ATLANTIS: a randomised multi-arm phase II biomarker-directed umbrella screening trial of maintenance targeted therapy after chemotherapy in patients with advanced or metastatic urothelial cancer

Fulton, Ben; Jones, Robert J.; Powles, Thomas; Crabb, Simon J.; Paul, James; Birtle, Alison; Hussain, Syed A.; Morris, Anna; Soulis, Eileen; Morrison, Paula

doi:10.1186/s13063-020-04283-5

Cited by 11 publications

(11 citation statements)

References 23 publications

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“…AFFILIATIONS 1 Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom 2 University of Sheffield and Sheffield Teaching Hospitals, Sheffield, United Kingdom 3 CRUK Glasgow Clinical Trials Unit, University of Glasgow, Glasgow, United Kingdom 4 The Christie NHS Foundation Trust, Manchester, United Kingdom 5 Velindre Cancer Centre, Cardiff, United Kingdom 6 Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom 7 Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom 8 Leicester Royal Infirmary NHS Trust, Leicester, United Kingdom 9…”

Section: Corresponding Authormentioning

confidence: 99%

“… 4 , 6 , 7 However, maintaining clinical benefit from first-line chemotherapy represents an attractive strategy to improve outcomes. 6 , 8 Avelumab maintenance immunotherapy, following first-line chemotherapy, improves survival and represents a new standard of care. 6 However, only a minority of patients appear to benefit from immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…We tested this in a randomized phase II signal-seeking study within the ATLANTIS clinical trial platform. 8 The study was performed before the availability of data that now support the use of maintenance avelumab, thereby justifying a placebo control arm. 6 …”

Section: Introductionmentioning

confidence: 99%

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A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma

Crabb

Hussain

Soulis

et al. 2023

JCO

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PURPOSE A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker–positive mUC. METHODS DRD biomarker–positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model. RESULTS Out of 248 patients, 74 (29.8%) were DRD biomarker–positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib. CONCLUSION Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.

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Section: Corresponding Authormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma

Crabb

Hussain

Soulis

et al. 2023

JCO

Self Cite

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“…The most commonly allowed adaptation was futility/efficacy monitoring (60.0%, 9/15). Other adaptive features observed were adaptive randomization (20.0%, 3/15) ( 38 , 39 ), sample size re-estimation (6.7%, 1/15) ( 40 ), addition of new arms (13.3%, 2/15) ( 23 , 41 ), and a two-stage design to terminate ineffective treatments in stage I (20%, 3/15) ( 23 , 42 , 43 ).…”

Section: Characteristics Of Conducted Umbrella Trialsmentioning

confidence: 99%

Design and analysis of umbrella trials: Where do we stand?

Ouma

Wason²,

Zheng³

et al. 2022

Front. Med.

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BackgroundThe efficiencies that master protocol designs can bring to modern drug development have seen their increased utilization in oncology. Growing interest has also resulted in their consideration in non-oncology settings. Umbrella trials are one class of master protocol design that evaluates multiple targeted therapies in a single disease setting. Despite the existence of several reviews of master protocols, the statistical considerations of umbrella trials have received more limited attention.MethodsWe conduct a systematic review of the literature on umbrella trials, examining both the statistical methods that are available for their design and analysis, and also their use in practice. We pay particular attention to considerations for umbrella designs applied outside of oncology.FindingsWe identified 38 umbrella trials. To date, most umbrella trials have been conducted in early phase settings (73.7%, 28/38) and in oncology (92.1%, 35/38). The quality of statistical information available about conducted umbrella trials to date is poor; for example, it was impossible to ascertain how sample size was determined in the majority of trials (55.3%, 21/38). The literature on statistical methods for umbrella trials is currently sparse.ConclusionsUmbrella trials have potentially great utility to expedite drug development, including outside of oncology. However, to enable lessons to be effectively learned from early use of such designs, there is a need for higher-quality reporting of umbrella trials. Furthermore, if the potential of umbrella trials is to be realized, further methodological research is required.

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“…In this study, BRCAness phenotype was retrospectively evaluated: HRR alterations were found in 44.7% of patients, illustrating platinum sensitivity of mUC with DDR deficiency. In contrast, the Atlantis trial is a biomarker-directed, multi-arm phase II study, in maintenance setting for mUC after platinum-based chemotherapy response or stable disease [ 12 , 13 ]. Results from the Atlantis rucaparib arm in DDR-selected mUC were recently presented: maintenance rucaparib was associated with promising benefit as compared to placebo (median PFS 35 versus 15 weeks respectively, HR 0.53, 80% CI 0.30–092; p = 0.07).…”

Section: Introductionmentioning

confidence: 99%

TALASUR trial: a single arm phase II trial assessing efficacy and safety of TALazoparib and Avelumab as maintenance therapy in platinum-Sensitive metastatic or locally advanced URothelial carcinoma

et al. 2022

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Background Urothelial carcinoma (UC) is the ninth most commonly diagnosed cancer worldwide, with a 3.8/1 male to female ratio. Platinum-based chemotherapy is the first line standard of care for fit patients with advanced UC. However, despite a response rate (RR) for approximately half of patients receiving standard chemotherapy, durable responses are rare (median progression-free progression (PFS) around 8 months). Recently, immune checkpoint inhibitors (ICI) have emerged as new therapeutic options. Among them, Avelumab, an anti-PD-L1 antibody, was assessed in maintenance treatment, demonstrating an overall survival improvement in the JAVELIN Bladder-100 phase III trial. These findings led to its approval as first line maintenance therapy for patients with locally advanced or metastatic UC who have not progressed on prior platinum-containing chemotherapy. However, disease progression as best response was noticed for 37% of patients under Avelumab as maintenance treatment. UC has targetable genomic alterations, including DNA damage repair (DDR) alterations. DDR deficiency is known to major sensitivity to both platinum-based chemotherapy and PD-1/PD-L1 blockade and the combination of ICI and PARP inhibitors showed promising results. It therefore warrants to assess the interest of combining ICI plus PARP inhibitors as maintenance treatment in UC patients. Methods The TALASUR trial is a single-arm multicenter phase 2 study aiming to assess the antitumor activity of the combination of Avelumab with Talazoparib among patients with locally advanced/metastatic UC in maintenance therapy after platinum-based chemotherapy. The primary objective is to determine the efficacy of the combination, assessed through PFS. Secondary objectives are as follows: safety profile of the association, objective response, duration of tumoral response, disease control rate, time to subsequent therapy, quality of life. A blood and tumor collections will be also constituted. Patient will receive the combination therapy of daily oral Talazoparib (1 mg/day) and intra-venous Avelumab 800 mg on days 1 and 15, in a 28-day cycle. Fifty patients will be enrolled. Discussion Talazoparib with Avelumab combination may have additive activity when administrated jointly. We hypothesize that combination will increase the antitumor activity in UC first line maintenance setting with an acceptable safety profile. Trial registration NCT04678362, registered December 21, 2020. Protocol version: Version 1.3 dated from 2020 09 11.

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ATLANTIS: a randomised multi-arm phase II biomarker-directed umbrella screening trial of maintenance targeted therapy after chemotherapy in patients with advanced or metastatic urothelial cancer

Cited by 11 publications

References 23 publications

A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma

A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma

Design and analysis of umbrella trials: Where do we stand?

TALASUR trial: a single arm phase II trial assessing efficacy and safety of TALazoparib and Avelumab as maintenance therapy in platinum-Sensitive metastatic or locally advanced URothelial carcinoma

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