UNiCAB: This phase II trial is using an oral drug (Cabozantinib) to treat patients with locally advanced or metastatic clear cell renal cell carcinoma who have previously received or are unable to receive immunotherapyA Phase II of Single Agent Cabozantinib in Patients With Locally Advanced or Metastatic Non-clear Cell Renal Cell Carcinoma Post Immunotherapy or Who Are Unsuitable for Immunotherapy

Inclusion

• Histologically confirmed un-resectable, locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic non-clear cell renal 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 renal cell carcinoma, Xp11 translocation (TFE3+ IHC) carcinoma, other renal carcinoma NOS

• Patient is either;

  1. Ineligible for checkpoint inhibitor immunotherapy due to pre-existing autoimmune 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 to Appendix 1)

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

  1. Bilirubin ≤ 1.5 x upper limit of normal (ULN) except for participants with known 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 with values within the ranges specified below):

  1. Creatinine ≤ 1.5x ULN, or Creatinine clearance (CrCl) ≥ 30mL/min (use Cockcroft-Gault Formula, refer to Appendix 2)
  2. Urinalysis (dipstick) negative for protein, or for those with positive protein detected on urinalysis (≥2+), urine protein-to-creatinine ratio (UPCR) ≤ 1mg/mg (≤ 113.2mg/mmol)
• Negative pregnancy test for female participants of childbearing potential within 72 hours prior to registration. If urine test cannot be confirmed as negative, a negative serum pregnancy test is required.
• Female participants of childbearing potential must be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for greater than 1 year.
• Male participants with sexual partners of childbearing age must agree to use an adequate method of contraception, must agree to use a condom during intercourse and must agree to refrain from sperm donation starting with the first dose of study therapy 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), which must be forwarded to the Centre for Biostatistics and Clinical Trials (BaCT) within 10 working days post registration (if not previously collected for the UNISoN study). Note: If FFPE tumour tissue block is not obtainable, then unstained slides are also acceptable. If archival tissue is not available, patient must be willing to provide a fresh tumour biopsy.
• Willing and able to start treatment within 14 days of registration, and to comply with all study requirements, including the timing and/or nature of the required treatment and assessments
• Has provided signed, written informed consent.