foundations
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Name [1]
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The Repat Foundation: Road Home Grant
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Address [1]
294126
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216 Daws Road,
Daw Park
South Australia 5041
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Country [1]
294126
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Australia
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Primary sponsor type
University
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Name
Flinders University
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Address
Flinders Drive, Bedford Park, South Australia - 5042
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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]
292958
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Address [1]
292958
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Country [1]
292958
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
295532
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Southern Adelaide Clinical Human Research Ethics Committee
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Ethics committee address [1]
295532
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Flinders Medical Centre
1 Flinders Drive,
Bedford Park,
South Australia - 5042
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Ethics committee country [1]
295532
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Date submitted for ethics approval [1]
295532
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23/07/2016
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Approval date [1]
295532
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13/09/2016
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Ethics approval number [1]
295532
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282.16
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Summary
Brief summary
The primary purpose of this trial is to evaluate the safety and tolerability of Metformin (MET) in combination with sodium valproate (VPA) for the treatment of prostate cancer.
Who is it for?
You may be eligible to participate in this trial if you are aged 18 or over and have been diagnosed with localised or locally advanced prostate cancer for which radical prostatectomy is planned within the next 6-8 weeks.
Study details
Participants enrolled in this trial will receive a combination of MET and VPA in increasing doses depending on the cohort they are enrolled in. The study drugs will be administered for a total of 4 weeks just prior to the planned surgery for removing the prostate
It is hoped that this trial will provide information on the optimal dose of MET plus VPA to administer to prostate cancer patients, which may be an effective treatment which is safe and tolerated by patients.
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Trial website
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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 Ganessan Kichenadasse
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Address
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Flinders Medical Centre/Flinders University
1 Flinders Drive,
Bedford Park,
South Australia - 5042
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Country
67650
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Australia
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Phone
67650
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+61 8 8204 6151
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Fax
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Email
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[email protected]
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Contact person for public queries
Name
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Ms Kelly Mead
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Address
67651
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Flinders Medical Centre/Flinders University
1 Flinders Drive,
Bedford Park,
South Australia - 5042
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Country
67651
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Australia
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Phone
67651
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+ 61 8 8204 6151
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Fax
67651
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Email
67651
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[email protected]
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Contact person for scientific queries
Name
67652
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Dr Ganessan Kichenadasse
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Address
67652
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Flinders Medical Centre/Flinders University
1 Flinders Drive,
Bedford Park,
South Australia - 5042
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Country
67652
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Australia
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Phone
67652
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+61 8 8204 6151
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Fax
67652
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Email
67652
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[email protected]
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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
Source
Title
Year of Publication
DOI
Embase
The combination of metformin and valproic acid induces synergistic apoptosis of prostate cancer cells via p53 activation and the intrinsic pathway.
2017
https://dx.doi.org/10.1158/1538-7445.AM2017-1062
N.B. These documents automatically identified may not have been verified by the study sponsor.
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