Evaluation of Perioperative Pembrolizumab Efficacy in Patients with Resectable Oligometastatic Renal Cell Carcinoma

Trial ID: 2024-512180-31-00
Protocol: PE-PE
Sponsor: Consorzio Oncotech

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Diseases & Conditions

Metastatic renal cell carcinoma

Objectives

The primary objective of this study is to evaluate the efficacy of **pembrolizumab** in delaying tumor progression in patients with oligo-metastatic renal cell carcinoma (mRCC) who are candidates for radical surgery and/or definitive radiotherapy (RT) on tumor metastases. This is clinically relevant as it aims to improve the management of mRCC by potentially extending the time before disease progression, which could lead to better patient outcomes and quality of life.

Secondary objectives include:

Evaluating the efficacy of pembrolizumab in delaying distant tumor progression in patients with oligo-metastatic mRCC who are candidates for radical surgery and/or definitive RT on tumor metastases.
Assessing if peri-operative pembrolizumab compared to local treatment alone increases the survival of mRCC patients.
Evaluating the safety of peri-operative pembrolizumab.
Evaluating the efficacy of perioperative pembrolizumab plus definitive RT in the local control of treated metastatic lesions.

Participants

The clinical trial involves participants diagnosed with **oligometastatic renal cell carcinoma**. The study population includes both male and female subjects who are at least 18 years of age. Participants must have a histologically confirmed diagnosis of clear cell renal cell carcinoma and have undergone either a partial or radical nephrectomy with negative surgical margins. The trial is open to individuals with evidence of oligo-metastatic disease eligible for local treatment with radiotherapy or surgery, characterized by specific criteria regarding the number and size of metastases. Participants should not have received prior systemic therapy for renal cell carcinoma and must have an ECOG performance status of 0 to 1. Adequate organ function is required, and female participants must not be pregnant or breastfeeding, adhering to contraceptive guidance if of childbearing potential. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on these criteria, ensuring a focus on individuals who are candidates for radical surgery and/or definitive radiotherapy on tumor metastases.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **pembrolizumab** in delaying tumor progression in patients with oligometastatic renal cell carcinoma who are candidates for radical surgery and/or definitive radiotherapy on tumor metastases. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on March 14, 2023, and conclude by April 1, 2028. Participants will be randomly assigned to receive either pembrolizumab or a control treatment, with the primary endpoint being relapse-free survival, defined as the time from randomization to the appearance of radiological progression of kidney cancer. Secondary endpoints include distant relapse-free survival, overall survival, and the incidence of adverse events.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, histologically confirmed diagnosis of clear cell renal cell carcinoma, and evidence of oligometastatic disease. Participants must have undergone nephrectomy with negative surgical margins and have no prior systemic therapy for renal cell carcinoma. Follow-up visits will occur at regular intervals to assess treatment efficacy and safety, with evaluations including imaging studies and clinical assessments. The end-of-study visit will finalize data collection and assess long-term outcomes.

Participant involvement is expected to last up to 49 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, would make continued participation detrimental to the participant's health. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their safety and well-being are prioritized throughout the study duration.

Treatment

The clinical trial involves the administration of **pembrolizumab**, marketed under the name **KEYTRUDA 25 mg/mL concentrate for solution for infusion**. This experimental medication is provided in the form of a concentrate for solution for infusion, specifically designed for intravenous infusion. The active substance, pembrolizumab, is a protein-based therapeutic agent. The maximum daily dose is set at 400 mg, with a total maximum dose of 3600 mg over the course of the treatment. The treatment period is limited to a maximum of 49 weeks. Pembrolizumab is administered intravenously, and the dosing schedule is determined based on the specific requirements of the study protocol. Compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the treatment plan.

In this study, pembrolizumab is the sole experimental treatment, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial aims to evaluate the efficacy of pembrolizumab in delaying tumor progression in patients with oligo-metastatic renal cell carcinoma (mRCC) who are candidates for radical surgery and/or definitive radiotherapy on tumor metastases. The study is conducted under the authorization of relevant regulatory bodies, ensuring adherence to clinical trial standards and protocols.

Efficacy

The efficacy of pembrolizumab in the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoint is the **relapsed free survival (RFS)**, which is defined as the length of time from randomization to the appearance of radiological progression of kidney cancer in patients who received pembrolizumab compared to those who did not. Secondary endpoints include the assessment of distant relapsed free survival (dRFS), overall survival, the overall incidence of adverse events, and the incidence of local progression in patients who received pembrolizumab plus radiotherapy compared to those who received radiotherapy alone. The dRFS is defined as the time from randomization to the appearance of distant metastases outside those treated with surgery or radiotherapy. Overall survival is measured from randomization to the patient's death or last contact.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of clear cell renal cell carcinoma will be enrolled in this study. 2. Have undergone a partial nephrectomy or radical complete nephrectomy with negative surgical margins. 3. Evidence of oligo-metastatic disease eligible for local treatment with radiotherapy or surgery, defined as: a) Appearance of new metastases within 5 years from previous eradication of primary tumors or previous metastasectomy. b) Presence of maximum 3 metastases in the same site or in different sites with the exception of bone metastases that cannot exceed the number of 2 if they are the sole disease site or one in case of multiple sites. c) Each metastasis should be less than 3 cm in the maximum diameter and less than 5 cm in the sum of the longest tumor diameters (this evaluation should apply also for lymph nodes). 4. Has received no prior systemic therapy for RCC. 5. Has ECOG performance status of 0 to 1 within 7 days of before the start of study intervention. 6. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. 7. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a primary tumor or tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slide. Newly obtained biopsies are preferred to archived tissue. Female participants: 8. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study treatment(s)) plus 30 days (a menstruation cycle) for study treatments with risk of genotoxicity after the last dose of study treatment. 9. Adequate organ function

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Exclusion Criteria

Has had major surgery, other than nephrectomy, within 4 weeks prior to randomization. Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. 2. Has residual thrombus post nephrectomy in the vena renalis or vena cava. 3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). 4. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible 5. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including NYHA Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, undergone CABG or PTCA, or cardiac arrhythmia. Note: Medically controlled arrhythmia stable on medication is permitted. 6. Has moderate to severe hepatic impairment (Child-Pugh B or C). 7. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 8. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed. 9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. 10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-muscle invasive bladder cancer, prostate cancer pT2 or less, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 12. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously surgically treated brain metastases may participate provided they are not radiological evidence of disease at the time of screening and without evidence of progression for at least 12 months by repeat imaging (note that the repeat imaging should be performed during study screening). 13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 14. Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. 15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
16.Has an active infection requiring systemic therapy. 17.Has a known history of Human Immunodeficiency Virus (HIV) infection. 18. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. 19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. 22. Has had an allogenic tissue/solid organ transplant. 23. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.