Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma

NCT ID: NCT03280667

Last Updated: 2023-03-29

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 59 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-12
• Study Completion Date: 2023-06-04

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), 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.

Conditions

Renal Cell Carcinoma, Clear Cell; Metastatic Kidney Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Pembrolizumab plus denosumab

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Keytruda and Xgeva

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Amgen

INDUSTRY

Sponsor Role: collaborator

Australian and New Zealand Urogenital and Prostate Cancer Trials Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Border Medical Oncology Research Unit

Albury, New South Wales, Australia

Northern Cancer Institute

Frenchs Forest, New South Wales, Australia

Calvary Mater Newcastle

Newcastle, New South Wales, Australia

St Vincent's Hospital Sydney

Sydney, New South Wales, Australia

St George

Sydney, New South Wales, Australia

Concord Repatriation General Hospital

Sydney, New South Wales, Australia

Sunshine Coast University Hospital

Birtinya, Queensland, Australia

Icon Cancer Care

Brisbane, Queensland, Australia

Royal Brisbane and Womens hospital

Herston, Queensland, Australia

Townsville Hospital

Townsville, Queensland, Australia

Flinders Medical Centre

Adelaide, South Australia, Australia

Box Hill

Box Hill, Victoria, Australia

Monash Health

Melbourne, Victoria, Australia

Peter MacCallum Cancer Center

Melbourne, Victoria, Australia

Ballarat Oncology & Haematology Services

Wendouree, Victoria, Australia

Fiona Stanley Hospital

Perth, Western Australia, Australia

Countries

Australia

Other Identifiers

20149171

Identifier Type: OTHER

Identifier Source: secondary_id

53963

Identifier Type: OTHER

Identifier Source: secondary_id

ANZUP1601

Identifier Type: -

Identifier Source: org_study_id