Clinical and Humoral Impact of Primary Tumor Ablation in Metastatic Renal Cell Carcinoma Treated with Immunotherapy.the Italic-Rcc Randomized Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Jul 2025 → ongoing

Decision date (initial)

2025-03-18

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Associazione Italiana per la Ricerca sul Cancro (AIRC)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others

To evaluate the effect of deferred CN on patients’ survival in those receiving standard of care (SOC) with anti-PD1-based therapies for metastatic renal cell carcinoma (mRCC)

Secondary objectives 8

1. To evaluate the effect of deferred CN on patients’ survival in those receiving SOC for metastatic renal cell carcinoma (mRCC) from the beginning of the anti-PD1-based therapy
2. To evaluate the effect of deferred CN on delaying tumor progression in patients receiving SOC for mRCC
3. To evaluate the effect of RT on primary tumor on patients’ survival in those receiving SOC for mRCC
4. To evaluate the effect of RT on delaying tumor progression in those receiving SOC for mRCC
5. To evaluate the safety of the CN and RT on primary tumor among patients receiving SOC for mRCC
6. To evaluate the quality of life before and after 8 weeks from the CN or RT on primary tumor among patients receiving SOC for mRCC
7. Translational objective:To describe as different strategies (CN or RT) affect the patient’s proteome and the correlation between the proteome profile at baseline or its changes with the outcome (i.e.: PFS and OS) to SOC
8. Translational objective: To describe the outcome based on some immunohistochemical markers

Conditions and MedDRA coding

metastatic or locally advanced renal cell carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Informed consent obtained before any study-specific procedures. Patients must be able to understand and be willing to sign a written informed consent
2. Male or female patient ≥18 years of age
3. Histological or cytological documentation of renal cell carcinoma with predominantly clear cell histology
4. Evidence of primary renal cancer
5. Measurable or not measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors criteria, version 1.1
6. Eastern Cooperative Oncology Group performance status of ≤1
7. Life expectancy of at least 9 months
8. Under treatment with SOC consisting in one anti-PD1 based therapy among axitinib + pembrolizumab or cabozantinib + nivolumab or lenvatinib + pembrolizumab or nivolumab alone after nivolumab + ipilimumab for at least 24 but not more than 52 weeks at the time of the signed informed consent and without evidence of progressive disease based on RECIST criteria v 1.1
9. Eligible to continue the combination of therapies for mRCC (or nivolumab alone in case of nivolumab + ipilimumab)
10. Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care
11. Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting to study treatment: a) Creatinine value <2.5 mg/dl and creatinine clearance > 30 ml/min evaluated by the Cockcroft-Gault Formula. b) Total bilirubin ≤1∙5 × the upper limit of normal (ULN); c) Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of their cancer); d) International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1∙5 × ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate if no prior evidence of an underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care; e) Platelet count ≥100 000/mm3, hemoglobin >9 g/dl, absolute neutrophil count >1,500/mm3; f) Alkaline phosphatase limit ≤2∙5 × ULN (≤5 × ULN for patients with liver involvement of their cancer).

Exclusion criteria 18

1. More than one treatment for metastatic or locally advanced renal cell carcinoma
2. Solitary kindney
3. Any contraindication to surgery or radiotherapy on primary renal tumor
4. Discontinuation (definitive) of one of the therapies for mRCC due to toxicity (previous discontinuation of ipilimumab in the ipilimumab + nivolumab combo is allowed).
5. Concurrent or previous cancer within 3 years before enrolment EXCEPT curatively treated cervical cancer in situ, non-melanoma skin cancer and pT2 prostate cancer with PSA<0.01 or non-muscle invasive bladder cancer
6. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before the signed informed consent
7. Pregnancy or breast-feeding. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before surgery or radiotherapy on primary tumor, and a negative result must be documented before start of treatment
8. Any cardiological condition among: a) Congestive heart failure of New York Heart Association class 3 or worse. b) Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of study drug. c) Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted). d) Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management). e) Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), pulmonary embolism within the 4 months before start of study.
9. Ongoing infection higher than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grade 2
10. Known history of human immunodeficiency (HIV) virus infection or known history of chronic hepatitis B or C
11. Any autoimmune reaction or toxicity that contraindicates the use of anti-PD1 therapy
12. Seizure disorder requiring medication
13. Symptomatic metastatic brain or meningeal tumors unless the patient is >2 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or tapering (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before and after screening radiographic studies).
14. History of organ allograft
15. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event of CTCAE grade 3 or higher within 4 weeks of start of study medication
16. Non-healing wound, ulcer, or bone fracture
17. Renal failure requiring hemodialysis or peritoneal dialysis
18. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is to assess the difference in overall survival (OS) between patients who receive or not the deferred citoreductive nephrectomy (CN) while on therapy with SOC for mRCC

Secondary endpoints 8

1. To assess the difference in overall survival (OS) between patients who receive or not the deferred citoreductive nephrectomy (CN) while on therapy with SOC for mRCC from the beginning of the anti-PD1-based therapy
2. To assess the difference in progression-free survival (PFS) between patients who receive or not the deferred citoreductive nephrectomy (CN) while on therapy with SOC for mRCC
3. To assess the difference in overall survival (OS) between patients who receive or not the radiotherapy on primary tumor while on therapy with SOC for mRCC among those with primary tumor up to 4 cm at randomization
4. To assess the difference in progression-free survival (PFS) between patients who receive or not the radiotherapy on primary tumor while on therapy with SOC for mRCC among those with primary tumor up to 4 cm at randomization.
5. To evaluate the safety of the CN and RT on primary tumor among patients receiving SOC for mRCC. Adverse events will be graded according to NCI CTCAE version 5.0
6. To evaluate the quality of life before and after 8 weeks from the CN or RT on primary tumor among patients receiving SOCfor mRCC evaluated by the questionnaires EQ-5D-5L and FKSI-19 and the surgical complications by the Clavien-Dindo classification
7. Translational endpoint: To describe as different strategies (CN or RT) affect the patient’s proteome and the correlation between the proteome profile at baseline or its changes with the outcome (i.e.: PFS and OS) to SOC
8. Translational endpoint: • To describe as the expression of some markers such as PD-L1, PBRM1, BAP1, and presence of CD4 and C8 lymphocytes correlated with the outcome (i.e.: PFS and OS) in the different groups of patients

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Sponsor organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Address

Largo Francesco Vito 1

City

Rome

Postcode

00168

Country

Italy

Scientific contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Roberto Iacovelli

Public contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Roberto Iacovelli

Third parties 2

Locations

1 EU/EEA country · 33 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications