Ablative Radioembolization of Renal Cell Carcinoma Trial

Renal cell carcinoma (RCC), the most common type of kidney cancer, is typically treated with surgery; however, there is no established therapy for patients who are not surgical candidates and who have tumours greater than 4.0 cm in size. Selective internal radiation therapy (SIRT) or radioembolization using radioactive spheres containing 90-Yttrium (Y-90) is successful at treating large tumours with high doses of radiation within the liver and might be similarly effective for treating larger RCC tumours in patients, particularly those who are not surgical candidates.

This prospective study will enroll 16 participants with RCC who are not candidates for surgery and treat them with Y-90 radioembolization using a high-dose therapy to see if it is an effective cancer therapy. Primary outcome will be RCC treatment response 1 year after the Y-90 radioembolization. Additionally, the safety, tolerability, and impact on kidney function of the therapy will be monitored for all participants. Patients will be followed for a total of 5 years to evaluate long-term outcome in cancer control and safety of the treatment.

Renal cell carcinoma (RCC) is the 8th most common cancer in the United States with 81,610 new cases diagnosed each year. 70% of new RCC cases are localized, non-metastatic at initial diagnosis; however, the risk of disease recurrence or progression to metastatic disease is higher for larger tumors and those with higher grade disease. The standard therapy for localized renal cell carcinoma (RCC) is surgery - either partial or radical nephrectomy. However, a substantial proportion of patients with RCC are not good surgical candidates, as the average age at diagnosis is 64-year-old, and obesity, smoking, hypertension and renal disease known risk factors. Currently there are no established standard-of-care therapies for patients who are not eligible for surgery.

Unmet Clinical Need:

There is a need to establish a definitive, minimally-invasive therapy patients for with large, non-metastatic RCC who are not surgical candidates. For non-surgical candidates with small RCC (\&lt; 4 cm or T1a) percutaneous ablation has been established as an effective minimally-invasive curative therapy. However, there is currently no minimally-invasive standard of care therapy for patients with larger localized RCC (\&gt; 4 cm) who are not surgical candidates, despite these patients being at higher risk for developing metastatic disease. Percutaneous ablation can be performed in patients with tumors \&gt; 4 cm; however, long term outcomes have not been established and those ablations carry higher risks of major bleeding complications than ablation of tumours \&lt; 4 cm. SBRT has shown some promising progression-free survival data for localized RCC; however, the radiation resistance of RCC cells require higher treatment doses to achieve cytotoxic effect. The achievable therapeutic dose of SBRT is currently limited to 30-60 Gy, often due to required reductions in the externally delivered dose to protect the commonly adjacent radiosensitive colon and/or small bowel that routinely abut the kidney.

Selective internal radiation therapy (SIRT) or Yittrium-90 (Y-90) radioembolization is an endovascular therapy whereby beads loaded with the radioactive Yittrium-90 atom are injected through a catheter into the artery or arteries supplying the tumor to deliver the radiation dose internally. Radioactive decay of the Y-90 atom within the tumor's arterial bed, deposits radiation dose within 2.5 mm (maximum 11 mm) of the bead location. As such, the internal delivery of radiation, rather than external delivery of SBRT, allows for higher doses to be delivered to the tumour without exposing adjacent vulnerable organs to significant dose. Y-90 radioembolization has great success treating hepatocellular carcinoma (HCC) in the liver, commonly achieving tumor dose levels that are nearly ten times higher than SBRT (e.g. 300-500 Gy vs. 40-50 Gy). Furthermore, it has become a standard of care therapy for HCC with recent inclusion in the major international treatment guidelines. Y-90 tumor dosage of \&gt;400 Gy is the typical target with one major explant study showing complete pathological necrosis of HCC tumors when this dose was achieved8.

RCC is a good potential disease target for Y-90 radioembolization as RCC is commonly hypervascular (similar to HCC) and the kidney is an end organ typically supplied by a single renal artery. Furthermore, the radioresistant tumour biology requires high radiation doses to achieve oncologic effect, which may be best achieved with the internal radiation delivery approach.

Existing Safety Data of Y-90 in the kidney:

Health Canada approval of Y-90 radioembolization is currently only for treatment of malignancies in the liver, where it is currently a standard of care therapy for treatment of HCC. The safety of Y-90 radioembolization in the kidney has been shown in preclinical studies as well as the RESIRT Phase I trial, which is the first and only human clinical trial of Y-90 radioembolization for RCC. The 21-patient RESIRT dose-escalation study had a heterogeneous patient population with both metastatic and non-metastatic RCC. The safety study showed no dose-limiting toxicity or reduction in renal function for treatment between 75-300 Gy; however, the secondary outcome of treatment response showed partial response in only 10% of patients without any complete response. The limited treatment response is potentially related to the administered dose being lower than the 400 Gy target used in the liver for complete pathologic necrosis. For HCC, complete pathologic necrosis from Y-90 SIRT requires an achieved tumour dose of ≥400 Gy. Within the liver, Y-90 administration of tumour doses ranging between 500-1000 Gy have been tolerated without serious adverse events.

