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Trial registered on ANZCTR


Registration number
ACTRN12619001078145
Ethics application status
Approved
Date submitted
2/07/2019
Date registered
5/08/2019
Date last updated
5/08/2019
Date data sharing statement initially provided
5/08/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Novel treatment of patients with Advanced Cancers using a combination of commonly available, low cost oral medications.
Scientific title
Treatment of Patients with Advanced Cancer by Targeting Cancer Stem Cells Using Modulators of the Renin-­Angiotensin System.
Secondary ID [1] 297964 0
Nil known
Universal Trial Number (UTN)
U1111-1189-9570
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma, 312365 0
Metastatic Melanoma 312366 0
Oral cavity Squamous cell carcinoma 312367 0
Head and Neck skin Squamous cell carcinoma 312368 0
Condition category
Condition code
Cancer 310923 310923 0 0
Brain
Cancer 310924 310924 0 0
Malignant melanoma
Cancer 310925 310925 0 0
Other cancer types
Cancer 310926 310926 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an interventional study aimed at modulating the Renin angiotension system (RAS) using a cocktail of existing medications in common use. Many epidemiological studies have shown reduced incidence of cancer and improved survival of patients taking RAS modulators eg ßblocker, ATRB, ACE inhibitors (ACEi), Aspirin (a COX2 inhibitor) and Metformin. Cathepsin B expression is associated with higher tumour grades and reduced survival in patients with Oral cavity squamous cell carcinoma (OCSCC). Treatment of Curcumin (inhibitor of cathepsin B), improves survival of OCSCC patients. Combined use of Aspirin, Propranolol and Metformin to treat breast cancer has been recently proposed. Our study adds Curcumin, Cilazapril (an ACEi) or Losartan (an ATRB) and Aliskerin (a PRR blocker) to treat cancer.
All medications are taken orally and are escalated at the discretion of the study doctor. Patients are reviewed fortnightly after their initial acceptance onto the trial. To ensure patient's are compliant with taking the medication they are initially given only two weeks at a time of required medications with a coloured chart of what the medications look like and when to take them. Patient's are advised to have a support person to assist with taking the medications accurately. The patient's verbal information regarding any side effects, as well as physical responses such as Blood pressure, pulse and physical examination by the study doctor will determine whether the medication will be escalated. Each oral medication stays the same or is escalated over a 3 month period and adjusted according to the patients responses.
Aliskerin (oral) 150mgs once a day (stays the same throughout trial (day 1-36 months).
Asprin (oral) 100mgs once a day (stays the same throughout trial (day 1-36 months).
Celecoxib(oral) 200mgs once a day (stays the same throughout trial (day 1-36 months).
Curcumin with Piperine 1000mgs (oral) twice a day (stays the same throughout trial (day 1-36mths).
Omeprazole 20mgs (Oral) daily (day 1-36 months).
Metformin (Oral) escalates from 250mgs daily (day 1 for 14), 250mgs twice a day for 14 days, 500mgs morning and 250mgs at night for 14 days, finally 500mgs twice daily for duration of the study.
Propranolol(Oral)escalates from 40mgs twice daily(commenced week 2 for 14 days), 80mgs morning and 40mgs at night from week 4 for duration of study.
Cilazapril (Oral)escalates from 1.25mgs once a day from week 6 for 14 days, 2.5mgs from week 8 for 14 days, 5mgs from week 10 for duration of study.
Losarten (Oral)escalates from 50mgs once a day(week 6 for 14 days)50mgs twice a day(8 to 10 weeks) to 50mgs three times a day for the duration of the study.(this drug is the alternative if Cilazapril not tolerated).
Baseline scan and bloods are taken and repeated at intervals as per protocol approved by HDEC. The overall observation period is 36 months or until the patient exists the study through choice or can no longer continue due to general decline.
Intervention code [1] 314188 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319748 0
Change in quality of life will be measured.
Measured using EORTC QLQ-C30 (universal),EORTC QLQ-BN20,
Karnofsky, FET PET/CT scan
Timepoint [1] 319748 0
Baseline-prior to commencement of intervention
8 weeks-post commencement of intervention,
4 months-post commencement of intervention,
6 months-post commencement of intervention,
8 months-post commencement of intervention,
10 months-post commencement of intervention,
12 months-post commencement of intervention,
14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 months-every 2 months post intervention to end point at 36 months
FET PET/CT scan
1-2 weeks before treatment/acceptance onto trial,
3 months-post commencement of intervention
6 months- post commencement of intervention
12 months- post commencement of intervention
Other scans as required. i.e., the patient has improved or is stable when compared to their baseline state.
Primary outcome [2] 319749 0
Slowing the progression of cancers assessed by FET/PET scans
Timepoint [2] 319749 0
Baseline before intervention, 3 months post commencement and on full intervention medications.
6 months post commencement and on full intervention of medications.
12 months- post commencement and on full intervention of medications
Other scans as required. i.e., the patient has improved or is stable when compared to their baseline state.

