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Trial registered on ANZCTR


Registration number
ACTRN12618000354280
Ethics application status
Approved
Date submitted
23/02/2018
Date registered
8/03/2018
Date last updated
15/02/2019
Date data sharing statement initially provided
15/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase II randomised controlled trial to establish if LEE0011 (ribociclib) is effective in inhibiting the growth of prostate cancer cells.
Scientific title
LEEP study
A Randomised controlled Phase II trial of the pharmacodynamic effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer
Secondary ID [1] 293995 0
NIL
Universal Trial Number (UTN)
Trial acronym
LEEP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 306507 0
Condition category
Condition code
Cancer 305620 305620 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment with 400mg of oral (tablet) ribociclib daily as well as best supportive care for 21 days, prior to prostate surgery.
The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each patient. The Pharmacy will also maintain a record of drug receipt and drug destruction as appropriate including a pill count to assess compliance.
Intervention code [1] 300271 0
Treatment: Drugs
Comparator / control treatment
The control group will not receive treatment with the study drug LEE011 (ribociclib). These patients will receive standard clinical care as per the participating sites' current clinical practice for the treatment of patients with prostate cancer.
Control group
Active

Outcomes
Primary outcome [1] 304908 0
To determine the effect of LEE011 on tumour cell proliferation (frequency of a 50% reduction in the Ki-67 proliferation index from the pre-treatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy)
Timepoint [1] 304908 0
Post treatment
Secondary outcome [1] 343584 0
Determination of CDK4/6 inhibition
Assessed using a biopsy sample obtained at surgery. Cycle cell arrest will be measured by E2F expression as determined by immunohistochemistry,
Timepoint [1] 343584 0
Post treatment
Secondary outcome [2] 343585 0
Marker of apoptotic cell death
Assessed using a biopsy sample obtained at surgery. Determined by examining the cleaved caspase-3 staining in tumour cells. Cleaved caspase-3 expression will be assessed by immunohistochemistry.
Timepoint [2] 343585 0
Post treatment
Secondary outcome [3] 343586 0
PSA levels in tumour and blood
Composite outcome and assessed by immunoassay. Defined as change in serum PSA and tumour cells pre-treatment and post- treatment with LEE011
Timepoint [3] 343586 0
Post treatment
Secondary outcome [4] 343587 0
Pathological regression
Assessed by histopathology to determine decreased AR signalling as defined by cancer cell atrophy, decreased nuclear size, increased chromatin density and pale cytoplasm.
Timepoint [4] 343587 0
Post treatment
Secondary outcome [5] 343588 0
Adverse events
The proportion of patients experiencing Grade 3 and 4 toxicities as defined by the Common Toxicity Criteria v4. of the National Cancer Institute.
Timepoint [5] 343588 0
Within 7 days prior to randomisation, during treatment , after treatment and 30-42 days post treatment.

Eligibility
Key inclusion criteria
1. Males with localised prostate cancer and at least clinical stage T3a Or Gleason score of between 8 and 10 Or Preoperative PSA greater than or equal to 20 ng/ml AND planned for radical prostatectomy
2. Age 18 yrs or older
3. ECOG performance 0-1
4. Histological confirmation of prostate cancer via a pre-treatment diagnostic transrectal ultrasound (TRUS) biopsy.
5. Adequate bone marrow function with platelets greater than or equal to 100 x 109/L, neutrophils greater than or equal to 1.5 x 109/L and haemoglobin greater than or equal to 90 g/L;
6. Adequate hepatic function with serum total bilirubin less than or equal to 1.5 x upper limit of normal range and ALT/SGPT and SGOT/AST less than or equal to 2.5x upper limit of normal range (or < 5.0 times ULN with documented liver metastases), serum albumin > 25 g/L, alkaline phosphatase less than or equal to 5x upper limit of normal range, and INR less than or equal to 1.5
7. Adequate renal function (with calculated creatinine clearance >50 ml/min based on the Cockcroft-Gault method, 24hour urine or GFR scan) and serum creatinine less than or equal to 1.5 x Upper Limit of Normal range (ULN);
8. Serum calcium, potassium and magnesium within normal range or corrected with supplements
9. Study treatment both planned and able to start within 7 days of randomisation.
10. Willing and able to comply with all study requirements, including treatment and biospecimen collection
11. Signed, written informed consent (main study and biospecimen banking)
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Major surgery less than or equal to 2 weeks prior to enrolment or who have not recovered from side effects of such therapy. Transrectal ultrasound (TRUS) biopsy is not considered major surgery in this study.
2. Known hypersensitivity to the study drug or its excipients
3. Patients with known disorders due to a deficiency in bilirubin glucuronidation (e.g. Gilbert’s syndrome)
4. Diarrhoea greater than or equal to CTCAE grade 2
5. Impaired cardiac function, including any one of the following:
a) History (or family history) of long QT syndrome
b) Ribociclib should be avoided in patients who already have or who are at significant risk of developing QTc prolongation. This includes patients with:
• long QT syndrome
• Mean QTcF greater than or equal to 450 msec on baseline ECG
• uncontrolled or significant cardiac disease including recent myocardial infarction,
• congestive heart failure, unstable angina and bradyarrhythmias
• electrolyte abnormalities

