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Trial registered on ANZCTR


Registration number
ACTRN12617000741381
Ethics application status
Approved
Date submitted
15/05/2017
Date registered
22/05/2017
Date last updated
10/12/2018
Date data sharing statement initially provided
10/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Nivolumab in renal transplant recipients with cancer
Scientific title
Nivolumab in renal transplant recipients with poor prognosis cancers - a safety study.
Secondary ID [1] 291936 0
Protocol CA209-993ISR
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Renal Transplant 303271 0
Cancer 303272 0
Condition category
Condition code
Renal and Urogenital 302698 302698 0 0
Kidney disease
Cancer 302699 302699 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This Phase 1, multicenter, open label, two tier safety study is designed to assess the safety of standard dosing of Nivolumab in kidney transplant patients with pretreated incurable cancer or defined metastatic solid tumours. Patient recruitment will be stratified by entry median fluorescent intensity (MFI) antibodies to donor antigens such that we envisage two tiers: patients at low immunological risk with no HLA donor specific antibodies; and intermediate immunological risk (HLA antibodies 600-4000 MFI). Nivolumab (3mg/kg) will be administered as an intravenous infusion over 60 minutes every 2 weeks (1 cycle) per cancer specific protocols and study treatment will continue as long as there is tumour response for up to 2 years. .
Intervention code [1] 298056 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302095 0
Rate of irretrievable renal graft rejection in transplant recipients with solid tumours not curable using standard treatment paradigms receiving a standard schedule of Nivolumab. Renal function will be measured and any rise in creatinine deemed to be significant by the treating physician will lead to renal transplant biopsy. Complete loss of kidney function with return to dialysis is the definition of irretrievable graft loss.
Timepoint [1] 302095 0
2-4 cycles of Nivolumab
Secondary outcome [1] 334740 0
To determine the safety (as per NCI Common Terminology Criteria for Adverse Events (v4.03: June 14, 2010)) of Nivolumab in recipients of renal transplants.
Timepoint [1] 334740 0
Up to 2 years
Secondary outcome [2] 334741 0
Tumour response to Nivolumab in patients with incurable, locally advanced or metastatic malignancy following failure of curative treatment tumours. Tumour must be known to be potentially responsive to Nivolumab as defined by Phase II and III studies. Tumour response defined by RECIST criteria.

Timepoint [2] 334741 0
Up to 2 years
Secondary outcome [3] 334742 0
Patient survival in patients treated with Nivolumab.
Timepoint [3] 334742 0
Up to 2 years
Secondary outcome [4] 334969 0
Renal allograft survival in patients treated with Nivolumab
Timepoint [4] 334969 0
2 years

Eligibility
Key inclusion criteria
*Patient has provided written informed consent prior to initiation of any study specific activities/procedures.
*Recipient of renal transplant aged 18 years or older more than 3 months post-transplant
*Recipients of multiple renal transplants will be allowed
*Incurable locally advanced or metastatic, histologically proven tumours, progressing on standard first line therapy or metastatic solid tumours requiring palliative treatment (the latter group of patients are not required to have had prior anti-cancer therapy) or in-operable tumours where standard curative treatment approaches will either have failed or are not applicable.
*ECOG 0-1 and 2 by discussion with medical monitor
*Disease that is measurable by RECIST
*Eligible tumour types include:
a. SCC of the skin
b. SCC of head and neck
c. Melanoma
d. Merkel Cell Carcinoma
e. NSCLC Lung cancer
f. Urothelial cancer
g. Colorectal cancer which is MSI-H
. h. Breast cancer (triple negative)
i. Any other solid tumour which is MSI-H
j. Any tumour which is deemed to be sensitive to PD-1 blockade
*Co-morbid conditions are stable
*Life expectancy >3 months
*Patient has adequate organ and bone marrow function within 14 days of study entry
a. Neutrophil count >1.5 x109/L
b. Platelets >100 x109/L
c. Hb >80g/L
d. Total bilirubin <1.5 upper limit of normal, (ULN)
e. ALT and AST <3.0 x ULN
f. Serum creatinine <1.5 x ULN
g. PT and APTT <1.3 x ULN
*Willing to stay on, restart or have no contraindications to immunosuppressive agents including calcineurin inhibitors, antiproliferative agents and prednisolone if deemed appropriate by the study investigators.
*For females of reproductive potential-negative pregnancy test prior to study entry and use of highly effective contraception
*For males of reproductive potential: use of condoms
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
An individual who meets any of the following criteria will be excluded from participation:
*Within 3 months of transplantation and at the time of initiation of Nivolumab.
*Unable to provide informed consent
*Not prepared or unable to re-join a renal dialysis program
*Unable to undertake monitoring for signs of rejection, toxicity or anti-tumour effect
*The patient has uncontrolled or significant intercurrent or recent illness including:
a) Auto-immune disorder or uncontrolled endocrinopathy
b) Cardiac disorder such as uncontrolled cardiac failure, unstable angina or NSTEMI or myocardial infarction, uncontrolled arrhythmia
c) Stroke or thromboembolic event within 3 months of study commencement
d) Active or uncontrolled severe infection
e) Active coagulopathy/bleeding diathesis
f) Cirrhosis, chronic active or untreated persistent hepatitis
* The patient is pregnant or lactating
* The patient doesn’t agree to use highly effective methods of contraception.
* Prisoners or subjects who are involuntarily incarcerated
* Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
* Donor specific antibody with MFI >4000 units