Given the known radioresistance of RCC, it is reasonable to expect that a similar or higher dose than HCC would be required to achieve an ablative therapy (i.e. ≥ 400 Gy). The RESIRT trial used resin beads for Y-90 delivery (SIRspheres, Australia) and arterial bed stasis (not permitting additional bead administration) occurred in 52% of the treated patients, which might have limited higher achievable RCC doses. Glass-sphere beads loaded with Y-90 (Therasphere, Boston Scientific) will be used instead of resin, which have higher Y-90 radiation activity per bead than the resin counterparts (2,500 Bq/bead vs. 50 Bq/bead). The higher activity per bead should overcome the maximum dose limitation in the RESIRT trial to achieve the 400+ Gy dose likely required to for complete pathologic necrosis. This is supported by a recent case report where radioembolization with Y-90 loaded on glass spheres achieved complete tumor response after delivering 1,050 Gy into a 1.5 cm RCC without any reported adverse events.

Planned Study:

A single-centre, phase II clinical trial is proposed to evaluate the oncologic efficacy of Y-90 radioembolization treatment within the kidney for patients with large (\&gt;4.0 cm), non-metastatic (localized) RCC who are not candidates or refuse the standard of care surgery. It is proposed that Y-90 radioembolization therapy with an ablative dose (400-600 Gy) into RCC within the kidney will achieve positive oncologic response and be tolerated clinically.

Eligibility Criteria:
Inclusion Criteria:

* Patients willing to participate and provide written consent
* Patients 18 years of age and older
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
* Biopsy confirmed RCC \&gt; 4.0 cm and no renal vein or IVC involvement (T1b or T2 disease)
* Not suitable for or declining standard of care nephrectomy or partial nephrectomy
* Adequate hepatic function, defined by the following laboratory results:
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) (or ≤5 × ULN if presence of liver metastases)
* Total bilirubin ≤3 × ULN
* Serum albumin ≥3.0 g/dL unless prothrombin time (PT) is within the normal range
* Adequate hematologic function, defined by the following laboratory results:
* Hemoglobin concentration ≥8.0 g/dL
* Absolute neutrophil count (ANC) ≥1000 cells/µL (≥1000 cells/mm3 )
* Platelets \>50 × 109 /L (100 × 103 /mm3 )
* For women of childbearing potential (WOCBP):
* Negative serum pregnancy test within 48 hours prior to the first dose of study treatment
* Agreement to use barrier contraception and a second form of highly effective contraception (Clinical Trials Facilitation Group \[CTFG\] 2020) while receiving study treatment and for 7 months following their last dose of study treatment. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* Sexually active male subjects must use a condom during intercourse while receiving treatment and for at least 120 days after the last dose of the study treatment and should not father a child during this period.
* Male study subjects whose sexual partners are WOCBP must also agree to use a second form of highly effective contraception (CTFG 2020) while receiving 90Y and for at least 4 months following their last dose. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject.
* Vasectomized men are also required to use a condom during intercourse, including with a male partner, to prevent delivery of the drug via seminal fluid.

Exclusion Criteria:

* Evidence of metastatic disease on CT or MRI
* Severely impaired renal function (GFR ≤ 30) and not on dialysis
* Bilateral RCC without plan for definitive therapy of the contralateral lesion
* RCC that is locally recurrent at prior surgery or ablation site (new location in same or contralateral kidney is permitted)
* Prior or concurrent kidney radiation therapy or systemic immunotherapy/TKI
* Lung shunt with estimated lung radiation dose \&gt; 30 Gy for single dose or \&gt; 50 Gy total.
* Planning angiogram cone beam CT from all accessible feeding arteries shows lack of perfusion to all or portions of the RCC tumour such that, in the investigator's opinion, Y-90 radioembolization would result in substantial RCC tumour being untreated or receive an inadequate dose.
* Contraindication to arterial renal angiogram, or both CT and MRI contrast medium
* History of severe allergy to CT contrast medium or any study product ingredients that cannot be managed medically
* History of chronic lung disease with baseline oxygen saturation \< 90% or requiring home oxygen therapy.
* Congestive heart failure with ejection fraction \< 40%
* Presence of active infection, defined by the investigator as clinically significant.
* Any chronic condition that is severe or unstable and, in the opinion of the investigator, would put the patient at unacceptable risk of adverse event related to the Y-90 radioembolization procedure. Such conditions include but are not limited to: unstable angina, congestive heart failure, interstitial lung disease, severe gastrointestinal disease with diarrhea.
* Life expectancy \&gt; 1 year
* Pregnant or breast-feeding patient