A Study of Catequentinib Hydrochloride (AL3818) in Endometrial, LGSOC, STS or GBM Cancers

AL-GB-900 is an international, multicenter, open-label, nonrandomized phase 1b/2a study of oral AL3818, a fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinase inhibitor. AL3818 is evaluated as monotherapy and in combination with oral AL58805, a PI3K/mTOR inhibitor, or with the alkylating agents temozolomide or lomustine. Phase 1b uses protocol-defined 3+3 dose-exploration cohorts to select a monotherapy recommended phase 2 dose (RP2D) and regimen-specific recommended combination doses (RCDs) based on dose-limiting toxicities (DLTs) during the first cycle. Cohort A1 evaluates AL3818 monotherapy in adults with recurrent or metastatic non-small cell lung cancer, small cell lung cancer, soft tissue sarcoma, thyroid cancer, endometrial cancer, low-grade serous ovarian cancer, or breast cancer. Cohort A2 evaluates AL3818 plus AL58805 in endometrial cancer, low-grade serous ovarian cancer, or soft tissue sarcoma. Cohort B1 evaluates an AL3818 monotherapy run-in in glioblastoma, and eligible participants may transition to Cohort B2 for separate dose evaluations of AL3818 plus temozolomide or AL3818 plus lomustine. Phase 2a evaluates preliminary efficacy and further safety at the selected doses. Cohort C evaluates AL3818 monotherapy in separate endometrial cancer molecular groups (TP53-mutated adenocarcinoma, TP53-associated carcinosarcoma, and TP53-wild-type disease) and in low-grade serous ovarian cancer. Cohort D evaluates AL3818 plus AL58805 in separate endometrial cancer, low-grade serous ovarian cancer, and soft tissue sarcoma groups. Cohort E evaluates AL3818 plus temozolomide and AL3818 plus lomustine in separate glioblastoma groups. For non-glioblastoma phase 2a groups, the primary activity measure is objective response rate according to RECIST version 1.1. For glioblastoma, the primary activity measure is the proportion of participants alive and progression-free at 6 months according to RECIST version 1.1. Imaging is generally performed at baseline and approximately every 8 weeks. Complete or partial responses are confirmed by repeat imaging 4 to 8 weeks later. Study treatment may continue for up to 12 months or until disease progression, unacceptable toxicity, withdrawal, intercurrent illness, or sponsor termination. Temozolomide or lomustine is administered for no more than 6 cycles; participants may continue AL3818 afterward if otherwise eligible. Participants who remain without progression and continue to benefit may continue protocol-specified compassionate-care treatment beyond 12 months at the investigator's discretion. The sponsor must reconcile the enrollment arithmetic, the glioblastoma statistical decision rule, and several dose specifications before the record is released.