c) History of clinically manifested ischemic heart disease less than or equal to 6 months prior to study start
d) History of heart failure or left ventricular (LV) dysfunction (LVEF less than or equal to 50%)
e) Clinically significant ECG abnormalities
f) History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes
g) Other clinically significant heart disease (e.g. uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
h) Clinically significant resting bradycardia (< 50 beats per minute)
i) Patients who are currently receiving treatment with any medication which has a relative risk of prolonging the QTcF interval or inducing Torsades de Pointes and cannot be discontinued or switched to an alternative drug prior to commencing start of treatment.
j) Obligate use of a cardiac pacemaker
6. Patients who have received prior antineoplastic therapy for advanced disease.
7. Prior treatment with an CDK4/6 inhibitor
8. Patients receiving chronic or high dose corticosteroids therapy (Inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed)
9. Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated.
10. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.

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



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Pharmacodynamics
Statistical methods / analysis
A two-stage design is used to determine the sample size to evaluate the frequency of pharmacodynamic (PD) responses in treated patients. A response is defined as 50% or greater decrease in Ki-67 expression in the paired prostate biopsy baseline sample compared with the radical prostatectomy sample.
With 95% confidence and a power of at least 90%, 37 patients will be sufficient to exclude an uninteresting PD response rate of 10% in favour of a more clinically interesting rate of 30%.
Ten untreated men will be enrolled in the control group to provide estimates of PD biomarkers as a basis for biological comparison giving a total sample size of 47 patients. It is anticipated that at least 33 patients in the treated cohort will be evaluable for response at study completion.
Analysis of efficacy endpoints (i.e., response, biomarkers) will include only evaluable patients.
Analysis of safety endpoints (i.e., toxicity) will be according to treatment received, including only patients who received at least 1 dose of the experimental treatment. Where appropriate p-values will be two tailed. A nominal significance level of 0.05 will be applied.

Analysis will be performed when evaluable tissue is available from 22 participants treated with LEE011 and at study completion.

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 in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 13159 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 25714 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 298623 0
Government body
Name [1] 298623 0
Cancer Australia
Address [1] 298623 0
300 Elizabeth St,
Surry Hills NSW 2010
Country [1] 298623 0
Australia
Primary sponsor type
Hospital
Name
University of Sydney
Address
Level 6, Jane Foss Russell Building G02, The University of Sydney, NSW 2006
Country
Australia
Secondary sponsor category [1] 297788 0
None
Name [1] 297788 0
Address [1] 297788 0
Country [1] 297788 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299583 0
St Vincent's Health Network
Ethics committee address [1] 299583 0
390 Victoria St,
Darlinghurst NSW 2010
Ethics committee country [1] 299583 0
Australia
Date submitted for ethics approval [1] 299583 0
31/08/2017
Approval date [1] 299583 0
08/12/2017
Ethics approval number [1] 299583 0

Summary
Brief summary
This study aims to examine the effect of a medication called Ribociclib on human prostate cancer

Who is it for?
You may be eligible for this study if you are older than 18 years and have localised prostate cancer with a planned radical prostatectomy.

Study details
Participants will be assigned by chance to either continue normal care or take a tablet of the study medication (in addition to the usual care) for the 21 days leading up to their prostatectomy. At each study visit participants will have various assessments such as blood testing, urine testing, scans, and questionnaire completion. A sample of prostate tissue will also taken during surgery.

It is hoped this research will help demonstrate the activity of this medication against prostate cancers, and lay the groundwork for more trials using this drug.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80918 0
Prof Lisa Horvath
Address 80918 0
119-143 Missenden Road
Camperdown NSW 2050

PO BOX M33 Missenden Road NSW 2050
Country 80918 0
Australia
Phone 80918 0
+61 2 85140142
Fax 80918 0
Email 80918 0
lisa.horvath@lh.org.au
Contact person for public queries
Name 80919 0
Ms LEEP Trial Coordinator
Address 80919 0
NHMRC Clinical Trials Centre
Lifehouse, Level 6
119–143 Missenden Road
Camperdown NSW 2050

Locked bag 77, Camperdown NSW 1450,
Country 80919 0
Australia
Phone 80919 0
+61 2 9562 5000
Fax 80919 0
Email 80919 0
leep@ctc.usyd.edu.au
Contact person for scientific queries
Name 80920 0
Prof Lisa Horvath
Address 80920 0
119-143 Missenden Road
Camperdown NSW 2050

PO BOX M33 Missenden Road NSW 2050
Country 80920 0
Australia
Phone 80920 0
+61 2 85140142
Fax 80920 0
Email 80920 0
lisa.horvath@lh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not currently planned and participant consent will be required.
What supporting documents are/will be available?
No other documents available
Summary results
No Results