Changes in CTCAE v6: Effect on dose-escalation and dose-limiting toxicity with repeat analysis of recent clinical trials.

143 Background: Several therapeutic modalities for cancer have associated myelosuppression. Amongst changes in CTCAE v6, grade (Gr) 4 thrombocytopenia (plts) has been redefined as a platelet count <10,000/dL (< 25,000/dL in CTCAE v.5) and lymphopenia is limited to Gr 0-2 (previously Gr 0-4). Common definition of dose-limiting toxicity (DLT) includes Gr 3 non-hematologic toxicity or Gr 4 hematologic toxicity. Using newer grading to define DLT may result in higher recommended phase 2 dose (RP2D) in future trials. Methods: We retrospectively reviewed prospectively collected data of 208 patients from phase 1 trials of targeted radionuclide therapy and/or chemotherapy in patients with advanced cancer (NCT03276572, NCT03042468, NCT04576871, NCT04506567, NCT04886986, NCT02913196, NCT04946370, NCT00967577) and regraded according to CTCAE v.6 adverse events list. Results: Across 8 studies 17 DLTs were discovered per CTCAE v5. Among them 6 (35.3%) were confirmed cases of Gr 4 thrombocytopenia’s (TCP) and 1 Gr 4 TCP and anemia (5.9%) Other DLTs included 3 Gr 1, 3 Gr 2 and 2 Gr 3 thrombocytopenia delaying cycle 2/C3 for >3 weeks, 1 Gr 3 Hypertension and 1 Gr 3 hepatic failure. Among these none (n=7) of the Gr 4 TCP would have been deemed DLT using CTCAE v6 criteria, with a 41% reduction in observed DLTs. Hence, the RP2D may have been different had the trials been conducted using the new criteria of adverse events. Conclusions: Changes in grading by CTCAE may result in different administered dose or schedule of drugs with associated myelosuppression in the near future. Clinical trial information: NCT03276572 , NCT03042468 , NCT04576871 , NCT04506567 , NCT04886986 , NCT02913196 , NCT04946370 , NCT00967577 . List of DLT according to clinical trials. Trial Subject DLT Platelet count CTCAE v.5 grading CTCAE v.6 grading DLT according to new grading system? NCT03276572 1 1 Gr 4 TCP 18,000k/uL Gr 4 Gr 3 No NCT04886986 2 1 Grade 2 and 1 Grade 3 TCP delaying cycle 2 for >3 weeks - Gr 2, Gr 3 Unchanged Yes NCT02913196 1 Grade 3 Hypertension - Gr 3 Unchanged Yes NCT04576871 2 1 Gr 4 TCP 11,000 K/uL Gr 4 Gr 3 No