Pharmacokinetic Study of Lurbinectedin in Combination With Irinotecan in Patients With Selected Solid Tumors

Description

Phase I dose escalation stage.

During the Phase I escalation stage, patients with selected advanced solid tumors will be divided into three groups: the Lurbinectedin Escalation Group, the Irinotecan Escalation Group and the Intermediate Escalation Group. Each group will have a different dose escalation scheme. A treatment cycle is defined as an interval of three weeks.

Three to six patients will be included at each dose level. If dose-limiting toxicity (DLT) occurs in less than one third of evaluable patients in each cohort, escalation can proceed to the next dose level within each group.

The MTD in each group will be the lowest dose level explored during dose escalation in which one third or more of evaluable patients develops a DLT in Cycle 1. At any dose level, if one among the first three evaluable patients has a DLT, the dose level should be expanded up to six patients. Dose escalation will be terminated once the MTD or the last dose level is reached, whichever occurs first, except if all DLTs occurring at a given dose level are related to neutropenia (i.e., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis) in which case dose escalation may be resumed, starting at the same dose level and following the same original schedule but with mandatory primary G-CSF prophylaxis.

Once the MTD has been reached, a minimum of nine evaluable patients will be recruited at the immediately lower dose level (or at the last dose level if the MTD is not defined yet): this level will be confirmed as the RD if less than one third of the first nine evaluable patients develop DLT during Cycle 1.

Phase II expansion stage.

If signs of activity are observed in one or more tumor types, there will be a phase II expansion stage after the RD is defined for each group. A tumor-specific expansion cohort (or cohorts if signs of activity are observed in more than one of the permitted tumor types) at each of these RDs may include approximately 20 treated patients per tumor type. If no indication of efficacy is observed in the dose escalation phase of a specific group, then recruitment of patients into that group may be terminated.

Furthermore, one new cohort of patients with neuroendocrine neoplasms (NENs), with approximately 40 treated patients, will be included in the Phase II expansion stage of this study. Patients in this cohort will be treated at the RD determined during the Phase I escalation stage in the Lurbinectedin Escalation Group (Lurbinectedin 2.0 mg/m2 plus irinotecan 75 mg/m2 with the administration of G-CSF). These patients will be divided into two groups of 20 treated patients each:

• Group 1 will include patients with NENs of gastroenteropancreatic origin or unknown primary site (excluding lung primary tumors) grade 3 (Ki67 >20%) according to the 2019 World Health Organization (WHO) classification of tumors of the digestive system, after progression to first-line chemotherapy with a platinum-based regimen.
• Group 2 will include patients with well differentiated pancreatic neuroendocrine tumors (P-NETs) grade 2 (Ki-67 3-20%) or low grade 3 (Ki-67 21-55%) according to the 2019 WHO classification of tumors of the digestive system, after progression to no more than three prior lines of systemic therapy.

Following the finding of promising efficacy to date, two expansion cohorts in the Lurbinectedin Escalation Group will be further expanded:

• The cohort of patients with small cell lung cancer (SCLC) will be expanded to at least 100 patients treated in second line.
• The cohort of patients with soft tissue sarcoma (STS) will be expanded with between 25 and 80 treated patients with synovial sarcoma (a subtype of STS)

Only in these two expansion cohorts, an Independent Review Committee (IRC) will determine the best patient's response and assign the date of first documentation of response and progression/censoring according to RECIST v.1.1. Operational details for the IRC and the algorithm and its validation by an expert panel are described in detail in the IRC charter.

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