Study Assessing Stereotactic Radiotherapy in Therapeutic Strategy of Oligoprogressive Renal Cell Carcinoma Metastases

Study Overview
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Brief Summary
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Every year, 12500 primary renal cell carcinoma (RCC) are diagnosed in France. Metastases occur in half of RCC patients. Management of metastatic RCC is based on systemic treatments (targeted therapies/immunotherapy). However, resistance to systemic treatment is frequent. In case of progression, usual therapeutic attitude is initiating another systemic therapy. Because of the emergence of resistant tumor clonal cells, some patients progress only on few sites while the rest of tumor burden is controlled. In this setting named oligoprogressive disease [isolated progression of <3-5 metastase(s)], ablative treatments of these evolving metastatic sites could allow a disease control and a reduced risk of new metastases occurrence by tumor-cell reembolization. Such strategy is challenging to prolong ongoing systemic treatment and delay further lines. Although RCC was considered radioresistant and radiotherapy with conventional fractionation was mainly used for palliation of symptoms, stereotactic radiotherapy (SRT), by delivering high dose in one or few fractions, allows local control for about 90% of RCC metastases through various radiobiological pathways. Furthermore, some data suggest that high-dose focal irradiation of RCC could induce a systemic antitumor response mediated by immunologic effectors(1). This phenomenon (abscopal effect) could be enhanced in patients under immunotherapy, including anti-PD1. Several retrospective studies and one non-randomized phase-II study highly suggest the interest of SRT as focal ablative treatment in RCC oligometastases with excellent local control rates and low toxicity(2,3). Furthermore, the multicentric retrospective study the sponsor recently conducted within the GETUG group among 101 metastatic RCC patients with oligoprogression under systemic therapy highlighted that SRT on progressive sites provided a median of 8.6-month progression-free survival and allowed to continue current systemic line for 10.5 months. However, to date, there are no prospective data assessing the interest of SRT for management of oligoprogressive metastatic RCC. The sponsor aim to prospectively evaluate the interest of SRT as a therapeutic strategy for local control of oligoprogressive metastatic RCC under ongoing systemic treatment, and consequently delay subsequent systemic treatment.

Official Title
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A Randomized Phase II Study Assessing Stereotactic Radiotherapy in Therapeutic Strategy of Oligoprogressive Renal Cell Carcinoma Metastases

Conditions
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Metastatic Renal Cell Carcinoma, Radiotherapy

Intervention / Treatment
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* Radiation: Steretactic radiotherapy
* Drug: Pursuit of ongoing systemic treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clear cell renal cancer histologically proved (association with other histologic component are permitted) Patients of good or intermediate prognostic, according to Heng criteria Extracerebral metastatic disease documented with imagery Patients treated in first or second line systemic therapy Systemic treatment may be targeted therapies (tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors) and/or immunotherapy according to French applicable standards; patients treated in a clinical trial are also eligible if allowed by trial sponsor Oligoprogressive disease documented with imagery, defined as the emergence or progression of 1 to 3 metastases and progression localized in up to 2 organs Oligoprogressive disease confirmed with 2 CT scans performed 2 months apart At least one measurable progressing metastasis according to R.E.C.I.S.T. criteria v1.1 All oligoprogressive target lesions measuring ≤ 4 cm Good general condition (WHO performance status ≤ 2) All progressive lesions have to be accessible to SRT, performed concurrently or sequentially No contraindication to systemic therapy and stereotactic radiation therapy Patients aged 18 years or older Signed informed consent form Patients affiliated to the social security system Exclusion Criteria: More than 3 progressive metastases Non measurable disease according R.E.C.I.S.T. criteria Patients who received 3 or more lines of systemic therapy Inability to treat all progressive metastatic sites with SRT Previous radiation therapy performed in ≥ 1 target lesion At least 1 oligoprogressive target lesion measuring > 4 cm Presence of brain metastases Presence of ultra-central pulmonary metastasis Progressing metastasis in a long bone At least 1 progressive metastasis requiring surgical treatment Current or past history of second neoplasm diagnosed within the last 5 years Pregnancy or breast feeding or inadequate contraceptive measures Patients who cannot be adequately followed up Patient deprived of freedom or under guardianship

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized 2:1 phase II trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Steretactic radiotherapy plus systemic treatment<br> | Radiation: Steretactic radiotherapy<br>* Steretactic radiotherapy<br>Drug: Pursuit of ongoing systemic treatment<br>* Pursuit of ongoing systemic treatment<br>|
| Active Comparator: Systemic treatment<br> | Drug: Pursuit of ongoing systemic treatment<br>* Pursuit of ongoing systemic treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 6 months post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | Until 1 month after end of treatment | 
| Local control rate |  | 3, 6 and 12 months after randomization | 
| Overall control rate |  | 3, 6 and 12 months after randomization |