Denosumab and Pembrolizumab in Clear Cell Renal Carcinoma (KEYPAD)

  • STATUS
    Recruiting
  • days left to enroll
    69
  • participants needed
    70
  • sponsor
    Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Updated on 22 March 2022
renal function
calcium
carcinoma
metastasis
neutrophil count
liver metastasis
pembrolizumab
serum calcium
renal function tests
clear cell renal cell carcinoma

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).

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.

Details
Condition Renal Cell Carcinoma, Clear Cell, Metastatic Kidney Cancer
Treatment Pembrolizumab plus denosumab
Clinical Study IdentifierNCT03280667
SponsorAustralian and New Zealand Urogenital and Prostate Cancer Trials Group
Last Modified on22 March 2022

Eligibility

Yes No Not Sure

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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note