This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously.~I. Dose Escalation Phase 1 of Study: The study will employ the standard cohort of three design (Storer, 1989). Three participants are treated at each of the 2 ascending dose levels. An additional 3 participants will be enrolled if a DLT is observed in one of the three initially-enrolled participants at each dose level. If no DLT occurs after the third participant in a dose level is on study for 6 weeks, enrollment will be opened for escalation to the next highest planned dose level. The DLT window is a total of 6 weeks. The MTD is defined as the highest safely tolerated dose of lurbinectedin, where not more than one participant experienced a DLT, with the next higher dose level having at least two participants who experienced DLT.~Participants in the dose escalation study may continue treatment at their designated dose levels until disease progression or unacceptable toxicity occurs or up to a maximum of one year of therapy (up to a maximum of 18 doses of LURBINECTEDIN, 26 doses of NIVOLUMAB, and 5 doses of IPILIMUMAB). No intra-participant dose escalation will take place.~Dose of IPILIMUMAB: 1 mg/kg IV over 30 min. q 12 weeks, beginning 2 weeks after the first dose of LURBINECTEDIN, until disease progression or unacceptable toxicity, up to a maximum of 5 doses~Dose of NIVOLUMAB: 3 mg/kg over 30 min. q 2 weeks, beginning 2 weeks after first dose of LURBINECTEDIN, until disease progression or unacceptable toxicity, up to a maximum of 26 doses~Dose of LURBINECTEDIN: Escalating doses of LURBINECTEDIN IV over 60 minutes q 3 weeks up to a maximum of 18 doses:~LURBINECTEDIN # Pts. Dose Level Dose,mg/m2 Max.Volume/24 hrs~Every 3 weeks 3-6 I 2.6 1000 ml Every 3 weeks 3-6 II 3.2 1000 ml~No dose-escalation will be performed until all the subjects have completed the DLT period of 6 weeks and evaluation of all clinical and laboratory data has been conducted. The phase 2 part of the study will not proceed until either the maximum tolerated dose (MTD) or maximum administered dose (MAD) has been determined.~Participants who do not complete the DLT period for reasons other than study drug-related toxicity will be replaced in the same dose cohort. At the discretion of the principal investigator/sponsor, dose escalation may be stopped before an MTD is reached. In this case, the MAD may be chosen based on the standard dose of LURBINECTEDIN of 3.2 mg/m2.
This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously.