CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study

Abstract

BackgroundConcurrent chemoradiotherapy is the standard of care for locally advanced cervical cancer. Concurrent chemoradiotherapy with programmed blockade of the cell death-1/programmed cell death-ligand 1 pathway may promote a more immunogenic environment through increased phagocytosis, cell death, and antigen presentation, leading to enhanced immune-mediated tumor surveillance.

Primary objective: The CALLA trial is designed to determine the efficacy and safety of the programmed cell death-ligand 1 blocking antibody, durvalumab, with and following concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in women with locally advanced cervical cancer.

Study hypothesis: Durvalumab concurrent with and following concurrent chemoradiotherapy will improve progression-free survival in patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 to IVA cervical cancer compared with concurrent chemoradiotherapy alone.

Trial design: CALLA is a phase III, randomized, multicenter, international, double-blind, placebo-controlled study. Patients will be randomized 1:1 to receive either durvalumab (1500 mg intravenously (IV)) or placebo every 4 weeks for 24 cycles. All patients will receive external beam radiotherapy with cisplatin (40 mg/m²) IV or carboplatin (area under the curve 2) IV once a week for 5 weeks, followed by image-guided brachytherapy.

Major inclusion/exclusion criteria: The study will enroll immunotherapy-naïve adult patients with histologically confirmed cervical adenocarcinoma, cervical squamous, or adenosquamous carcinoma FIGO 2009 stages IB2-IIB node positive and stage IIIA-IVA with any node stage. Patients will have had no prior definitive surgical, radiation, or systemic therapy for cervical cancer.

Primary endpoint: The primary endpoint is progression-free survival (assessed by the investigator according to Response Evaluation Criteria in Solid Tumors v1.1, histopathological confirmation of local tumor progression or death).

Sample size: Approximately 714 patients will be randomized 1:1 to receive either durvalumab + concurrent chemoradiotherapy or placebo + concurrent chemoradiotherapy.

Estimated dates for completing accrual and presenting results: Patient enrollment is continuing globally with an estimated completion date of April 2024.

Trial registration: NCT03830866.

Keywords: intestine, large; pain; peritoneal neoplasms; ureter; uterus.

Figure 1

Concurrent chemoradiotherapy + anti-programmed cell death-1/PD-L1 therapies: proposed mechanism of action. Data from pre-clinical and early clinical studies provide the rationale for adding anti-PD-1/PD-L1 therapies to CCRT to improve anti-tumor responses by recruiting the immune system. ATP, adenosine triphosphate; CD8, cluster of differentiation 8; CCRT, concurrent chemotherapy and radiation therapy; CRT,chemotherapy and radiation therapy; HMGB1, high-mobility group box 1; HPV, human papilloma virus; IC, immune cell; IFN, interferon; MHC, major histocompatibility complex; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1.

Figure 2

CALLA study design. CALLA is a phase III, randomized, double-blind, placebo-controlled, multicenter study. ADA, anti-drug antibody; Brachy, brachytherapy; CR, complete response; EBRT, external beam radiotherapy; FIGO, International Federation of Gynecology and Obstetrics; HRQoL, health-related quality of life; M, metastasis; N, node; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; Q4W, once every 4 weeks; R, randomization; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 3

Planned study sites. Approximately 131 sites including 114 sites outside the United States are planned.