A phase I trial of lurbinectedin in combination with cisplatin in patients with advanced solid tumors
Tóm tắt
Background In vitro/in vivo data showed synergism of cisplatin and lurbinectedin in ovarian cancer cells and grafts. This phase I trial investigated the recommended phase II dose (RD) of cisplatin and lurbinectedin combination, with (Group A) or without aprepitant (Group B), in patients with advanced solid tumors. Patients and Methods All patients received 60 mg/m2 cisplatin 90-min intravenous (i.v.) infusion followed by lurbinectedin 60-min i.v. infusion at escalating doses on Day 1 every 3 weeks (q3wk). Patients in Group A additionally received orally 125 mg aprepitant one hour before cisplatin on Day 1 and 80 mg on Days 2 and 3. Toxicity was graded according to the NCI-CTCAE v.4. Results RD for Group A was cisplatin 60 mg/m2 plus lurbinectedin 1.1 mg/m2. RD for Group B was cisplatin 60 mg/m2 plus lurbinectedin 1.4 mg/m2. The most frequent grade ≥ 3 adverse events were hematological [neutropenia (41%), lymphopenia (35%), leukopenia (24%), thrombocytopenia (18%)] and fatigue (35%) in Group A (n = 17), and neutropenia (50%), leukopenia (42%), lymphopenia (29%), and fatigue (13%) and nausea (8%) in Group B (n = 24). Four patients (2 in each group) had a partial response. Disease stabilization for ≥ 4 months was observed in 4 and 10 patients, respectively. Conclusion The combination of lurbinectedin with cisplatin was not possible in meaningful therapeutic dosage due to toxicity. The addition of aprepitant in combination with cisplatin did not allow increasing the dose due to hematological toxicity, whereas omitting aprepitant increased the incidence of nausea and vomiting. Modest clinical activity was observed in general. Clinical trial registration
www.ClinicalTrials.gov
code: NCT01980667. Date of registration: 11 November 2013.
Tài liệu tham khảo
Santamaria Nunez G, Robles CM, Giraudon C, Martinez-Leal JF, Compe E, Coin F, Aviles P, Galmarini CM, Egly JM (2016) Lurbinectedin specifically triggers the degradation of phosphorylated RNA polymerase II and the formation of DNA breaks in cancer cells. Mol Cancer Ther 15:1–14
Belgiovine C, Bello E, Liguori M, Craparotta I, Mannarino L, Paracchini L, Beltrame L, Marchini S, Galmarini CM, Mantovani A, Frapolli R, Allavena P, D’Incalci M (2017) Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer 117:628–638
Trigo J, Subbiah V, Besse B, Moreno V, López R, Sala MA, Peters S, Ponce S, Fernández C, Alfaro V, Gómez J, Kahatt C, Zeaiter A, Zaman K, Boni V, Arrondeau J, Martínez M, Delord J-P, Awada A, Kristeleit R, Olmedo ME, Wannesson L, Valdivia J, Rubio MJ, Anton A, Sarantopoulos J, Chawla SP, Mosquera-Martinez J, D’Arcangelo M, Santoro A, Villalobos VM, Sands J, Paz-Ares L (2020) Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol 21:645–654
Metaxas Y, Fruh M, Eboulet EI, Grosso F, Pless M, Zucali PA, Ceresoli GL, Mark M, Schneider M, Maconi A, Perrino M, Biaggi-Rudolf C, Froesch P, Schmid S, Waibel C, Appenzeller C, Rauch D, von Moos R, Swiss Group for Clinical Cancer R (2020) Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16). Ann Oncol 31:495–500
Cruz C, Llop-Guevara A, Garber JE, Arun BK, Perez Fidalgo JA, Lluch A, Telli ML, Fernandez C, Kahatt C, Galmarini CM, Soto-Matos A, Alfaro V, Perez de la Haza A, Domchek SM, Antolin S, Vahdat L, Tung NM, Lopez R, Arribas J, Vivancos A, Baselga J, Serra V, Balmana J, Isakoff SJ (2018) Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy. J Clin Oncol 36:3134–3143
Soares DG, Machado MS, Rocca CJ, Poindessous V, Ouaret D, Sarasin A, Galmarini CM, Henriques JA, Escargueil AE, Larsen AK (2011) Trabectedin and its C subunit modified analogue PM01183 attenuate nucleotide excision repair and show activity toward platinum-resistant cells. Mol Cancer Ther 10:1481–1489
Vidal A, Munoz C, Guillen MJ, Moreto J, Puertas S, Martinez-Iniesta M, Figueras A, Padulles L, Garcia-Rodriguez FJ, Berdiel-Acer M, Pujana MA, Salazar R, Gil-Martin M, Marti L, Ponce J, Mollevi DG, Capella G, Condom E, Vinals F, Huertas D, Cuevas C, Esteller M, Aviles P, Villanueva A (2012) Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer. Clin Cancer Res 18:5399–5411
Baumhäkel M, Kasel D, Rao-Schymanski RA, Böcker R, Beckurts KT, Zaigler M, Barthold D, Fuhr U (2001) Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Int J Clin Pharmacol Ther 39:517–528
Masek V, Anzenbacherová E, Machová M, Brabec V, Anzenbacher P (2009) Interaction of antitumor platinum complexes with human liver microsomal cytochromes P450. Anticancer Drugs 20:305–311
Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, Pita AS, Teruel CF, Siguero M, Cullell-Young M, Szyldergemajn S, Ratain MJ (2014) First-In-Human Phase I Study of Lurbinectedin (PM01183) in Patients with Advanced Solid Tumors. Clin Cancer Res 20:2205–2214
Sauri T, Awada A, Calvo E, Moreno V, Szyldergemajn S, Elez E, Barthelemy P, Boni V, Doger B, Fernandez Teruel C, Soto-Matos A, Tabernero J, Aftimos P (2016) Lurbinectedin (PM01183) administered once (C1) every 3 weeks (q3w) in combiantion with capecitabine (XEL) in patients (pts) with metastatic breast (MBC), colorectal (CRC) or pancreatic (PaC) cancer. Eur J Cancer 27:392P
Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, Galmarini CM, Nunez R, Kahatt C, Paz-Ares L (2019) ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line. Future Oncol 15:231–239
Ponce Aix S, Coté G, Falcón A, Jimenez-Aguilar E, Lin JJ, Sánchez Simón I, Flor MJ, Núñez R, Jiménez AM, Jiménez E, Siguero M, Kahatt C, Zeaiter A, Paz-Ares L (2020) OA11.04 - Lurbinectedin With Irinotecan in Relapsed Small Cell Lung Cancer. Results From the Expansion Stage of a Phase I-II Trial IASLC; 2020 World Conference on Lung Cancer; January 21, Singapore (virtual meeting)
Sessa C, Cresta S, Noberasco C, Capri G, Gallerani E, De Braud F, Zucchetti M, D’Incalci M, Locatelli A, Marsoni S, Corradino I, Minoia C, Zintl P, Gianni L (2009) Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours. Eur J Cancer 45:2116–2122
Sessa C, Del Conte G, Christinat A, Cresta S, Perotti A, Gallerani E, Lardelli P, Kahatt C, Alfaro V, Iglesias JL, Fernandez-Teruel C, Gianni L (2013) Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors. Invest New Drugs 31:1236–1243
Vidal L, Magem M, Barlow C, Pardo B, Florez A, Montes A, Garcia M, Judson I, Lebedinsky C, Kaye SB, Salazar R (2012) Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors. Invest New Drugs 30:616–628