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)
Allocation is not concealed
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 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
With a sample size of 30 patients, we will consider a Simon’s two stage accrual process whereby accrual will be halted if we see greater than 2 allograft rejections amongst the first 15 patients and greater than 3 amongst the first 30 patients. Given these stopping thresholds, if the true underlying rate of allograft rejections is 0.07 then the overall probability of discontinuation after stage 2 of accrual is 20% and if the true underlying rate of allograft rejections is 0.24 then the overall probability of discontinuation after stage 2 of accrual is 95% However, since the original statistical analysis (defining minimal rejection rate and hypothesized rejection rates) there have been additional cases reports to further define rates of rejection. It is hoped that with careful patients selection and monitoring a rejection rate of 15% would be clinically acceptable and based on these data, greater than 2 rejections in the first 8 for each of the immunological tiers and a total of 8 rejections in the first 30 (for the combined low and intermediate risk groups) would be the stopping parameters.

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,QLD,SA,VIC
Recruitment hospital [1] 8013 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 8016 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 10441 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [4] 10442 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [5] 12691 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 15996 0
5000 - Adelaide
Recruitment postcode(s) [2] 15999 0
3168 - Clayton
Recruitment postcode(s) [3] 22146 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 22147 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 296443 0
Hospital
Name [1] 296443 0
Royal Adelaide Hospital Research Fund
Address [1] 296443 0
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [1] 296443 0
Australia
Primary sponsor type
Hospital
Name
Central Northern Adelaide Local Health Network, Royal Adelaide Hospital
Address
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country
Australia
Secondary sponsor category [1] 295395 0
None
Name [1] 295395 0
Address [1] 295395 0
Country [1] 295395 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297673 0
Royal Adelaide Hosptial
Ethics committee address [1] 297673 0
Royal Adelaide Hospital
North Terrace
SA5000
Ethics committee country [1] 297673 0
Australia
Date submitted for ethics approval [1] 297673 0
30/11/2016
Approval date [1] 297673 0
24/02/2017
Ethics approval number [1] 297673 0
HREC/16/RAH/508

Summary
Brief summary
The main focus of this study it to determine if giving immune activating anti-cancer therapy (Nivolumab) is safe in kidney transplant patients with incurable cancer.

Who is it for?
You may be eligible to join this study if you are a recipient of renal transplant (at least 3 months post- transplant) aged 18 years or above and have been diagnosed with an incurable cancer.

Study details
All study participants will receive Nivolumab (3mg/kg) as an intravenous infusion over 60 minutes every 2 weeks and study treatment will continue as long as there is clinical benefit up to 2 years.
Nivolumab is an antibody (a type of human protein) that is being tested to see if it will allow the body’s immune system to work against tumour cells. That is using the body’s immune reaction to destroy cancer cells.
Currently kidney transplant patients are excluded from clinical trials of this anti-cancer therapy - because they are taking anti-rejection medication. This trial is about trying to decide the balance between giving anti-rejection drugs and anti-cancer therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74770 0
Dr Robert Peter Carroll
Address 74770 0
Central Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road
Adelaide SA 5000
Country 74770 0
Australia
Phone 74770 0
+61 8 7074 4700
Fax 74770 0
+61 8 8429 6059
Email 74770 0
robert.carroll@sa.gov.au
Contact person for public queries
Name 74771 0
Dr Robert Peter Carroll
Address 74771 0
Central Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road
Adelaide SA 5000
Country 74771 0
Australia
Phone 74771 0
+61 8 7074 4700
Fax 74771 0
+61 8 8429 6059
Email 74771 0
robert.carroll@sa.gov.au
Contact person for scientific queries
Name 74772 0
Dr Robert Peter Carroll
Address 74772 0
Central Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road
Adelaide SA 5000
Country 74772 0
Australia
Phone 74772 0
+61 8 7074 4700
Fax 74772 0
+61 8 8429 6059
Email 74772 0
robert.carroll@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Phase 1 study-will review at end of study
What supporting documents are/will be available?
No other documents available
Summary results
No Results