ARISTOTLE UNIVERSITY OF THESSALONIKI SCHOOL OF MEDICINE POSTGRADUATE STUDIES PROGRAMME “Clinical and Industrial Pharmacology - Clinical Toxicology” Master Thesis “Lurbinectedin (PM01183): Under the spotlight on the treatment of relapsed small cell lung cancer (SCLC)” By Theodora Theodoropoulou Regional Medical Liaison Supervisor: Chrysoula Pourzitaki Assistant Professor Laboratory of Clinical Pharmacology at Aristotle University of Thessaloniki Advisory Committee: Demitrios Kouvelas: Professor and Head of Clinical Pharmacology at Aristotle University of Thessaloniki Georgios Papazisis: Associate Professor of Basic and Clinical Pharmacology at Aristotle University of Thessaloniki NOVEMBER 2020 0 ARISTOTLE UNIVERSITY OF THESSALONIKI SCHOOL OF MEDICINE POSTGRADUATE STUDIES PROGRAMME “Clinical and Industrial Pharmacology - Clinical Toxicology” Master Thesis “Lurbinectedin (PM01183): Under the spotlight on the treatment of relapsed small cell lung cancer (SCLC)” By Theodora Theodoropoulou Regional Medical Liaison Supervisor: Chrysoula Pourzitaki Assistant Professor Laboratory of Clinical Pharmacology at Aristotle University of Thessaloniki Advisory Committee: Demitrios Kouvelas: Professor and Head of Clinical Pharmacology at Aristotle University of Thessaloniki Georgios Papazisis: Associate Professor of Basic and Clinical Pharmacology at Aristotle University of Thessaloniki NOVEMBER 2020 1 Acknowledgements I would like to acknowledge my supervisor Chrysoula Pourzitaki, for her support and the learning opportunities provided by her throughout my studies. I would like to extend my sincere thanks to my colleagues and advisors, Alkistis Papoulia, Despoina Timotheatou and Kiki Karvounis, for their valuable guidance and for sharing their wealth of knowledge in the fields of Oncology and clinical trials. They provided me with helpful advice that I needed to successfully complete this project. 2 Contents List of Images ...................................................................................................................... 5 List of tables ........................................................................................................................ 6 Abbreviations ...................................................................................................................... 7 Summary ........................................................................................................................... 10 Abstract ............................................................................................................................. 11 Introduction ....................................................................................................................... 12 1. Small-cell lung cancer (SCLC) ...................................................................................... 13 2. Pathological diagnosis of SCLC ................................................................................... 15 3. Initial evaluation and staging of SCLC .......................................................................... 15 3.1 Localised disease ................................................................................................... 17 3.2 Metastatic disease .................................................................................................. 17 4. Lurbinectedin (PM01183).............................................................................................. 21 4.1 Mechanism of Action and Preclinical Data of Lurbinectedin .................................. 21 4.2 Pharmacodynamics ................................................................................................ 23 4.3 Pharmacokinetics ................................................................................................... 24 4.4 Nonclinical Toxicology ............................................................................................ 25 5. Regulatory History ........................................................................................................ 25 6. Clinical Development of Lurbinectedin ......................................................................... 26 6.1. Phase I trial (Elez ME et al., 2014) ........................................................................ 28 6.2 Phase I Study of Lurbinectedin (PM01183) in Combination with Paclitaxel, With or Without Bevacizumab, in Selected Advanced Solid Tumors ......................................... 32 6.3 Ovarian Cancer ...................................................................................................... 33 6.4 Metastatic Breast Cancer ....................................................................................... 36 6.5 Endometrial Cancer ................................................................................................ 38 6.6 Malignant Pleural Mesothelioma ............................................................................ 38 6.7 Clinical trials with relevance to pediatrics, adolescents and young adults ............. 39 6.7.1. Advanced Acute Leukemia and Relapsed/refractory Myelodysplastic Syndrome ................................................................................................................... 39 6.7.2. Ewing Family of Tumors ................................................................................. 40 7. Small cell lung cancer – background and rational of lurbinectedin’s clinical development 40 3 7.1 Phase I Lurbinectedin plus Doxorubicin in SCLC patients (Calvo et al., 2017) ..... 41 7.2 Phase Ib trial - Expansion cohort - Lurbinectedin plus doxorubicin [Forster et al., 2018] .............................................................................................................................. 45 7.3 Phase II Basket trial monotherapy [Trigo et al., 2020] ........................................... 46 7.4 Phase III ATLANTIS [Farago et al., 2018].............................................................. 52 8. Lurbinectedin with other systemic therapies in SCLC .............................................. 58 Conclusions - Discussion ................................................................................................ 58 Appendix .......................................................................................................................... 64 References ....................................................................................................................... 82 4 List of Images Figure 1. Number of new cases and deaths in 2018, both sexes, all ages [GLOBOCAN 2018]. .................................................................................................................................. 12 Figure 2. Initial management algorithm of SCLC. [Adapted from Wang et al., 2019] ........ 18 Figure 3. Select Ongoing and Recruiting Trials Classified by Therapeutic Targets of Interest in SCLC [Adapted from Wang et al., 2019] ............ Error! Bookmark not defined. Figure 4. Chemical structure and schematized actions of lurbinectedin. (A) Chemical structure of lurbinectedin. (B) Schematic representation of lurbinectedin mechanism of action for binding DNA, inhibiting active transcription and inducing DNA breaks. (C) Schematic representation of lurbinectedin interactions with the tumor microenvironment [Farago et al., 2018]. .......................................................................................................... 23 Figure 5. Features and properties of lurbinectedin [Markham et al., 2020]. ...................... 24 Figure 6. Key milestones in the development of lurbinectedin, focusing on its use in the treatment of small cell lung cancer. [Markham et al., 2020] ............................................... 26 Figure 7. Objective responses in SCLC. [Forster et al., 2018, poster P1.12-20] ............... 46 Figure 8. Study design [Farago et al., 2018] ...................................................................... 53 Figure 9. Analysis plan [Farago et al., 2018]. ..................................................................... 57 5 List of tables Table 1. TNM classifcation (AJCC 8th edition) [Domine et al., 2020] ............................. 16 Table 3: General overview and key design features of phase I study of Lurbinectedin in patients with solid tumors [Elez et al., 2014] ..................................................................... 28 Table 4. Baseline characteristics of patients (n = 31) [Elez et al., 2014] ........................ 29 Table 5. Drug-related adverse events (_10% of patients) and laboratory abnormalities (hematologic and biochemical) at the recommended dose for phase II studies [Elez et al., 2014] ................................................................................................................................. 31 Table 6. Phase I Study of Lurbinectedin (PM01183) in Combination with Paclitaxel, With or Without Bevacizumab, in Selected Advanced Solid Tumors [www.clinicaltrials.gov, NCT01831089] .................................................................................................................. 32 Table 7. Key design features of studies PM1183-A-004-10, PM1183-A-007-13, PM1183-A-008-13, PM1183-B-002-11 and PM1183-C-004-14 in patients with ovarian cancer [www.clinicaltrials.gov] .......................................................................................... 34 Table 8. Key design features of studies PM1183-A-003-10, PM1183-A-004-10, PM1183-A-006-12, PM1183-007-13, PM1183-B-003-11 and P 83-B-005-14