Expanding eligibility criteria for renal and liver function in NCI-sponsored immunotherapy clinical trials.
Authors: Shin Sarah , Chen Alice P. , Kruhm Martha , Loose David , O'Sullivan Coyne Geraldine Helen , Takebe Naoko , Sharon Elad 
Published: June 2023

e13610 Background: Stringent eligibility criteria can slow accrual, impede evaluation of potentially promising anticancer therapies, and limit applicability of trial results to the larger population. Immuno-Oncology (IO) clinical trials utilizing anti-PD1/PDL1 monoclonal antibodies (mAb) are ideal candidates to broaden organ function (fcn) eligibility, as their kinetics are independent of renal or hepatic fcn. Herein we present an analysis of the current landscape of renal and hepatic eligibility criteria in NCI CTEP-sponsored IO clinical trials to determine if these meet the recommended guidelines for broadened criteria. Methods: We conducted a retrospective analysis of renal and hepatic fcn eligibility criteria of NCI-sponsored IO trials in the CTEP networks initiated by the data cut-off date of 4/24/22. At least one treatment arm on all included trials had an anti-PD1/PDL1 mAb either alone or in combination with other agents. ASCO and Friends of Cancer Research (ASCO/Friends) recommendations and the NCI broadened eligibility criteria were used to assess the trials. ASCO/Friends broadens inclusion criteria for renal fcn to a creatinine clearance (CrCl) of > 30 mL/min but gives no specific hepatic fcn cutoff. NCI recommends broadened criteria to glomerular filtration rate (GFR) of ≥ 60 mL/min/1.73m2 for the Experimental Therapeutics Clinical Trials Network and all phase 1 trials or GFR ≥ 50 mL/min/1.73m2 for National Clinical Trials Network (NCTN) trials, unless safety data exists for lower renal fcn values, and no lower than 30 mL/min/1.73m2. NCI suggests hepatic fcn criteria with total bilirubin ≤ institutional upper limit of normal (ULN) and AST/ALT ≤ 3 × ULN. CrCl and GFR were deemed interchangeable in this analysis. Results: A total of 182 IO trials were identified. Of these, 45 (25%) required CrCl > 30 mL/min. Three trials (2%) allowed for CrCl < 30 mL/min: one trial each requiring CrCl > 25 mL/min, 20 mL/min, and 15 mL/min. One trial had no renal criteria. Ninety-five trials (52%) were compliant with the suggested NCI template guidance but not ASCO/Friends: 20 trials with CrCl > 60 mL/min, 48 trials with > 50 mL/min, 10 trials with > 45 mL/min, and 17 trials with > 40 mL/min as the renal eligibility criteria. Thirteen trials (7%) did not abide by either guidance: 6 NCTN trials with CrCl > 60 mL/min and 4 trials requiring CrCl > 70 mL/min. Serum creatinine alone was utilized for renal fcn in 22 trials. For hepatic criteria, 82 trials (45%) complied with NCI recommendations. The other 100 trials (55%) did not utilize the suggested NCI template cutoff for AST/ALT of 3 x ULN, but 81 of these trials allowed for AST/ALT at 2.5 x ULN with 27 of the 81 trials allowing for 5 x ULN for AST/ALT if liver metastases were present. Conclusions: Our results demonstrate that clinical trials have updated toward broadening hepatic eligibility criteria but require further guidance to facilitate a less cautious approach with renal fcn.