Dataset Information

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.

SUBMITTER: Mayadev J

PROVIDER: S-EPMC7398223 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

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.

Mayadev Jyoti J Nunes Ana T AT Li Mary M Marcovitz Michelle M Lanasa Mark C MC Monk Bradley J BJ

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 20200523 7

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.<h4>Primary objective</h4>The CALLA trial is designed to determine the efficacy and safety of the programmed cell deat ...[more]

PMID: 32447296

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Project description:PurposeInduction chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy alone are both standard treatment regimens for managing locally advanced nasopharyngeal carcinoma. However, the results of comparisons between them in clinical trials vary. Therefore, we designed this meta-analysis to illustrate their advantages and disadvantages in patients with locally advanced nasopharyngeal carcinoma.MethodsWe thoroughly searched the PubMed, EMBASE, and Cochrane Library databases and then merged the effect indicators of hazard ratios and risk ratios using RevMan 5.1.ResultsSeven randomized controlled trials totaling 2,319 patients were included in our research. The synthesized results showed that induction chemotherapy plus concurrent chemoradiotherapy improved overall survival (HR = 0.75, 95% CI: 0.63-0.89, P = 0.001), progression-free survival (HR = 0.69, 95% CI: 0.60-0.80, P < 0.001), distant metastasis-free survival (HR = 0.65, 95% CI: 0.53-0.80, P < 0.001) and locoregional recurrence-free survival (HR = 0.68 95%, CI: 0.54-0.86, P = 0.001) versus concurrent chemoradiotherapy alone. It also increased the risk of anemia, thrombocytopenia, and neutropenia during concurrent chemoradiotherapy. However, the incidence of leukopenia and mucositis was similar in induction chemotherapy and induction chemotherapy plus concurrent chemoradiotherapy. Furthermore, the subgroup analysis showed better survival outcomes with induction chemotherapy plus concurrent chemoradiotherapy than with concurrent chemoradiotherapy alone in the triweekly cisplatin subgroup (all P < 0.01), whereas induction chemotherapy plus concurrent chemoradiotherapy could only improve progression-free survival and locoregional recurrence-free survival in the weekly cisplatin subgroup (HR = 0.78, P = 0.02; and HR = 0.66, P = 0.03, respectively).ConclusionsInduction chemotherapy plus concurrent chemoradiotherapy improved survival outcomes in patients with locally advanced nasopharyngeal carcinoma versus concurrent chemoradiotherapy. For the weekly cisplatin regimen subgroup, it did not improve remote control or overall survival versus concurrent chemoradiotherapy alone, warranting further clarification.

Project description:BackgroundConcurrent chemoradiotherapy followed by adjuvant chemotherapy (CCRT-AC) is currently recommended as the standard treatment for locally advanced nasopharyngeal carcinoma (LA-NPC). Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NAC-CCRT) is an alternative strategy for decreasing tumor size and controlling micrometastases before main treatment. The aim of this study was to investigate and compare survival outcomes between LA-NPC patients treated with CCRT-AC and those treated with NAC-CCRT.MethodsThis retrospective cohort study included consecutive histologically confirmed LA-NPC patients that were treated with NAC-CCRT or CCRT-AC at Siriraj Hospital during the March 2010 to October 2014 study period. CCRT in both protocols consisted of 3-week cycles of cisplatin 100 mg/m2 with concurrent radiotherapy. Either NAC or AC consisted of 3-week cycles of cisplatin on day 1 and fluorouracil/leucovorin on days 1-4 for a maximum three cycles. The primary endpoint was 5-year overall survival (OS). Flexible parametric survival analysis was used, because the proportional hazards assumption of Cox regression was violated.ResultsOf the 266 LA-NPC patients that received treatment during the study period, 79 received NAC-CCRT and 187 received CCRT-AC. Median follow-up was 37 months. Significantly more patients with advanced clinical stage (stage IVA-IVB) received NAC-CCRT (86% in NAC-CCRT vs. 29% in CCRT-AC; p < 0.001). Compared to CCRT-AC in crude analysis, 3-year and 5-year OS of NAC-CCRT were 72% vs. 86% and 62% vs. 75% respectively (p = 0.059). Interestingly, the 3-year and 5-year post-estimation adjusted OS was 84% and 74% for NAC-CCRT and 81% and 70% for CCRT-AC, respectively (HR: 0.83, 95% confidence interval (CI): 0.45-1.56; p = 0.571). Also, adjusted analysis of distant-metastasis survival, NAC-CCRT showed HR was 0.79 (95% CI:0.37-1.72, p = 0.557). Conversely, adjusted analysis of locoregional relapse (LLR)-free survival revealed NAC-CCRT to have a significantly higher risk of LRR (HR: 2.18, 95% CI: 0.98-4.87; p = 0.057).ConclusionsThe results suggested that prognosis in the NAC-CCRT treated patients was not superior to that of the CCRT-AC treated individuals. In patients that receive neoadjuvant chemotherapy, locoregional relapse should be of concern. High-risk distant metastasis patients (N3 stage) that could achieve survival advantage from NAC-CCRT is an interesting and important topic for further study.

Project description:The benefit of adjuvant hysterectomy after definitive concurrent chemoradiotherapy (CCRT) for locally-advanced cervical cancer (LACC) is controversial. The purpose of the present study was to systematically search the literature and perform a meta-analysis to compare overall survival (OS) and disease-free survival (DFS) between patients subjected to CCRT with hysterectomy and those who underwent CCRT alone. The PubMed, Scopus, Embase and Google scholar databases were searched. A meta-analysis to determine hazard ratios (HRs) and odds ratios (ORs) with meta-regression was performed for the following moderators: Disease stage, histology and proportion of radical hysterectomy. Data from 14 studies were included. The results indicated that patients who received CCRT with hysterectomy had significantly better OS (HR, 0.72; 95% CI, 0.56 to 0.91; I2=19%; P=0.007) and DFS (HR, 0.72; 95% CI, 0.56 to 0.93; I2=27%; P=0.01) than those treated with CCRT alone. However, in a subgroup analysis by study type, the results were significant only for retrospective studies but not for randomized controlled trials (RCTs). However, only 2 RCTs were included with small sample size, heterogeneity and low overall quality. Subgroup analyses based on the use of brachytherapy in the CCRT with hysterectomy group demonstrated no difference in OS and DFS between the two groups. Regarding the absolute numbers of death and recurrence events, no significant difference in mortality (OR, 0.91; 95% CI, 0.62 to 1.33; I2=0%; P=0.64) was determined between the two groups, but a significantly reduced incidence of recurrence was observed in the CCRT with hysterectomy group (OR, 0.61; 95% CI, 0.47-0.79; I2=29%; P=0.0002). The meta-regression results point to a significant influence of the proportion of stage II patients on OS. Despite the overall analysis indicating improved OS and DFS with the use of adjuvant hysterectomy after CCRT, subgroup analysis based on similar treatment protocols failed to demonstrate any significant benefit of hysterectomy in LACC. However, the results indicated that the recurrence rate may be higher in patients undergoing CCRT without hysterectomy. The limited quality of the studies included and selection bias from retrospective studies restrict the possibility to draw strong conclusions.

Dataset Information

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.

Primary objective

Study hypothesis

Trial design

Major inclusion/exclusion criteria

Primary endpoint

Sample size

Estimated dates for completing accrual and presenting results

Trial registration

Publications

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.

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