COMPANION-002: A Phase 2/3 Randomized Study Design of CTX-009 Combination in Second-Line BTC

Biliary tract cancer (BTC) is typically associated with a poor prognosis and a limited range of treatment options.¹

Systemic chemotherapy typically involves using gemcitabine, platinum agents, and a checkpoint inhibitor, followed by 5-fluorouracil, oxaliplatin, or irinotecan.²

The delta-like ligand (DLL)/Notch signaling pathway is widely recognized as a significant contributor to the development of cholangiocarcinogenesis.³

Additionally, there have been reports of vascular endothelial growth factor A (VEGF-A) overexpression in BTC tumors, which has shown a correlation with the stage, metastasis, and prognosis of the disease.⁴

CTX-009 is a recombinant bispecific antibody that blocks DLL4 and VEGF-A. It is the only DLL4 and VEGF bispecific antibody demonstrating monotherapy activity in the colorectal and gastric cancer clinic.^5,6

CTX-009 is being evaluated in a phase 2/3 open-label, randomized, controlled study (COMPANION-002, NCT05506943) in patients with previously treated, advanced, or metastatic BTC.

Eligible patients must have the following: unresectable advanced or recurrent BTC radiologically documented progression after a prior gemcitabine and platinum-containing chemotherapy regimen, ≥1 measurable lesions, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

A total of 150 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. Patients will be stratified by stage (locally advanced vs metastatic), anatomic subsite of primary tumor (intrahepatic cholangiocarcinoma vs other [ie, extrahepatic cholangiocarcinoma, gallbladder, or ampullary]), and an ECOG performance status of 0 to 1.

CTX-009 is a recombinant bispecific antibody that blocks DLL4 and VEGF-A. It is the only DLL4 and VEGF bispecific antibody demonstrating monotherapy activity in the colorectal and gastric cancer clinic.

Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg intravenously on day 1 and day 15, and paclitaxel administered at 80 mg/m² on day 1, day 8, and day 15, or paclitaxel alone administered at 80 mg/m² on day 1, day 8, and day 15. The patients randomized to the paclitaxel arm can cross over after disease progression if selection criteria continue to be met.

The primary objective is to assess the efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone in patients with BTC who have received 1 systemic therapy for advanced disease, as measured by the overall response rate assessed by an independent central radiology review.

The primary endpoint is the percentage of patients whose best overall response is assessed as a complete response or partial response as assessed by RECIST (version 1.1). Secondary objectives and endpoints include disease control rate, duration of response, progression-free survival, overall survival, safety, quality of life, and exposure response through pharmacokinetic analysis. This study is currently enrolling patients.⁷

References

1. Bramel ER, Sia D. Chapter 6: novel insights into molecular and immune subtypes of biliary tract cancers. In: Sirica AE, Fisher PB (eds). Advances in Cancer Research. Vol. 156. Academic Press. 2022;167-199.
2. Ramjeesingh R, Chaudhury P, Tam VC, et al. A practical guide for the systemic treatment of biliary tract cancer in Canada. Curr Oncol. 2023;30(8):7132-7150.
3. Rauff B, Malik A, Bhatti YA, et al. Notch signalling pathway in development of cholangiocarcinoma. World J Gastrointest Oncol. 2020;12(9):957-974.
4. Schirizzi A, De Leonardis G, Lorusso V, et al. Targeting angiogenesis in the era of biliary tract cancer immunotherapy: biological rationale, clinical implications, and future research avenues. Cancers. 2023;15(8):2376.
5. Patel SA, Nilsson MB, Le X, et al. Molecular mechanisms and future implications of VEGF/VEGFR in cancer therapy. Clin Cancer Res. 2023;29(1):30-39.
6. Zhao Q, Zong H, Zhu P, et al. Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs. Exp Hematol Oncol. 2024;13(1):6.
7. Aranha O, Hu I, Faridi A, et al. A phase 2/3 randomized study of CTX-009 combination in 2L biliary tract cancer: COMPANION-002. San Francisco, CA, & online: presented at ASCO Gastrointestinal Cancers Symposium; January 18-20, 2024: poster P16.