Renal Cell Carcinoma, Clear CellPhase 2KEYPADNCT03280667
Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma
A Phase 2 study testing Pembrolizumab plus denosumab in people with Renal Cell Carcinoma, Clear Cell and Metastatic Kidney Cancer, run by Australian and New Zealand Urogenital and Prostate Cancer Trials Group at 16 sites in Australia.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Cell Carcinoma, Clear Cell, Metastatic Kidney Cancer
- What is being tested?
- Pembrolizumab plus denosumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 59 participants
- Where
- 16 sitesAustralia
- Study dates
- 12 Dec 2017to 4 Jun 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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 syndrome
- 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
Who cannot join
- 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
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- Active infection requiring systemic therapy within 14 days before the first dose of pembrolizumab
- Receipt of live attenuated vaccination within 30 days of the planned first dose of pembrolizumab
- Active dental or jaw condition that precludes administration of denosumab:
- 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.
Trial locations and contacts
16 sites in 1 country.
16 sites in 1 country
Australia16 sites
Flinders Medical Centre
Adelaide, South Australia
Border Medical Oncology Research Unit
Albury, New South Wales, 2640
Sunshine Coast University Hospital
Birtinya, Queensland, 4575
Box Hill
Box Hill, Victoria, 3128
Icon Cancer Care
Brisbane, Queensland
Northern Cancer Institute
Frenchs Forest, New South Wales, 2086
Royal Brisbane and Womens hospital
Herston, Queensland, 4029
Monash Health
Melbourne, Victoria
Peter MacCallum Cancer Center
Melbourne, Victoria
Calvary Mater Newcastle
Newcastle, New South Wales, 2298
Fiona Stanley Hospital
Perth, Western Australia, 6150
St Vincent's Hospital Sydney
Sydney, New South Wales, 2010
St George
Sydney, New South Wales, 2229
Concord Repatriation General Hospital
Sydney, New South Wales
Townsville Hospital
Townsville, Queensland, 4814
Ballarat Oncology & Haematology Services
Wendouree, Victoria
About this study
Official title: Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma: a Phase II Trial (ANZUP 1601)
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).
Read the 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), in patients with disease progression during or after VEGFR TKI treatment.
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.
70 eligible participants will be recruited from 15 sites in Australia and New Zealand over a 2 year period.
- Being tested
- Pembrolizumab plus denosumab
- Medical subject headings
- Carcinoma, Renal Cell, Kidney Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pembrolizumab plus denosumabDrug
Also called Keytruda and Xgeva
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
| Study group | Role | What they receive |
|---|---|---|
| Pembrolizumab plus Denosumab | Experimental | 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 Receives: Drug: Pembrolizumab plus denosumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective tumour response
The objective tumour response rate, as assessed by RECIST1.1 - This is defined as the proportion of participants in the analysis set with a confirmed complete response (CR) or partial response (PR) divided by the number of participants in the analysis set.
Measured: Through study completion, on average 3.5 years
Secondary outcomes (6)
Progression-free survival (PFS)
Progression-free survival is defined as proportion alive and progression-free at 6 months, RECIST 1.1, iRECIST
Measured: 6 months
Disease control rate (DCR)
Disease control rate is defined the proportion in CR, PR, or SD at 6 months iRECIST) rate (DCRR)
Measured: 6 months
Time to objective tumour response (OTR)
Objective tumour response is defined as duration of OTR using RECIST 1.1 and iRECIST
Measured: Through study completion, on average 3.5 years
Time to first skeletal related event (SRE)
This is defined as the interval from date of registration to the date of first evidence of first skeletal related event.
Measured: Through study completion, on average 3.5 years
Frequency and severity of adverse events
The number of patients with adverse events, particularly immune-related adverse events, that are related to study drug, as assessed and graded according to CTCAE v4.03
Measured: From time of patient registration, until 100 days after the last dose of treatment
Frequency of treatment delays and discontinuation due to toxicity
The number of participants with permanent discontinuation of treatment or delays due to toxicity, as assessed and graded according to CTCAE v4.03
Measured: From time of patient registration, until 30 days after the last dose of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Sep 2017
- Study start12 Dec 2017
- Primary completion4 Jun 2023 (estimated)
- Study completion4 Jun 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Renal Cell Carcinoma, Clear CellStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Single-arm, multicentre, phase 2 trial
- Masking
- None (open label)
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- Australian and New Zealand Urogenital and Prostate Cancer Trials Group
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Amgen
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03280667
- Sponsor's protocol ID
- ANZUP1601
- Other IDs
- 20149171, 53963
- Acronym
- KEYPAD
- Status last verified
- Feb 2023
- First submitted
- 7 Sep 2017
- Last updated
- 29 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All IPD that underlie results in a publication
Study at a glance
From the registry record, last updated by the sponsor on 29 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma: a Phase II Trial (ANZUP 1601)
- ClinicalTrials.gov ID
- NCT03280667
- Acronym / sponsor ID
- KEYPAD / ANZUP1601
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 59 participants (actual)
- Lead sponsor
- Australian and New Zealand Urogenital and Prostate Cancer Trials GroupUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Amgen
- Study start
- 12 Dec 2017 (actual)
- Primary completion
- 4 Jun 2023 (estimated)
- Study completion
- 4 Jun 2023 (estimated)
- First posted
- 12 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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), in patients with disease progression during or after VEGFR TKI treatment.
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.
70 eligible participants will be recruited from 15 sites in Australia and New Zealand over a 2 year period.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Single-arm, multicentre, phase 2 trial
| Arm | Type | Receives |
|---|---|---|
| Pembrolizumab plus Denosumab | Experimental | Drug: Pembrolizumab plus denosumabPembrolizumab 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pembrolizumab plus denosumabAlso: Keytruda and XgevaPembrolizumab 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 | Drug | Pembrolizumab plus Denosumab |
Primary outcome
Objective tumour response
Time frame: Through study completion, on average 3.5 years
The objective tumour response rate, as assessed by RECIST1.1 - This is defined as the proportion of participants in the analysis set with a confirmed complete response (CR) or partial response (PR) divided by the number of participants in the analysis set.
6 secondary outcomes
Progression-free survival (PFS)
Time frame: 6 months
Disease control rate (DCR)
Time frame: 6 months
Time to objective tumour response (OTR)
Time frame: Through study completion, on average 3.5 years
Time to first skeletal related event (SRE)
Time frame: Through study completion, on average 3.5 years
Frequency and severity of adverse events
Time frame: From time of patient registration, until 100 days after the last dose of treatment
Frequency of treatment delays and discontinuation due to toxicity
Time frame: From time of patient registration, until 30 days after the last dose of treatment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Mar 2023.
- Individual participant dataSharing planned: Yes. All IPD that underlie results in a publication
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Renal Cell Carcinoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
16 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pembrolizumab plus denosumab in people with Renal Cell Carcinoma, Clear Cell and Metastatic Kidney Cancer, run by Australian and New Zealand Urogenital and Prostate Cancer Trials Group at 16 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective tumour response (time frame: Through study completion, on average 3.5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2023.