ANZUP - Non-clear Cell Post Immunotherapy CABozantinib (UNICAB)

Inclusion Criteria:

• Histologically confirmed un-resectable, locally advanced (defined as disease notamenable to curative surgery or radiation therapy) or metastatic non-clear cellrenal cell histology (comprising greater than 50% of the tumour) including:

1. Papillary renal cell carcinoma (type 1)

2. Papillary renal cell carcinoma (type 2)

3. Other subtypes: including chromophobe renal cell carcinoma, sarcomatoid renalcell carcinoma, Xp11 translocation (TFE3+ IHC) carcinoma, other renal carcinomaNOS

• Patient is either;

1. Ineligible for checkpoint inhibitor immunotherapy due to pre-existingautoimmune disorder in the opinion of the investigator, or

2. Has progressed following treatment with checkpoint inhibitor immunotherapy

• Be greater than 18 years of age on the day of signing informed consent

• At least 1 target lesion according to RECIST v1.1

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (refer toAppendix 1)

• Adequate bone marrow function (performed within 14 days prior to registration andwith values within the ranges specified below):

1. Haemoglobin ≥ 90g/L

2. Platelets ≥ 100x109/L

3. Neutrophil count ≥ 1.5x109/L

• Adequate liver function (performed within 14 days prior to registration and withvalues within the ranges specified below):

1. Bilirubin ≤ 1.5 x upper limit of normal (ULN) except for participants withknown Gilbert's syndrome who can have total bilirubin < 3.0 mg/dL

2. AST or ALT ≤ 3.0 x ULN (or ≤ 5.0x ULN in the presence of liver metastases)

• Adequate renal function (performed within 14 days prior to registration and withvalues within the ranges specified below):

1. Creatinine ≤ 1.5x ULN, or Creatinine clearance (CrCl) ≥ 30mL/min (useCockcroft-Gault Formula, refer to Appendix 2)

2. Urinalysis (dipstick) negative for protein, or for those with positive proteindetected on urinalysis (≥2+), urine protein-to-creatinine ratio (UPCR) ≤ 1mg/mg (≤ 113.2mg/mmol)

• Negative pregnancy test for female participants of childbearing potential within 72hours prior to registration. If urine test cannot be confirmed as negative, anegative serum pregnancy test is required.

• Female participants of childbearing potential must be willing to use two methods ofbirth control or be surgically sterile, or abstain from heterosexual activity forthe course of the study through 120 days after the last dose of study medication.Participants of childbearing potential are those who have not been surgicallysterilized or have not been free from menses for greater than 1 year.

• Male participants with sexual partners of childbearing age must agree to use anadequate method of contraception, must agree to use a condom during intercourse andmust agree to refrain from sperm donation starting with the first dose of studytherapy through 120 days after the last dose of study therapy.

• Able to provide a formalin-fixed paraffin embedded (FFPE) tumour block,representative of the participant's primary or metastatic disease (preferred), whichmust be forwarded to the Centre for Biostatistics and Clinical Trials (BaCT) within 10 working days post registration (if not previously collected for the UNISoNstudy). Note: If FFPE tumour tissue block is not obtainable, then unstained slidesare also acceptable. If archival tissue is not available, patient must be willing toprovide a fresh tumour biopsy.

• Willing and able to start treatment within 14 days of registration, and to complywith all study requirements, including the timing and/or nature of the requiredtreatment and assessments

• Has provided signed, written informed consent.

Exclusion Criteria:

• Patients with urothelial or transitional cell carcinoma of the renal pelvis orureter

• Predominant clear cell renal cell carcinoma. A minority of clear cell histology (<50%) is acceptable, but there must be >50% non-clear cell histology predominant.

• Untreated brain or leptomeningeal metastases or current clinical or radiologicalprogression of known brain metastases or requirement for steroid therapy for brainmetastases. Participants with treated brain metastases are eligible if metastaseshave been shown to be stable on repeat imaging post treatment and steroid treatmenthas been ceased for ≥ 3 weeks.

• Serious Cardiovascular disorders:

1. Congestive heart failure New York Heart Association class 3 or 4, unstableangina pectoris, serious cardiac arrhythmias.

2. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100mm Hg diastolic despite optimal antihypertensive treatment.

3. Stroke (including TIA), myocardial infarction, or other ischemic event, orthromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before randomization.

• Active infection requiring systemic therapy within 14 days before registration.

• Concurrent treatment with strong CYP3A4 inducers or inhibitors (such as ketoconazoleand rifampicin), P-glycoprotein substrates (such as fexofenadine, ambrisentan,dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine,saxagliptin, sitagliptin, talinolol and tolvaptan), MRP2 inhibitors (such ascyclosporine, efavirenz and emtricitabine), or direct oral anticoagulants such asthrombin inhibitors or factor Xa inhibitors. Use of low molecular weight heparin (LMWH) is permitted.

• Life expectancy of less than 3 months.

• Prior systemic therapy, surgery or radiation therapy within 4 weeks beforeregistation. Note: If the participant has undergone major surgery, complete woundhealing must have occurred 1 month prior to registration. Patients must not havereceived prior targeted therapy or chemotherapy, but may have received previouscheckpoint immunotherapy, for example, via the UNISoN trial (NCT03177239)

• History of another active malignancy except for locally curable cancers that havebeen apparently cured, such as low-grade thyroid carcinoma, prostate cancer notrequiring treatment (Gleason grade ≤ 6), basal or squamous cell skin cancer,superficial bladder cancer, melanoma in situ or carcinoma in situ of the prostate,cervix, or breast. Participants who have been treated for other malignancies andhave a <5% chance of relapse according to the investigator are eligible for thisstudy.

• Other significant active infection, including hepatitis B, hepatitis C and HIV.Hepatitis and HIV testing is not mandatory unless clinically indicated.

• Participants should be excluded if they have a history of allergy to study drugcomponents or problems of galactose intolerance, the Lapp lactase deficiency orglucose galactose malabsorption

• Serious medical or psychiatric conditions that might limit the ability of thepatient to comply with the protocol

• Patient is pregnant or breastfeeding.