Search

Purpose In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, this exposure–response analysis characterized the relationship of cabozantinib exposure with clinical endpoints. Methods Dose modification was allowed with cabozantinib (holds and reductions) to manage adverse events (AEs). The population pharmacokinetics analysis was updated and used to generate individual predicted cabozantinib exposure measures. Kaplan–Meier plots and time-to-event Cox proportional hazard (CPH) exposure–response models characterized the relationship of cabozantinib exposure with PFS, dose modifications, and selected AEs. Results Kaplan–Meier plots showed no clear difference in PFS across cabozantinib exposure quartiles. Cabozantinib exposure did not significantly affect the hazard of PFS in the CPH base model nor in the final model. In contrast, baseline albumin and nivolumab clearance had a significant effect on PFS. There was no significant relationship between cabozantinib clearance and risk of dose modification, but a significant relationship was identified between cabozantinib exposure and Grade ≥ 1 palmar-plantar-erythrodysesthesia and Grade ≥ 3 diarrhea in the exposure–response analysis. Conclusion To optimize individual cabozantinib exposure, these data support the dose modification strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when combined with nivolumab.

Background: XB002 is an antibody drug conjugate (ADC), with a high affinity human mAb directed against tissue factor (TF) conjugated to a novel cytotoxic agent (payload), ZLA (Zymelink Auristatin). TF is a protein overexpressed in many solid tumors and is associated with disease progression and poor prognosis. XB002 binds to TF without interfering with the coagulation pathway. With its mechanism of action, XB002 has been designed to improve the therapeutic potential of ADCs targeting TF and has demonstrated activity in several solid tumor xenograft models. The purpose of this ongoing first-in-human study is to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity (anti-drug antibodies) and preliminary antitumor activity of XB002. Presented here is the trial design. Methods: This is a phase 1, non-randomized, open-label, multicenter, dose-escalation and dose expansion study (NCT04925284). Patients must be ≥18 years old and have an ECOG performance status of 0-1 and adequate organ and marrow function. Patients will be treated until radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or unacceptable toxicity. The dose-escalation stage will use a modified i3+3 design; patients with advanced solid tumors (~21 patients) will receive XB002 IV once every 3 weeks. The primary endpoint for dose escalation is the maximum tolerated dose (MTD)/recommended dose (RD) of XB002 per Cohort Review Committee. The MTD/RD will be further evaluated in multiple tumor-specific expansion cohorts of advanced solid tumors (~30 patients per cohort) using a Simon’s 2-stage design. Tumor-specific cohorts (number of prior lines of systemic therapy for advanced disease) include: non-small cell lung cancer (≤3); urothelial cancer (≤3); platinum-resistant epithelial ovarian cancer (≤3); cervical cancer (≤2); squamous cell carcinoma of head and neck (≤3); and pancreatic cancer (1-2). Patients must have measurable disease per RECIST v1.1 and had radiographic progression during or after their last systemic therapy. The primary endpoint for cohort expansion is objective response rate per RECIST v1.1 by investigator. Additional endpoints include safety/tolerability, XB002 pharmacokinetics and immunogenicity, duration of response and PFS per RECIST v1.1 by investigator, overall survival, and changes in tumor markers from baseline. Citation Format: Melissa Johnson, Susanna Ulahannan, Andrae Vandross, Haeseong Park, Leo Faoro, Raffaella Faggioni, Jing Li, Yu-Lin Chang, Shailaja Uttamsingh, Anthony Tolcher. A first-in-human phase 1 study of the safety and pharmacokinetics of XB002 in patients with inoperable locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT254.