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A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

ABSTRACT: We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m². Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

SUBMITTER: Okonogi N

PROVIDER: S-EPMC10342070 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

Okonogi Noriyuki N Murata Kazutoshi K Yamada Shigeru S Habu Yuji Y Hori Makoto M Kurokawa Tomoya T Inaba Yosuke Y Fujiwara Tadami T Fujii Yasuhisa Y Hanawa Michiko M Kawasaki Yohei Y Hattori Yoko Y Suzuki Kazuko K Tsuyuki Kyoko K Wakatsuki Masaru M Koto Masashi M Hasegawa Sumitaka S Ishikawa Hitoshi H Hanaoka Hideki H Shozu Makio M Tsuji Hiroshi H Usui Hirokazu H

International journal of molecular sciences 20230623 13

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m<sup>2</sup>. Durvalumab w ...[more]

PMID: 37445743

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Project description:IntroductionConcurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects.ObjectiveWe will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer.Methods and analysisThis study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation.Ethics and disseminationThe Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences.Trial registration numberJapan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

Project description:BackgroundCurrently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). Forty percent of patients present with disease recurrence. This study aims to investigate the feasibility, safety and efficacy of neoadjuvant chemotherapy (NACT) with weekly cisplatin and paclitaxel (TP) followed by CCRT.MethodsWe are conducting a phase III trial comparing the efficacy and side effects of patients with cervical cancer (FIGO 2018 stage IIB to IVA) who were assigned to four cycles of NACT with cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly followed by CCRT or CCRT alone. In this report, we studied the medium-term effect of 50 patients enrolled in the NACT + CCRT arm. The primary endpoints were the response rate post-NACT and 12 weeks post-CCRT evaluated by MR/CT based on RECIST v 1.1. The secondary endpoints were 3-year OS (overall survival) and PFS (progression-free survival) measured by the Kaplan-Meier method.ResultsAmong 50 patients enrolled in the NACT + CCRT arm, the complete and partial response rates were 10.4% and 68.8%, post-NACT. Twelve weeks after treatment completion, the complete response rate was 72.0%, whereas the total response rate (complete and partial response) was 90.0%. After a median follow-up of 28 months, the 3-year OS rate was 83.9%, and the 3-year PFS rate was 73.6%. NACT response was related to superior PFS and OS compared with NACT nonresponse (P < 0.01). Late AEs were exiguous, while early AEs mainly included myelosuppression and gastrointestinal AEs.ConclusionsThis study showed a good response rate achieved by dose-dense weekly cisplatin and paclitaxel followed by standard CCRT. The treatment regimen is feasible, as evidenced by the acceptable toxicity of NACT and by the high compliance with radiotherapy.Trial registrationProtocol version number and date. Chinese clinical trial registry, ChiCTR1900025327; http://www.chictr.org.cn . Registered 24 August 2019. Retrospectively registered, medresman.org.cn/ChiCTR1900025326. The date recruitment began 01-01-2019.

Project description:Background: Metastatic anaplastic thyroid cancer (ATC) has a poor prognosis. This pilot study aims to evaluate tremelimumab plus durvalumab with stereotactic body radiotherapy (SBRT) to improve overall survival (OS). Methods: Eligible patients received up to 4 doses tremelimumab (75 mg) given q4 weeks and up to 1 year of durvalumab (1500 mg) given q4 weeks. SBRT at 9 Gy × 3 fractions was given within the first 2 weeks of the start of treatment. Paired biopsies (pretreatment and between 3 and 10 weeks after the first dose of the drug treatment) were done in the medically qualified patients. Major inclusion criteria are metastatic ATC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no prior immunotherapy, and last anticancer treatment >7 days before starting the study. The primary endpoint was 1 year OS with the combination of durvalumab, tremelimumab, and SBRT in metastatic ATC patients with a target of 1 year OS in ≥2 out of 12 patients. Results: A total of 13 patients signed consent but only 12 patients ultimately participated in this trial. One patient who consented to the protocol became ineligible for this study due to continued decline in performance status. Patient characteristics were as follows: male (n = 6) with a median age of 71 years (range: 49-82), and ECOG = 1. Nine patients had prior neck radiation and nine patients had prior chemotherapy. Next-generation sequencing and PD-L1 staining were done in the nine patients where tissue was available. High microsatellite instability (MSI) corresponding to mismatch repair defect was noted in two patients. There were zero confirmed responses and only one patient had stable disease and was treated with ≥4 cycles of study drugs. The median time that the patients were under treatment was 11 weeks (1-28 weeks). MSI status did not affect treatment response. High MSI patients were on treatment for 8-14 weeks before disease progression. The median OS was 14.5 weeks with only 1 patient alive beyond 1 year. The presence of a BRAF or p53 mutation did not appear to affect treatment outcome. Conclusions: Tremelimumab and durvalumab with SBRT did not improve OS for ATC. Future research is needed to examine other novel immunotherapy combinations with or without radiotherapy in the treatment of ATC. Clinical Trial Registration: NCT03122496.

Dataset Information

A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

Publications

A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

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