PRISM – A Phase II trial testing alternate schedules of combination Ipilimumab-Nivolumab therapy for patients with advanced and metastatic renal cell carcinoma

INTERVENTION: Eligible participants are randomised 2:1 to one of two groups. Those in the first group receive a modified schedule of IV Ipilimumab combined with IV Nivolumab every 12 weeks (Weeks 1, 13, 25, 37) with fortnightly flat dose IV Nivolumab between combination doses. Those in the second group receive the standard treatment schedule of combination IV Ipilimumab and IV Nivolumab every 3 weeks for 4 doses (Weeks 1, 4, 7, 10). Patients will receive treatment in specialist hospital cancer units either fortnightly or every 4 weeks. Upon receipt of four combination doses in either arm, flat dose IV Nivolumab is administered fortnightly until disease progression or treatment discontinuation (due to either treatment related toxicities or other reasons). The duration of the trial intervention is variable for individual participants and continues until disease progression, death or treatment discontinuation for any reason. The trial follows participants to disease progression or death (whichever occurs earlier), with safety follow‐up continuing until 100 days post last dose of trial drug. CONDITION: Specialty: Cancer, Primary sub‐specialty: Renal Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasms of urinary tract ; Cancer ; Renal Cancer PRIMARY OUTCOME: The proportion of participants experiencing a grade 3/4 adverse reaction within initial 12 months of treatment as measured via adverse event (AE) reporting, where an AE has been clearly marked as an adverse reaction (AR) by the investigator. All grade 3/4 AEs judged by the investigator or sponsor as having a reasonable suspected causal relationship to nivolumab, ipilimumab or the combination of the two, will qualify as grade 3/4 ARs. AEs will be collected for all participants from the time of start of protocol treatment until 100 days post cessation of trial therapy and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events V4.03 (NCI‐CTCAE), with those ARs occurring within the first 12 months of receiving the first dose of any trial drug contributing to this endpoint. SECONDARY OUTCOME: Key Secondary outcome measure:; Progression free survival as measured by time in days from randomisation until disease progression of death. Disease progression will be locally assessed by 12 weekly CT scans, with progression defined according to the RECIST v1.1 criteria; details of deaths occurring within the trial will be collected. The key secondary endpoint will be the proportion of patients alive and progression free at 12 months post randomisation.; ; Secondary outcome measures:; 1. Safety and toxicity as reported based on the occurrence of ARs, serious adverse events (SAEs), serious adverse reactions (SARs) and SUSARs as graded by CTCAE v4.03 and as defined in section 15.1 of the trial protocol. AEs will be collected for all participants from the time of start of protocol treatment until 100 days post cessation of trial therapy with those AEs judged by the investigator or sponsor as having a reasonable suspected causal relationship to nivolumab, ipilimumab or the combination of the two, qualifying as ARs, SARs or SUSARs as appropriate. Additionally, AEs that satisfy the seriousness criteria defined in section 15.1 of the protocol qualify as SAEs.; 2. Treatment tolerability as measured by the proportion of participants experiencing a dose delay or interruption during treatment.; 3. Discontinuation rates due to treatment related toxicity as measured by the proportion of participants whose treatment was discontinued specifically due to treatment‐related toxicities at any point during the trial; 4. Discontinuation rates due to 'other' reasons as measured by the proportion of participants whose treatment was discontinued for any reason other than treatment‐related toxicities at any point during the trial; 5. Overall response rate as measured by the proportion of participants who achieve either partial response or complete response (PR or CR) as their best response to treatment prior to first progression (both as defined under RECIST v1.1) assessed via 12‐weekly CT scans; 6. Duration of response as measured by the length of time in days between the first observation of at least PR in a participant until either disease progression or death; 7. Response rate post‐progression (for those receiving treatment beyond progression) as measured by the proportion of participants that were treated beyond progression who show a PR or CR best response compared to measurements of disease taken at the time of first RECIST‐defined progression; 8. Overall survival as measured by the length of time in days from the date of randomisation to the date of death from any cause for a participant. Participants who are still alive at the time of analysis will become censored at the date they were last known to be alive; 9. Health related quality of life as measured by EQ‐5D‐5L, EORTC QLQ‐C30, FACT FKSI‐19 and study‐specific symptoms questionnaires at Baseline, Week 7, Week 13, then every 12 weeks until disease progression or Week 60, whichever is earlier INCLUSION CRITERIA: 1. Aged 18 years or over 2. Diagnosed with advanced (not amenable to curative surgery) or metastatic RCC 3. Histopathologically confirmed clear cell renal cell cancer (or with a component of clear cell) 4. Evidence of measurable disease as per RECIST v1.1 (ie, =1 malignant tumour mass that can be accurately measured in at least 1 dimension = 20 mm with conventional computerized tomography scan or Magnetic Resonance Imaging [MRI], or =10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable 5. Life expectancy of = 6 months 6. Karnofsky Performance Status (KPS) of at least 70% 7. Required laboratory values within 14 days prior to registration: 7.1. WBC = 2000/µL 7.2. Neutrophils = 1500/µL 7.3. Platelets = 10