NCT03793166.

Study name	PDIGREE
Methods	Study type: RCT, phase III, parallel assignment Blinding: no, open‐label Accrual period: May 9, 2019 ‐ April 9, 2022 (estimated study completion date) Countries: multicentre, 804 study locations Cross‐over study: no Status: Recruiting (as of June 3, 2022)
Participants	Estimated enrolment: N=1046 Inclusion criteria: histologically documented renal cell carcinoma with clear cell component, including patients who have sarcomatoid features any metastatic disease, including visceral, lymph node, other soft tissue and bone, measurable per RECIST 1.1 measurable disease as defined in the protocol Must be intermediate or poor risk patient per International Metastatic Renal Cell Carcinoma Database (IMDC) criteria Central nervous system (CNS) disease permitted, if stable and not otherwise causing symptoms or needing active treatment Karnofsky performance status >= 70%. no prior treatment with PD‐1, PD‐L1, or CTLA‐4 targeting agents (including but not limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting T‐cell co‐stimulation or checkpoint pathways. The only exception is for prior treatment with nivolumab or other PD‐1/PD‐L1/CTLA‐4 targeting therapy on pre‐ or post‐operative trials, as long as > 1 year since completion of systemic therapy no prior previous systemic therapy for renal cell carcinoma (prior HD IL‐2 [> 28 days] and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as above are allowed) no cancer therapy less than 28 days prior to registration; this includes radiation therapy, except for bone lesions less than 14 days prior to registration. There must be a complete recovery and no ongoing complications from radiotherapy all sexes, age >= 18 years STEP 2 registration eligibility criteria successful completion of at least 1 cycle of ipilimumab/nivolumab resolution of any treatment‐related adverse events to grade 1 or less per dose modification section (this criteria does not include any adverse events [AEs] not attributable to treatment which are present due to disease). Exceptions for this criteria include patients receiving replacement hormone treatments (such as levothyroxine for treatment‐related hypothyroidism or glucocorticoid replacement for adrenal insufficiency). Please contact study chair if further discussion is needed no more than 70 days from last dose of ipilimumab/nivolumab Exclusion criteria: active autoimmune disease requiring ongoing therapy ongoing acute toxicity > grade 2 from previous treatment major surgery less than 28 days prior to registration significant cardiac ischemias events (ST elevation myocardial infarction [STEMI] or non‐ST elevation myocardial infarction [NSTEMI]) within 6 months or active NY Heart Association class 3‐4 heart failure symptom More inclusion criteria on CT.gov.
Interventions	Experimental arm: nivolumab + cabozantinib Control arm: nivolumab + ipilimumab
Outcomes	Primary outcome(s): OS (time frame: from registration to date of death from any cause for non‐randomised patients, from time of randomisation until death from any cause for randomised patients, assessed up to 5 years) Secondary outcome(s): PFS (time frame: from date of registration to date of progression or death from any cause, whichever occurs first, assessed up to 5 years) proportion of participants who discontinue protocol‐directed treatment (time frame: up to 5 years) AEs (time frame: up to 5 years) Relevant to this review but not reported: QoL, SAEs, TFST Other outcomes (not relevant to this review): CR, OR
Starting date	09.05.2019
Contact information	Tian Zhang
Notes	Funding sources: National Cancer Institute (NCI)