Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma (KEYPAD)

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).

Study Overview

Status

Active, not recruiting

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

59

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • New South Wales
      • Albury, New South Wales, Australia, 2640
        • Border Medical Oncology Research Unit
      • Frenchs Forest, New South Wales, Australia, 2086
        • Northern Cancer Institute
      • Newcastle, New South Wales, Australia, 2298
        • Calvary Mater Newcastle
      • Sydney, New South Wales, Australia, 2010
        • St Vincent's Hospital Sydney
      • Sydney, New South Wales, Australia
        • Concord Repatriation General Hospital
      • Sydney, New South Wales, Australia, 2229
        • St George
    • Queensland
      • Birtinya, Queensland, Australia, 4575
        • Sunshine Coast University Hospital
      • Brisbane, Queensland, Australia
        • Icon Cancer Care
      • Herston, Queensland, Australia, 4029
        • Royal Brisbane and Womens Hospital
      • Townsville, Queensland, Australia, 4814
        • Townsville Hospital
    • South Australia
      • Adelaide, South Australia, Australia
        • Flinders Medical Centre
    • Victoria
      • Box Hill, Victoria, Australia, 3128
        • Box Hill
      • Melbourne, Victoria, Australia
        • Monash Health
      • Melbourne, Victoria, Australia
        • Peter MacCallum Cancer Center
      • Wendouree, Victoria, Australia
        • Ballarat Oncology & Haematology Services
    • Western Australia
      • Perth, Western Australia, Australia, 6150
        • Fiona Stanley Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 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

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 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:

    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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pembrolizumab plus Denosumab
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
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
Other Names:
  • Keytruda and Xgeva

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Through study completion, on average 3.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free survival (PFS)
Time Frame: 6 months
Progression-free survival is defined as proportion alive and progression-free at 6 months, RECIST 1.1, iRECIST
6 months
Disease control rate (DCR)
Time Frame: 6 months
Disease control rate is defined the proportion in CR, PR, or SD at 6 months iRECIST) rate (DCRR)
6 months
Time to objective tumour response (OTR)
Time Frame: Through study completion, on average 3.5 years
Objective tumour response is defined as duration of OTR using RECIST 1.1 and iRECIST
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
This is defined as the interval from date of registration to the date of first evidence of first skeletal related event.
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
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
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
The number of participants with permanent discontinuation of treatment or delays due to toxicity, as assessed and graded according to CTCAE v4.03
From time of patient registration, until 30 days after the last dose of treatment

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
Through study completion, on average 3.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 12, 2017

Primary Completion (Anticipated)

June 4, 2023

Study Completion (Anticipated)

June 4, 2023

Study Registration Dates

First Submitted

September 7, 2017

First Submitted That Met QC Criteria

September 10, 2017

First Posted (Actual)

September 12, 2017

Study Record Updates

Last Update Posted (Actual)

March 29, 2023

Last Update Submitted That Met QC Criteria

March 27, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All IPD that underlie results in a publication

IPD Sharing Time Frame

Within 12 months of study completion

IPD Sharing Access Criteria

Authorised personnel as defined in the study contracts

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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