Primary Tumor Ablation and Outcome in Metastatic Renal Cell Carcinoma Treated With Immunotherapy Combinations. (ITALIC-RCC)

Clinical and Humoral Impact of Primary Tumor Ablation in Metastatic Renal Cell Carcinoma Treated With Immunotherapy. The ITALIC-RCC Randomized Study.

This is Phase IV, randomized, multi arm, multicenter, low interventional clinical trial, aiming to evaluate if treatment of primary tumor in mRCC patients with initial benefit to anti-PD1- based therapy (SOC) can improve the overall survival.

All patients eligible according to inclusion and exclusion criteria will be enrolled and randomized to different treatment options based on tumor extension of the primary kidney cancer.

Those with primary kidney cancer ≤ 4 cm will be randomized 1:1:1 to receive:

• Cytoreductive Nephrectomy + standard of care (SOC) or
• RT on primary tumor + SOC or SOC alone.

Those with primary kidney cancer > 4 cm will be randomized 1:1 to receive:

• Deferred Cytoreductive Nephrectomy + SOC or SOC alone. Patients randomized to Deferred Cytoreductive Nephrectomy can be treated with one among radical nephrectomy; partial nephrectomy or lumpectomy.

Patients randomized to RT should be treated with single shot of 25 Gy (or with multiple fractions with equivalent biological dose).

The SOC medical therapy is the continuation of the combination of medical therapy for mRCC including one of the available combination among axitinib + pembrolizumab or cabozantinib + nivolumab or lenvatinib + pembrolizumab or nivolumab alone after nivolumab + ipilimumab.

Study Overview

• Status: Recruiting
• Conditions: Kidney Cancer; Renal Cell Cancer; Radiotherapy; Immunotherapy; Surgery Programmed; Kidney Neoplasm
• Intervention / Treatment: Radiation: Radiotherapy + medical treatment; Procedure: Deferred Cytoreductive Nephrectomy + medical treatment; Drug: Medical therapy

• Study Type: Interventional
• Enrollment (Estimated): 409
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Roberto Iacovelli, M.D.; Ph.D.; Phone Number: +390630157373; Email: roberto.iacovelli@policlinicogemelli.it

Study Locations

• Italy
  • Roma, Italy, 00168
    • Recruiting
    • Fondazione Policlinico Universitario A. Gemelli IRCCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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 [22].
6. Eastern Cooperative Oncology Group performance status of ≤1.
7. Life expectancy of at least 9 months.
8. Under treatment with one anti-PD1 based therapy (SOC) 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 [21].
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:

    1. Creatinine value <2.5 mg/dl and creatinine clearance > 30 ml/min evaluated by the Cockcroft-Gault Formula.
    2. Total bilirubin ≤1∙5 × the upper limit of normal (ULN);
    3. Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of their cancer);
    4. 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;
    5. Platelet count ≥100 000/mm3, hemoglobin >9 g/dl, absolute neutrophil count >1,500/mm3;
    6. Alkaline phosphatase limit ≤2∙5 × ULN (≤5 × ULN for patients with liver involvement of their cancer).

Exclusion Criteria:

1. More than one treatment for metastatic or locally advanced renal cell carcinoma.
2. Solitary kidney
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:

   1. Congestive heart failure of New York Heart Association class 3 or worse.
   2. 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.
   3. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted).
   4. Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management).
   5. 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 6.0 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiotherapy; Patients with tumors up to 4 cm can receive RT single shot of 25 Gy (or with multiple fractions with equivalent biological dose).	Radiation: Radiotherapy + medical treatment; Patients randomized to RT should be treated with single shot of 25 Gy (or with multiple fractions with equivalent biological dose). Patients will continue to receive the ongoing medical treatment before the randomization.
Experimental: Deferred Cytoreductive Nephrectomy; Patients randomized to Deferred Cytoreductive Nephrectomy can be treated with one among radical nephrectomy; partial nephrectomy or lumpectomy.	Procedure: Deferred Cytoreductive Nephrectomy + medical treatment; Patients randomized to Deferred Cytoreductive Nephrectomy can be treated with one among radical nephrectomy; partial nephrectomy or lumpectomy. Patients will continue to receive the ongoing medical treatment before the randomization.
Active Comparator: Control; patients in the control arm continue to receive immuno-based medical treatment for mRCC.	Drug: Medical therapy; Medical therapy is the continuation of the immune-based combo for mRCC including one of the available options among axitinib + pembrolizumab or cabozantinib + nivolumab or lenvatinib + pembrolizumab or nivolumab alone after nivolumab + ipilimumab.; Other Names: Standard of Care (SOC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-months Overall Survival for surgery vs. control	The primary endpoint of the study is to assess the difference in 30-months overall survival (OS) between patients who receive or not the deferred citoreductive nephrectomy (CN) while on therapy with SOC for mRCC.	30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median overall survival for surgery vs. control	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.	30 months
Median Progression Free Survival for surgery vs. control	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.	30 months
Median Overall Survival for radiotherapy vs. control	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.	30 months
Median Progression Free Survival for radiotherapy vs. control	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.	30 months
Incidence of adverse events	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.	30 months
Difference in EQ-5D-5L quality of life test	To evaluate the quality of life before and after 8 weeks from the surgery or radiotherapy on primary tumor among patients receiving SOC for mRCC evaluated by the questionnaires EQ-5D-5L.	Baseline and 8 weeks after surgery or radiotherapy.
Difference in FKSI-19 quality of life test	To evaluate the quality of life before and after 8 weeks from the surgery or radiotherapy on primary tumor among patients receiving SOC for mRCC evaluated by the questionnaires FKSI-19.	Baseline and 8 weeks after surgery or radiotherapy.
Incidence in of surgical complications.	To evaluate the incidence of surgical complications by the Clavien- Dindo classification.	8 weeks after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in the proteomic profile	The study aims also to describe the change of proteome after surgery or radiotherapy on primary tumor compared to the baseline and to evaluate if specific proteome profiles at baseline are related to different outcomes. A blood tumor sample will be performed at the time of randomization for all patients and after eight weeks from CN or the end of RT to assess the proteomic profile.	Before and 8 weeks after surgery or radiotherapy.

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Collaborators: AIRC (Italian Association for Cancer Research)
• Investigators: Principal Investigator: Roberto Iacovelli, M.D.; Ph.D., Catholic University of Rome, Italy

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: March 24, 2025
• First Submitted That Met QC Criteria: March 24, 2025
• First Posted (Actual): March 30, 2025

Study Record Updates

• Last Update Posted (Actual): July 3, 2025
• Last Update Submitted That Met QC Criteria: June 30, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: radiotherapy; renal cancer; primary tumor; cytoreductive nephrectomy; immunothreapy
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms
• Other Study ID Numbers: 7056

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Not planned at this time.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No