Secondary outcome [1] 372603 0
As these patients have a terminal cancer and are deemed not to survive, assessments will be carried out at each clinic appointment. Patients are followed up with their GP's in between study visits. Progression notes from the GP are forwarded to study Doctor at regular intervals.
Timepoint [1] 372603 0
Baseline appointment prior to commencement of intervention
Fortnightly from baseline to end of month 3, then every 2 months until 36 months post intervention.

Eligibility
Key inclusion criteria
Patients with the types of cancer listed below who have exhausted conventional treatment options where further conventional treatment has a low prospect of a beneficial outcome.
They will have a Kanofsky score of at least 60 and good performance status.
Patients may be undergoing palliative care.
OCSCC-(Oral cavity squamous cell carcinoma)
HNsSCC-(Head and Neck skin squamous cell carcinoma)
GBM-(Glioblastoma)
MM-(metastatic melanoma)
Minimum age
16 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria
(1)Cancer patients who have a life expectancy of less than 6 months and/or the state of terminal decline;
(2)Patients with a Karnovsky score <60
(3)Patients who have failed the reasonable general health assessment and deemed not to have good performance status;
(4)Patients who are not motivated including noncompliance, e.g. continue to smoke, abuse
alcohol
(5)Children less than 16 years
(6)Patients who are older than 80 years;
(7)Patients who are not competent to give consent personally
(8)Patients who are currently participating in or have received an investigational treatment within 30 days or 5 half­lives of the investigational drug, whichever is longer
(9)Presence of contraindications to any of the study treatments including asthma/CORD, drug allergies, medications that interfere with the treatment
(10)Presence of significant immune compromise including HIV infection, organ transplant patients on immunosuppression, chronic lymphocytic leukaemia
(11)Patients who are pregnant or plan to be pregnant
(12) Patients with renal impairment
(13)Presence of a terminal organ failure
(14)A second cancer that is not expected to impact on the results of the study.
(15)Diabetic patients requiring treatment except those treated with Metformin.
(16) Connective tissue disorders.
(17)Patients who are on medications that increase renin levels such as calcium channel blockers and dieuretics.

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
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
This study will use a before and after comparison (pre-test versus post-test) of the data using the patient as their own controls. The most powerful statistical test for this purpose is the t-test for related samples. The sample size calculation for this method requires the following parameters:
a = The threshold probability for rejecting the null hypothesis (Type I Error) 0.050 for a two-sided test. But as the patients are not expected to get better a one-sided value is used 0.100. ß = The probability of failing to reject the null hypothesis (Type II Error).
E = The Effect size. A common convention is to use the standardised value 0.500 where this is unknown.
S is the Standard Deviation of the outcome in the population obtained from survival studies. Here it is 2.000 (estimated from published survival studies).
S(?) = The Standard Deviation of the CHANGE in the outcome.
Where this is unknown it is found using the formula S(?) = S(2(1-r within)1/2 Here 2.000 is substituted for S, and rwithin is 0.875. The result is A (= 1.000).
The standard normal deviate for a is Za = 1.645, and for ß = Zß = 0.842.
When A =1.000 and B = (Za + Zß)2 = 6.183 & C = (E/S(?))2 = 0.250.
Then AB/C = 24.73 (25) cases for the present study. (For a two-sided test the sample would have required 31 cases)47, 48.
Any quantifiable measure will be tested using the t-test for related samples. This includes results from the Quality of Life questionnaires, performance status of the patients, tumour number and size and activity (measured by PET CT) of the primary site and/or metastases.


Recruitment
Recruitment status
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 outside Australia
Country [1] 21402 0
New Zealand
State/province [1] 21402 0

Funding & Sponsors
Funding source category [1] 302483 0
Other Collaborative groups
Name [1] 302483 0
Gillies McIndoe Research Institute
Address [1] 302483 0
PO Box 7184
Newtown

Wellington
6242
New Zealand
Country [1] 302483 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
Gillies McIndoe Research Institute
Address
Gillies McIndoe Research Institute
PO Box 7184
Newtown

Wellington
6242
New Zealand
Country
New Zealand
Secondary sponsor category [1] 302382 0
None
Name [1] 302382 0
None
Address [1] 302382 0
None
Country [1] 302382 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303145 0
Central Health and Ethics Disability Committee
Ethics committee address [1] 303145 0
Ministry of Health
PO box 5013
Wellington
6011
Ethics committee country [1] 303145 0
New Zealand
Date submitted for ethics approval [1] 303145 0
11/01/2017
Approval date [1] 303145 0
14/03/2017
Ethics approval number [1] 303145 0
17/CEN/8

Summary
Brief summary
Patients with advanced cancer that have relapsed following conventional treatments, and for whom no other options are available or further conventional treatment has a low prospect of beneficial outcomes and/or unacceptable to the patients, will be recruited for this study. This proposed study is based on
:(1)the discovery of cancer stem cells(CSCs)–the proposed origin of cancer, and
(2)their inbuilt common regulatory system – the reninangiotensin system (RAS), in many types of cancers;
(3)numerous epidemiological studies showing reduced incidence of cancer, and significantly improved cancer survival, in patients who take medications that modulate the RAS. The proposed treatment targets the CSCs by modulating the RAS using a cocktail of simple and low cost medications that are commonly used, often in combinations, for treating other conditions. The aim is to control, slow the progression and cause regression of the cancer, so as to improve the quality of life and/or survival of the cancer sufferers
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92630 0
Dr Swee Tan
Address 92630 0
Gillies McIndoe Research Institute
PO Box 7184
Newtown
Wellington
6242
New Zealand
Country 92630 0
New Zealand
Phone 92630 0
+64 216 31000
Fax 92630 0
Email 92630 0
swee.tan@gmri.org.nz
Contact person for public queries
Name 92631 0
Mrs Frances Fitzjohn
Address 92631 0
Gillies McIndoe Research Institute
PO Box 7184
Newtown
Wellington
6242
New Zealand
Country 92631 0
New Zealand
Phone 92631 0
+64 212407073
Fax 92631 0
Email 92631 0
frances.fitzjohn@gmri.org.nz
Contact person for scientific queries
Name 92632 0
Dr Swee Tan
Address 92632 0
Gillies McIndoe Research Institute
PO Box 7184
Newtown
Wellington
6242
New Zealand
Country 92632 0
New Zealand
Phone 92632 0
+64 216 31000
Fax 92632 0
Email 92632 0
swee.tan@gmri.org.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the Individual participant data (de-identified) collected during the trial will be shared.
When will data be available (start and end dates)?
Data availability will be after publication of outcomes (and any protection of IP that is thought necessary). End date of study at this stage is 01/05/2022. This may be extended depending on whether enough participants have been collected in the 3 year time frame. No specific end date has been decided on for when data will be available.
Available to whom?
Anyone who wishes to access the data
Available for what types of analyses?
No restrictions on analyses are predicted
How or where can data be obtained?
Requests for data will have indication of what data is required
Requests to be made to the Principal Investigator via email or website
https://www.gmri.org/
Dr Swee Tan
Gillies McIndoe Research Institute
PO Box 7184
Newtown
Wellington
6242
New Zealand
What supporting documents are/will be available?
Study protocol
Ethical approval
How or where can supporting documents be obtained?
Type [1] 2638 0
Study protocol
Citation [1] 2638 0
Link [1] 2638 0
Email [1] 2638 0
Other [1] 2638 0
Type [2] 2640 0
Ethical approval
Citation [2] 2640 0
Link [2] 2640 0
Email [2] 2640 0
Other [2] 2640 0
Summary results
No Results