Lurbinectedin (PM01183) Combined With Pembrolizumab in Small Cell Lung Cancer.

This is a prospective, open-label, uncontrolled and multicenter phase I/II study of PM01183 in combination with pembrolizumab in patients with relapsed small cell lung cancer (SCLC). The study will be divided into two stages: * A dose-ranging phase I stage with escalating doses of PM01183 in combination with a fixed dose of pembrolizumab, followed by: * A non-randomized phase II stage as an expansion study at the recommended dose (RD) determined during the phase I stage. The phase I stage will focus on the selection of the RD based on safety/tolerability, while the phase II stage will assess the overall response rate (ORR) and clinical response.

• During the phase I stage, patients will start receiving pembrolizumab at a fixed dose of 200 mg as a 30-min intravenous (IV) infusion followed by PM01183 at a starting dose of 2.4 mg/m2 as a 1-h IV infusion on Day 1, both every 3 weeks (Q3W). A cycle is defined as an interval of 3 weeks. PM01183 dose will be escalated from the starting dose in successive cohorts of patients, with a pre-established fixed dose increase (in mg/m2) of approximately 30%. Dose escalation will follow a classical 3+3 design, according to the observed tolerance and safety. All evaluable patients within a dose level will be followed for at least one cycle (i.e., 3 weeks) before dose escalation may proceed. The maximum tolerated dose (MTD) will be the lowest dose level explored during dose escalation at which one third or more of evaluable patients experience a dose-limiting toxicity (DLT) in Cycle 1. Dose escalation will be terminated once the MTD or the last dose level (i.e., DL2) is reached, whichever occurs first, except if all DLTs occurring at a given dose level are related to neutropenia. If this is the case, dose escalation may be resumed, starting at the lowest dose level at which exclusively neutropenia-related DLTs were observed, and will follow the same original schedule but with mandatory primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. An expansion cohort to complete a minimum of 6 evaluable patients will be recruited at the immediate lower dose level from the MTD, or at DL2 if the MTD is not defined yet. This level will be confirmed as the RD if less than one third of the first 6 evaluable patients experience DLT during Cycle 1. Intermediate dose levels could be tested upon agreement of the Scientific Steering Committee members, as defined in Section 8.4, if deemed appropriate. This will also be discussed with Pharma Mar and MSD. • During the phase II stage, patients will receive pembrolizumab at a fixed dose of 200 mg as a 30-min IV infusion followed by PM01183 as a 1-h IV infusion on Day 1 Q3W at the RD determined during the phase I stage. A cycle is defined as an interval of 3 weeks. No dose escalation will be allowed during the phase II stage. Regardless of stage, patients will receive PM01183 in combination with pembrolizumab until progression, unacceptable toxicity, consent withdrawal or if it is not considered in their best interest to continue, after specific agreement between the Investigators and the Sponsor (this will also be discussed with Pharma Mar and MSD). Maximum treatment period with pembrolizumab is 35 dose administrations (approximately 2 years). After 35 dose administrations, patients might continue on treatment with lurbinectedin alone. Radiological tumor assessments will be done every 6 weeks (± 2 weeks), or prior to every second subsequent cycle, while on treatment. After treatment discontinuation, patients will be followed until resolution or stabilization of all toxicities, if any. Patients discontinuing treatment without disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 will be followed every 6 weeks (± 2 weeks) until disease progression as per RECIST 1.1, start of a new anti-cancer therapy, death or the end-of-study date (clinical cutoff, as described in Section 2.1.1), whichever occurs first. After one year of follow-up, patients will be evaluated every 9 weeks (± 2 weeks) until the end of the study. After disease progression as per RECIST 1.1 or start of a new anti-cancer therapy, patients will be followed up for survival every 12 weeks (± 2 weeks) until death or the end-of-study date, whichever occurs first (a phone contact will be acceptable). An exception will be those patients who are clinically stable at the time of disease progression as per RECIST 1.1, who could remain on treatment according to the Investigator's criteria up to the next radiological assessment. If no disease progression as per immune RECIST (iRECIST) 1.1 is observed in this assessment, treatment will continue until disease progression as per iRECIST 1.1. If at the end of the study (i.e., clinical cut-off, as defined in Section 2.1.1) any patients are still on treatment with lurbinectedin monotherapy, the investigator will evaluate if it is appropriate that they continue receiving that treatment. If needed, the Sponsor may facilitate appropriate measures to ensure access to lurbinectedin and maintenance of safety reporting obligations beyond study closure in those cases. According to the end of study definition (see Section 2.1.1), no patients will remain under treatment with pembrolizumab at the clinical cut-off. Safety will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5, whereas antitumor response will be assessed using the RECIST 1.1, and also the iRECIST 1.1 whenever applicable. These methods are generally accepted as standard clinical procedures in oncological studies.