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Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Vasoconstrictor Agents

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All Drugs and Chemicals

Hematinics

Antineoplastic Agents

Epinephrine

Liver Extracts

Sunitinib

Racepinephrine

Epinephryl borate

Stereotactic radiotherapy will be administered for up to five areas of metastatic sites showing oligo-progression within the same time period. During the Sunitinib break period, stereotactic radiotherapy will be delivered in a single fraction or up to a maximum of eight fractions. The number of fractions will depend on how many sites are being irradiated.

SRT to all areas of oligo-progression as follows: BRAIN: 20-24 Gy in 1 fraction if \< 2 cm,18 Gy in 1 fraction if 2-3 cm,15 Gy in 1 fraction for 3-4 cm, alternatively 25-30 Gy in 5 fractions can be used; SPINE: 18-24 Gy in 1-2 fractions,24 Gy in 3 fractions or 30-40 Gy in 5 fractions; NON-SPINE BONE: 30-40 Gy in 5 fractions; LUNG: 48-60 Gy in 4 fractions or 54-60 Gy in 3 fractions for peripheral lung tumours,50 Gy in 5 fractions or 60 Gy in 8 fractions for central lung tumours; LIVER: 30-60 Gy in 3-6 fractions,higher doses for central liver lesions and lower doses for peripheral liver lesions depending on proximity to adjacent organ (stomach, small bowel, large bowel or kidney); ADRENAL OR KIDNEY TUMOURS: 30-40 Gy in 5 fractions; LYMPHADENOPATHY: 30-40 Gy in 5 fractions.

Stereotactic radiotherapy

Georg A. Bjarnason, MD, FRCPC

Patrick Cheung, MD, FRCPC

Stereotactic radiotherapy (SRT) is a newer type of focused radiation therapy that precisely and accurately delivers high dose radiation to a tumour, while sparing much of the nearby normal organs. The use of stereotactic radiotherapy results in high rates of tumour destruction with minimal side effects which are very well tolerated. Often stereotactic radiotherapy has been used to try to cure patients who have an early stage cancer which has not spread, but there is less experience with using it in patients with cancer which has spread.

The purpose of this study is to measure how well stereotactic radiotherapy can destroy kidney cancer tumours which are no longer being controlled by Sunitinib and to measure how much longer such an approach will allow patients to stay on Sunitinib before needing to switch to another medication. Stereotactic radiotherapy will be used to treat only the growing tumours and then patients will continue with Sunitinib.

A Phase II study, single arm study, open-label, safety and efficacy study

Stereotactic Radiotherapy for Metastatic Kidney Cancer Being Treated With Sunitinib

A Phase II, Multi-Centre Study, of Stereotactic Radiotherapy for Oligo-Progression in Metastatic Renal Cell Cancer Patients Receiving 1st Line Sunitinib Therapy

Patients will have evidence of measurable metastatic kidney cancer according to RECIST 1.1 criteria. All progressing metastases sites will be amenable to stereotactic radiotherapy. The primary endpoint of local control will be defined as the absence of local failure in the irradiated site(s). Progressive enlargement will be defined as a 20% enlargement observed on two consecutive scans from baseline scan.

Progression free survival will be evaluated via disease assessments of radiology scans completed every three months from the time of stereotactic radiotherapy until progression is confirmed. Progressive disease will be defined as a 20% increase in RECIST 1.1 criteria measurements observed on two consecutive scans from the baseline scan.

Acute and late toxicities to stereotactic radiotherapy will be assessed from adverse events, vital signs and by clinically significant changes in laboratory evaluations. Adverse events will use the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. These events will be followed until resolution or for a maximum of two years, which ever occurs first.

Pfizer

Sunnybrook Health Sciences Centre

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

ccRCC molecular subgroup 1 -\> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

ccRCC molecular subgroup 1 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

ccRCC molecular subgroup 4 -\> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

ccRCC molecular subgroup 4 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

ccRCC molecular subgroup 2 -\> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.

ccRCC molecular subgroup 2 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

ccRCC molecular subgroup 3 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

ccRCC molecular subgroup 3 -\> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1A and 4A:

Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 1B, 2B, 3B and 4B:

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

For Arms 1B, 2B, 3B and 4B:

Ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks combined with Nivolumab administered IV over 60 minutes at 3 mg/kg for 4 doses until disease progression, unacceptable toxicity or other reasons specified in the protocol.

For Arms 2C and 3C (TKI pazopanib or sunitinib):

Pazopanib 800 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Pazopanib

For Arms 2C and 3C (TKI pazopanib or sunitinib):

Sunitinib 50 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Yann-Alexandre VANO, MD

Disease and Stage: naïve metastatic kidney cancer.

