Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma: a Phase II Trial (ANZUP 1601)

Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma



Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Oversight Info

Has Dmc


Is Fda Regulated Drug


Is Fda Regulated Device


Brief Summary

This Single-arm, multicentre, phase 2 trial aims determine the activity and safety of
pembrolizumab and denosumab in advanced clear cell renal cell carcinoma (ccRCC).

Detailed Description

Renal cell carcinoma (RCC) is the 9th most common cancer in Australia, the 10th most common
cancer in Western populations1. Approximately 75% of kidney cancers are clear-cell renal cell
carcinomas (ccRCC). Current treatments for metastatic ccRCC include VEGFR tyrosine kinase
inhibitors (TKIs) and mTOR inhibitors and while many patients benefit from first-line VEGFR
TKIs, progression is inevitable and these treatments remain palliative. Second-line VEGFR
TKIs and mTOR inhibitors have some benefit but in a smaller increment than first-line
treatment. ccRCC is highly immunogenic with benefit from adjuvant autologous vaccines,
high-dose IL2 in selected patients and spontaneous remissions seen in a fraction of patients.
Cytokine immunotherapy delivered durable complete responses in a subset of patients who
survived the very high toxicity of these agents, but use of cytokine immunotherapy is
uncommon in modern practice.

Preclinical data and case reports suggest that denosumab, an inhibitor of RANKL signalling,
might potentiate the anti-tumour effects of immunotherapy with pembrolizumab, an antibody
directed against PD-1, without overlapping toxicities.

This study aims to determine the activity and safety of pembrolizumab and denosumab in
advanced clear cell renal cell carcinoma (ccRCC).

Adults with unresectable or metastatic ccRCC progressing after treatment with a VEGFR TKI.
Key eligibility criteria include target lesion(s) according to RECIST 1.1, good performance
status (ECOG PS 0-2), no history of significant autoimmune disease, tumour sample available
(archival or recent biopsy), and no previous treatment with immunotherapy.

All participants will receive the study interventions of pembrolizumab and denosumab. All
participants will receive the study interventions of pembrolizumab and denosumab.
Pembrolizumab will be given every 3 weeks at a dose of 200mg and denosumab will be given on
day 1, day 8, day 22 and then every 21 days (3 weekly) thereafter as a single subcutaneous
injection. Treatment with pembrolizumab and denosumab will continue until evidence of
clinical progression or prohibitive toxicity, or withdrawal of consent, up to a maximum
duration of 2 years.

7- eligible participants will be recruited from 15 sites in Australia and New Zealand over a
2 year period.

Overall Status


Start Date


Completion Date


Primary Completion Date



Phase 2

Study Type


Primary Outcome


Time Frame

Objective tumour response
Through study completion, on average 3.5 years

Secondary Outcome


Time Frame

Progression-free survival (PFS)
6 months
Disease control rate (DCR)
6 months
Time to objective tumour response (OTR)
Through study completion, on average 3.5 years
Time to first skeletal related event (SRE)
Through study completion, on average 3.5 years
Frequency and severity of adverse events
From time of patient registration, until 100 days after the last dose of treatment
Frequency of treatment delays and discontinuation due to toxicity
From time of patient registration, until 30 days after the last dose of treatment





Intervention Type


Intervention Name


Pembrolizumab 200 mg IV every 3 weeks plus denosumab 120 mg SC on day 1, 8, 22 and then every 3 weeks with daily oral calcium and vitamin D

Arm Group Label

Pembrolizumab plus Denosumab

Other Name

Keytruda and Xgeva



Inclusion Criteria:

- Adults, aged 18 years and older, with histologically confirmed unresectable or
metastatic renal cell carcinoma with a clear cell component

- Disease progression during or after VEGFR TKI treatment

- At least 1 target lesion according to RECIST v1.1

- ECOG performance status of 0-2

- Adequate bone marrow function (done within 14 days prior to registration

- Haemoglobin ≥ 90g/L

- Platelet ≥ 75x109/L

- Neutrophil count ≥ 1.5x109/L

- Adequate liver function (done within 14 days prior to registration and with values
within the ranges specified below):

- Bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's

- AST or ALT ≤ 3.0 x ULN (or ≤ 5.0x ULN in the presence of liver metastases)

- Adequate renal function (done within 14 days prior to registration and with values
within the ranges specified below):

- Creatinine ≤ 1.5x ULN OR

- Creatinine clearance (CrCl) ≥ 30mL/min

- Serum calcium or albumin-adjusted serum calcium ≥2.0 mmol/L

- Tumour tissue available for tertiary correlative studies

- Willing and able to start treatment within 14 days of registration, and to comply with
all study requirements, including the timing and/or nature of the required treatment
and assessments

- Signed, written informed consent

Exclusion Criteria:

- Prior treatment with pembrolizumab, or with any other anti-PD-1, anti-PD-L1,
Anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting
T cell co-stimulation or immune checkpoint pathways

- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Any condition requiring systemic treatment with either corticosteroids (>10mg daily
prednisone or equivalent dose of alternative corticosteroid) or other
immunosuppressive medications within 14 days of pembrolizumab administration.
Intranasal, inhaled or topical steroids are permitted in the absence of active
autoimmune disease.

- Prior treatment with denosumab.

- Untreated brain or leptomeningeal metastases or current clinical or radiological
progression of known brain metastases, or requirement for steroid therapy for brain
metastases. Patients with treated brain metastases are eligible if they have been
stable and off steroids for ≥ 3 weeks.

- Prior allogeneic organ transplant, inflammatory bowel disease, pneumonitis,
tuberculosis, or primary immunodeficiency

- Active infection requiring systemic therapy within 14 days before the first dose of

- Receipt of live attenuated vaccination within 30 days of the planned first dose of

- Active dental or jaw condition that precludes administration of denosumab:

i) Significant dental/oral disease, including prior history or current evidence of
osteonecrosis/osteomyelitis of the jaw, or; ii) Active dental or jaw condition which
requires oral surgery, or; iii) Non-healed dental/oral surgery, or; iv) Planned
invasive dental procedures during the course of the study

- Clinically significant hypersensitivity to denosumab or any components of denosumab

- Targeted small molecule therapy, surgery or radiation therapy within 2 weeks before
registration, or persisting adverse event(s) of Grade 2 or more due to a previously
administered agent. Note that participants who have had recent major surgery must have
recovered adequately before registration.

- Life expectancy of less than 3 months.

- History of an active malignancy within the previous 5 years, except for locally
curable cancers that have been apparently cured, such as low-grade thyroid carcinoma,
prostate cancer not requiring treatment (Gleason grade ≤ 6), basal or squamous cell
skin cancer, superficial bladder cancer, melanoma in situ, or carcinoma in situ of the
prostate, cervix, or breast. Patients who have been free of other malignancies for ≥ 5
years prior to registration are eligible for this study.

- Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. -
Serious medical or psychiatric conditions that might limit the ability of the patient
to comply with the protocol

- Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal,
infertile, or use a reliable means of contraception. Women of childbearing potential
must have a negative pregnancy test done within 7 days prior to registration. Men must
have been surgically sterilised or use a (double if required) barrier method of
contraception. Subject is excluded if pregnant or breast feeding, or planning to
become pregnant within 5 months after the end of treatment. Female subject of child
bearing potential is excluded if they are not willing to use, in combination with her
partner, highly effective contraception during treatment and for 5 months after the
end of treatment.



Minimum Age

18 Years

Maximum Age


Healthy Volunteers


Overall Contact

Last Name

Simran Chawla








Northern Cancer Institute
Frenchs Forest New South Wales 2086 Australia
Last Name: Laurence Krieger
Email: [email protected]
Calvary Mater Newcastle
Newcastle New South Wales 2298 Australia
Last Name: Craig Dr Gedye
Email: [email protected]
St George
Sydney New South Wales 2229 Australia
Last Name: Carole Dr Harris
Email: [email protected]
Concord Repatriation General Hospital
Sydney New South Wales Australia
Last Name: Lili Truong
Email: [email protected]
Icon Cancer Care
Brisbane Queensland Australia
Last Name: Stephanie Airey
Email: [email protected]
Royal Brisbane and Womens hospital
Herston Queensland 4029 Australia
Last Name: Jeffrey Goh
Email: [email protected]
Flinders Medical Centre
Adelaide South Australia Australia
Last Name: Dania Ruminski-Smith
Email: [email protected]
Box Hill
Box Hill Victoria 3128 Australia
Last Name: Ian Prof Davis
Email: [email protected]
Monash Health
Melbourne Victoria Australia
Not yet recruiting
Last Name: Stephanie Kaladis
Email: [email protected]
Peter MacCallum Cancer Center
Melbourne Victoria Australia
Last Name: Courtney Thornley
Email: [email protected]

Location Countries



Verification Date


Lastchanged Date


Firstreceived Date


Responsible Party

Responsible Party Type


Has Expanded Access


Condition Browse

Secondary Id



Number Of Arms


Intervention Browse

Mesh Term



Arm Group

Arm Group Label

Pembrolizumab plus Denosumab

Arm Group Type



Pembrolizumab 200 mg IV every 3 weeks plus denosumab 120 mg SC on day 1, 8, 22 and then every 3 weeks with daily oral calcium and vitamin D, continued until disease progression or prohibitive toxicity

Firstreceived Results Date


Overall Contact Backup

Last Name

Margaret McJannett






Other Outcome


Identification of tumour markers to predict outcomes

Time Frame

Through study completion, on average 3.5 years


Identifying tissue and circulating biomarkers that are prognostic and predictive of response to treatment, safety and resistance to study treatment (associations of biomarkers with clinical outcomes).

Patient Data

Sharing Ipd


Ipd Description

All IPD that underlie results in a publication

Firstreceived Results Disposition Date


Study Design Info

Intervention Model

Single Group Assignment

Intervention Model Description

Single-arm, multicentre, phase 2 trial

Primary Purpose



None (Open Label)

Study First Submitted

September 7, 2017

Study First Submitted Qc

September 10, 2017

Study First Posted

September 12, 2017

Last Update Submitted

May 16, 2018

Last Update Submitted Qc

May 16, 2018

Last Update Posted

May 17, 2018 processed this data on May 17, 2018


Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.

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