First-In-Human Phase I Study of Lurbinectedin (PM01183) in Patients with Advanced Solid Tumors

Elez, Maria Elena; Tabernero, Josep; Geary, David; Macarulla, Teresa; Kang, Soonmo Peter; Kahatt, Carmen; Pita, Arturo Soto-Matos; Teruel, C. Fernandez; Siguero, Mariano; Cullell-Young, Martín; Szyldergemajn, Sergio; Ratain, Mark J.

doi:10.1158/1078-0432.ccr-13-1880

Cited by 79 publications

(81 citation statements)

References 11 publications

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“…The incidence of severe hematological abnormalities found here was higher than that observed among the 15 patients (47% women) with advanced solid tumors treated at 7.0 mg FD in the first-in-human study, where 53% and 7% of patients had grade 3/4 neutropenia and grade 3/4 thrombocytopenia, respectively, and without febrile neutropenia [7]. Ongoing PK/PD modeling of pooled phase I/II data has shown some covariates [ascites, albumin, aprepitant, body surface area (BSA)] that might affect neutropenia and thrombocytopenia (unpublished data).…”

Section: Discussionmentioning

confidence: 57%

Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer

et al. 2017

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Background PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer.Patients and methodsPatients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1–5 q3wk or weekly (every 4 weeks, q4wk).ResultsORR was 23% (95% CI, 13%–37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5–6.9 months), and 23% (95% CI, 0%–51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%–49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7–5.6 months), and 5.0 months (95% CI, 2.7–6.9 months) for patients with platinum-resistant disease.Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183.ConclusionPM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2).Trial codeEudraCT 2011-002172-16.

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Section: Discussionmentioning

confidence: 57%

Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer

et al. 2017

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“…In this study, we show the redistribution of EWS-FLI1 occurs with lurbinectedin at 5-10 nmol/L while the Cmax of this drug is around (182.2 ng/mL or >200 nmol/L)(49). Furthermore, we show that irinotecan potentiates lurbinectedin-mediated EWS-FLI1 suppression.…”

Section: Discussionmentioning

confidence: 76%

“…Therefore, we evaluated a second-generation trabectedin analog, lurbinectedin, which is known to have an improved pharmacokinetic profile and to accumulate in serum to levels greater than 170 ng/mL (215 nmol/L)(18). Lurbinectedin redistributed EWS-FLI1 to the nucleolus to the same degree as trabectedin at 5 nmol/L (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In essence these effects recapitulate the results seen with siRNA silencing of EWS-FLI1 that has been previously reported as well as the differentiation we observed here in animal models (7). Importantly, the in vitro exposures with washout are more reflective of the exposures seen in the mouse although higher concentration and longer exposures should be attainable in patients consistent with the overall goals of the study (18,46). …”

Section: Resultsmentioning

confidence: 99%

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Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus

et al. 2016

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There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analog lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30-70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma.

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“…The formation of these adducts induces double-strand breaks, accumulation of cells in the S phase, and apoptosis. 83 It is under clinical trials, including a phase I study to evaluate doselimiting toxicities 84 and several studies in combination with paclitaxel or gemcitabine in patients with advanced solid tumors and non-small cell lung cancer, respectively. 85 Due to the complexity of the trabectedin structure, extensive studies have been carried out on the preparation of simpler analogs.…”

Section: Figure 615mentioning

confidence: 99%

Anticancer Drugs That Interact with the DNA Minor Groove

Avendaño

Menéndez²

2015

Medicinal Chemistry of Anticancer Drugs

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First-In-Human Phase I Study of Lurbinectedin (PM01183) in Patients with Advanced Solid Tumors

Cited by 79 publications

References 11 publications

Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer

Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer

Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus

Anticancer Drugs That Interact with the DNA Minor Groove

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