A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer

Research Hypothesis: Molecular groups of ccrcc will define patients who will respond to nivolumab alone, nivolumab combined with ipilimumab, or VEGFR-TKI (sunitinib or pazopanib) in subjects with previously untreated metastatic renal cell carcinoma (mRCC).

Conditions:

* Advanced or metastatic RCC: previously untreated in metastatic setting.
* Frozen tumor samples available for molecular group determination.
* Determination of molecular subgroup prior to randomization.

Product(s):

* ARM A: nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks (molecular group 1 and 4).
* ARM B : Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks

starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference (Arm A and B),

- ARM C: TKI (molecular group 2 and 3), pazopanib or sunitinib according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Biological assessments:

Molecular groups (1 to 4) will be determined for all patients from frozen tumor tissue samples or from fresh tumor samples immediately stored in "RNA later" medium.

Further exploratory biological assessments will be performed in order to define predictive biomarkers of response to N+I, N alone or TKI (sunitinib or pazopanib) by analyzing tumor specimens and blood samples:

* To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.
* Gene expression analysis will be performed from frozen and FFPE tumor tissue in order to compare the two methods.
* To assess the density and phenotype of selected immune populations (CD8, CD3/CD20, PD-1, TIM-3, LAG3, FoxP3) as well as the phenotype of tumor cells (PD-L1, PD-L2) by immunohistochemistry (IHC) in the primary tumor and metastases, before treatment initiation and at progression if safely achievable.
* To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.
* To quantify plasmatic angiogenesis-related (i.e. VEGF-A, VEGF-C its soluble receptors VEGFR-1 and 2 and co-receptors neuropilin 1 and 2, angiopoietins, SDF-1, PDGFs...)) and endothelial cell-derived molecules (i.e. endoglin, VE-cadherin) before treatment initiation, during treatment, and at progression.
* To correlate plasmatic angiogenesis-related molecules with tumor vascularization studied by immunofluorescence (IF) and a multi-spectral analyzer (Vectra technology) on tumor tissue.
* To investigate a predictive role of the response of CXCL7 and sCD146 to TKI, nivolumab and/or nivolumab+ipilimumab.
* To determine whether the mutation and methylation analysis of circulating tumor DNA can be used as predictive biomarker of response, resistance to treatment or progression.
* Identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors
* Evaluate association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors
* Evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.

Statistical Considerations:

An adaptative design will be used to ensure that conclusions can be made with a limited number of patients in each molecular group, which is the major constraint of the study.

Sample Size: Approximately 150 patients are planned to be treated. Given an expected failure rate of molecular grouping of less than 20%, 150-200 patients must be included.

A BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer

A Phase 2 BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer

ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment (nivolumab monotherapy, nivolumab combined with ipilimumab, or TKI: sunitinib or pazopanib), based on Investigator assessments.

progression-free survival (PFS) in subjects with previously untreated mRCC according to molecular groups and assigned treatment, based on Investigator radiological assessments.

To evaluate OS in subjects with previously untreated mRCC according to molecular groups and assigned treatment.

To evaluate objective response rate at 22 weeks as a surrogate of other endpoints according to molecular groups and assigned treatment.

To evaluate the duration of treatment (DOT) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1\&4 vs 2\&3).

To evaluate the duration of response (DOR) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1\&4 vs 2\&3).

To estimate the incidence of AEs associated with nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in all treated subjects with previously untreated mRCC.

To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.populations (CD3, CD8...) and regulatory markers (PD-1, LAG-3...) within the primary tumor, and metastases whenever possible, using frozen and FFPE tumor tissue.

Gene expression levels obtained from FFPE tumor tissue (exploratory method) will be compared to those obtained with frozen tumor tissue (standard method).

To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.

To explore the association between non-immune tissue and circulating biomarkers and outcomes (ORR, ORR at 22 weeks, OS and PFS).

The initial rate of ctDNA and its evolution will be correlated to the clinical evolution of patients and progression-free survival.

To identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors.

To evaluate the association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors.

To evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.

Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

sunitinib 50 mg orally 4 weeks on/ 2 weeks off or pazopanib 800 mg orally continuously

Cytoreductive nephrectomy + sunitinib 50 mg orally 4 weeks on/ 2 weeks off or pazopanib 800 mg orally continuously

sunitinib or pazopanib

Cytoreductive nephrectomy and first-line treatment

Cytoreductive nephrectomy

Giuseppe Procopio, MD

Two randomized trials in the cytokine era clearly showed that cytoreductive nephrectomy (CN) had a role in metastatic renal cell carcinoma (mRCC) increasing life expectancy. The survival benefit of tyrosine kinase inhibitors (TKIs) including first-line sunitinib and pazopanib in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy.

Therefore it is unknown if similar survival benefit could be achieved without CN with these new targeted agents.

