A dose-escalation and expansion study of the safety and pharmacokinetics of XB002 in subjects with inoperable locally advanced or metastatic solid tumors (301)

Objectives: Cervical cancer and epithelial ovarian cancer (EOC) are two of the most prevalent gynecologic cancers associated with high mortality. Despite recent advancements in therapy, there is an unmet need for novel treatments to improve survival outcomes. XB002 is an antibody-drug conjugate (ADC) that targets tissue factor (TF). TF is a protein overexpressed in many solid tumors, including gynecologic cancers, and is associated with disease progression and poor prognosis. XB002 is a human mAb (25A3) directed against TF conjugated to a novel cytotoxic agent (payload) N-acyl sulfonamide auristatin, ZD02044. XB002 has been designed to improve the therapeutic potential of ADCs targeting TF as a new therapeutic strategy in cancers. XB002 has demonstrated activity in several solid tumor xenograft models. The objective of this ongoing first-in-human study is to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), and preliminary antitumor activity of XB002 in patients with advanced solid tumors with limited treatment options. Presented here are the trial design and details of the cervical and EOC cohorts. Methods: In this phase 1, non-randomized, open-label, multicenter, dose-escalation, and dose-expansion study (NCT04925284), patients with advanced solid tumors will receive XB002 IV every three weeks at a starting dose of 0.16 mg/kg. In the dose-escalation stage, an i3+3 study design will be used to identify the maximum tolerated dose (MTD)/recommended dose (RD) and/or the maximum allowed dose of XB002. Dose level decisions will be made by the Cohort Review Committee after review of all available safety and PK data. In the cohort-expansion phase, the MTD/RD will be further evaluated for safety and preliminary efficacy in multiple tumor-specific expansion cohorts that will be enrolled using a Simon's 2-stage design. Patients will be treated until radiographic progression per RECIST v1.1 or unacceptable toxicity. Patients in the cervical and EOC expansion cohorts must have received ≤2 (cervical) or ≤3 (EOC) lines of prior systemic anticancer therapy for locally advanced or metastatic disease. Patients must have received prior platinum-containing therapy in both cohorts, and patients must have platinum-resistant disease in the EOC cohort. The primary endpoint of the cohort-expansion stage will be objective response rate (ORR) per RECIST v1.1 assessed by the investigator. Other endpoints will include duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 assessed by the investigator, and overall survival; ORR, DOR, and PFS may also be assessed by a blinded independent radiology committee in select expansion cohorts. The effects of XB002 on tumor and blood biomarkers, including TF expression, will be assessed in exploratory analyses. For patients with EOC, blood samples for CA125 assessment will be collected at screening and throughout treatment in both stages of the study.