Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Swisher, Elizabeth M.; Lin, Kevin K.; Oza, Amit M.; Scott, Clare L.; Giordano, Heidi; Sun, James; Konecny, Gottfried E.; Coleman, Robert L.; Tinker, Anna V.; O’Malley, David M.; Kristeleit, Rebecca; Ma, Ling; Bell‐McGuinn, Katherine M.; Brenton, James D.; Cragun, Janiel M.; Oaknin, Ana; Ray‐Coquard, Isabelle; Harrell, Maria I.; Mann, Elaina; Kaufmann, Scott H.; Floquet, Anne; Leary, Alexandra; Harding, Thomas C.; Goble, Sandra; Maloney, Lara; Isaacson, Jeff; Allen, Andrew R.; Rolfe, Lindsey; Yelensky, Roman; Raponi, Mitch; McNeish, Iain A.

doi:10.1016/s1470-2045(16)30559-9

Cited by 1,044 publications

(1,001 citation statements)

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“…Inhibition of these transporters has also been demonstrated in vitro with the PARP inhibitor veliparib and other drugs (39,40). Some AEs observed with rucaparib treatment, The benefits of PARP inhibitors for treatment of germline BRCA1/2-mutated ovarian cancer are well established, with response rates in the range of 38% to 60% reported in patients with platinum-sensitive disease (16,18,19,24,(41)(42)(43). In the 42 patients with platinum-sensitive, relapsed HGOC associated with a germline BRCA1/2 mutation enrolled in part 2A of this study (600 mg twice daily), the investigator-assessed ORR was 59.5% by RECIST and 83.3% by RECIST/CA-125 criteria.…”

Section: Discussionmentioning

confidence: 98%

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Kristeleit

Shapiro

Burris

et al. 2017

Clinical Cancer Research

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Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate singleagent oral rucaparib at multiple doses.Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately doseproportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2-mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC. Clin Cancer Res; 23(15); 4095-106. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 98%

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Kristeleit

Shapiro

Burris

et al. 2017

Clinical Cancer Research

Self Cite

220

160

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“…Recent advancements in PARP inhibitors have proven the clinical utility of DDR-based therapies in ovarian cancer, breast cancer, and mCRPC patients with deleterious BRCA and ATM mutations, or even beyond, DNA-repair defects in general (36)(37)(38)(39)(40)(41)(42)(43). Deficiency of ARID1A, the paralog of ARID1B, has been shown to impair DNA-damage checkpoint and sensitize cancer cells to PARP inhibitors in vitro and in vivo (44).…”

Section: Discussionmentioning

confidence: 99%

Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer

Fan

Zhu²,

et al. 2018

Clinical Cancer Research

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Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood.Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM.Results: The status of EGFR-activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development.Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need.

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“…26,131,132 Emerging targets of therapeutic interest in oesophageal cancer include dysregulation cell cycle regulators such as CDK6 which have been successfully targeted in breast cancer by palbociclib and ribocicib, and impaired DNA damage repair mechanisms which have been exploited in ovarian cancer using olaparib and rucaparib). [133][134][135][136] Finally, immunotherapy using checkpoint inhibitors such as programmed cell death protein 1 (anti-PD-1) antibodies has resulted in survival benefits for patients with some other cancers, and gastro-oesophageal cancer is an attractive target for immunooncology intervention due to its relatively high mutation burden. [137][138][139][140] Results from early phase trials in oesophageal cancer have been encouraging with response rates to the anti-PD1 antibody pembrolizumab reported as 29% for OSCC and 40% for OAC in an RCT of 23 programmed death-ligand 1 positive patients.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Oesophageal cancer

et al. 2017

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SummaryOesophageal cancer is a clinically challenging disease requiring a multidisciplinary approach.The extensive treatment may be associated with serious limitations in health-related quality of life and yet still a poor prognosis. Recent decades have witnessed a gradual improvement in prognosis in many countries. Endoscopic procedures have increasingly been used in the treatment of premalignant and early oesophageal tumours. Neoadjuvant therapy with chemotherapy or chemoradiotherapy has supplemented surgery as standard treatment of locally advanced oesophageal cancer. Surgery has become more standardised and centralised. There are several therapeutic alternatives for palliative treatment. This review aims to provide insights into the current clinical management, on-going controversies and future needs in oesophageal cancer.3

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Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Cited by 1,044 publications

References 40 publications

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer

Oesophageal cancer

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