At the same time there is a need to better understand mechanisms of primary and secondary resistance to TKIs in mRCC patients and to identify eighter prognostic and predictive biomarkers to better define risk factors and potentially druggable targets.

Two randomized trials in the cytokine era clearly showed that CN had a role in mRCC increasing life expectancy. The survival benefit of TKIs including first-line sunitinib and pazopanib in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy.Therefore it is unknown if similar survival benefit could be achieved without CN with these new targeted agents.

At the same time there is a need to better understand mechanisms of primary and secondary resistance to TKIs in mRCC patients and to identify eighter prognostic and predictive biomarkers to better define risk factors and potentially druggable targets.

The hypothesis of this study is that CN followed by TKIs will improve overall survival (OS) when compared to TKIs alone in subjects with mRCC. Circulating blood biomarkers (CBBs) promise to become non-invasive real-time surrogates for tissue-based biomarkers. Circulating tumor cells (CTCs) shed from both primary tumors and metastases, and circulating tumor DNA (ctDNA) released into the bloodstream from dying tumor cells, are likely to capture the entire tumor heterogeneity providing a clear picture of the tumor genetic landscape. Moreover, CTCs fluctuations reflect and possibly anticipate treatment outcome. Through comparison of CBBs before and after disease becomes refractory to therapy, the investigators would be able to address challenging research questions regarding TKIs resistance mechanisms.

This study was designed to compare clinical benefit as measured by Overall Survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety provided by CN followed by TKIs vs upfront TKIs in mRCC subjects.To prospectively collect blood samples from patients at commencement of TKIs therapy and on development of resistance, with the purpose of analyzing CTCs and ctDNA mutational profile to highlight mechanisms underlying TKIs resistance. The investigators additionally aim to assess the role of CTCs as prognostic and pharmacodynamic biomarkers and prospectively collect demographic and clinical outcome data so that molecular and pathological analyses can be measured against clinical endpoints.

Rationale for TKIs treatment choice:

Pazopanib and sunitinib were compared to each other as a therapy for previously untreated patients with mRCC within the phase 3 non inferiority COMPARZ trial which represented the first-ever head-to-head comparison of first-line treatments for mRCC. Overall, the median PFS and OS with pazopanib compared to sunitinib were statistically non-inferior, showing that both agents are active and provide similar high quality care. For this reason the TKI will be assigned based on patients characteristics according to the guidelines of every single institution involved in the study.

Statistical plan:

The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and subjects randomized to receive TKIs (main study endpoint). A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of TKIs vs. CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a hazard ratio (HR) corresponds to an increase in the 5-year OS, from an anticipated value 10% for TKIs to 21.5% for CN followed by TKIs. The investigators estimate that approximately 270 patients (135 in each arm), recruited over 3 years and with a minimum follow up of 2 years, will be necessary to see the necessary number of deaths.

An interim analysis of OS based on O'Brien-Fleming stopping rules is planned at 96 deaths at approximately 34 months after randomisation.

Targeted Therapy With or Without Nephrectomy in Metastatic Renal Cell Carcinoma: Liquid Biopsy for Biomarkers Discovery

To explore the association between baseline CTCs count and OS or PFS

To compare baseline CTCs count and CTCs at the time of RECIST 1.1 PD on TKIs therapy, with the aim of better understand progressive changes in the tumor as resistance develops

To compare clinical benefit, as measured by Overall Survival (OS), provided by CN followed by TKIs vs upfront TKIs in subjects with mRCC

To compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs

Safety profile of cytoreductive nephrectomy with TKIs vs upfront TKIs. (according to Common Terminology Criteria for Adverse Events -CTCAE- v 4.03). All Adverse events will be reported according to National Cancer Institute Criteria. The incidence of adverse events will be summarized according to the primary system-organ class (SOC) and within the category defined in the CTCAE v4.03. The summaries will be overall (severity grades 1-4) and for grade ≥3 events and will also report the actions taken in terms of treatment discontinuation. Similar summaries will be made for serious adverse events. The safety set will be considered.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Stereotactic Radiotherapy for Metastatic Kidney Cancer Being Treated With Sunitinib	NCT02019576	Clear Cell Meta...	Stereotactic ra...	18 Years -	Sunnybrook Health Sciences Centre
A BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer	NCT02960906	Clear Cell Meta...	Nivolumab Ipilimumab Pazopanib Sunitinib	18 Years -	Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
Targeted Therapy With or Without Nephrectomy in Metastatic Renal Cell Carcinoma: Liquid Biopsy for Biomarkers Discovery	NCT02535351	Clear-cell Meta...	sunitinib or pa... Cytoreductive n...	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Spots Global Cancer Trial Database for clear cell metastatic renal cell carcinoma