Lurbinectedin (PM01183) Combined With Pembrolizumab in Small Cell Lung Cancer.
- Conditions
- Small Cell Lung Carcinoma
- Interventions
- Registration Number
- NCT04358237
- Lead Sponsor
- Antonio Calles Blanco
- Brief Summary
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.
- Detailed Description
• 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 28
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Experimental: lurbinectedin (PM01183) + pembrolizumab Lurbinectedin 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 lurbinectedin at a starting dose of 2.4 mg/m2 as a 1-h IV infusion on Day 1, both every 3 weeks (Q3W). Lurbinectedin 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%. During the phase II stage, patients will receive pembrolizumab at a fixed dose of 200 mg as a 30-min IV infusion followed by lurbinectedin as a 1-h IV infusion on Day 1 Q3W at the redommended dose (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. Experimental: lurbinectedin (PM01183) + pembrolizumab Pembrolizumab 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 lurbinectedin at a starting dose of 2.4 mg/m2 as a 1-h IV infusion on Day 1, both every 3 weeks (Q3W). Lurbinectedin 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%. During the phase II stage, patients will receive pembrolizumab at a fixed dose of 200 mg as a 30-min IV infusion followed by lurbinectedin as a 1-h IV infusion on Day 1 Q3W at the redommended dose (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.
- Primary Outcome Measures
Name Time Method Phase I: Maximum tolerated dose (MTD) and recommended phase II dose (RD) of lurbinectedin in combination with pembrolizumab in patients with relapsed SCLC. 12 months The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients develop a DLT in Cycle 1. The RD will be the highest dose level explored at which less than one third of evaluable patients develop a DLT during Cycle 1.
Phase II: Efficacy of lurbinectedin in combination with pembrolizumab in terms of overall response rate (ORR), according to RECIST 1.1, in patients with relapsed SCLC. 38 months ORR is defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR).
The ORR will be assessed using the RECIST 1.1 on a set of measurable lesions identified at baseline as target lesions or as non-target lesions (if any), and followed until PD by an appropriate method.
- Secondary Outcome Measures
Name Time Method Phase I: MTD and RD of lurbinectedin in combination with pembrolizumab with mandatory primary prophylaxis with G-CSF in patients with relapsed SCLC (if DLTs of this combination are exclusively related to neutropenia). 12 months The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients develop a DLT in Cycle 1. The RD will be the highest dose level explored at which less than one third of evaluable patients develop a DLT during Cycle 1.
Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Duration of response (DOR). 38 months During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).
Both stages: Pharmacogenetic (PGt) analysis. 38 months A blood sample will be collected at any time during the trial (but preferably just before treatment start in Cycle 1 along with the first PK sample) to analyze germline DNA for the presence or absence of mutations or polymorphisms in genes relevant for the metabolism and/or transport of lurbinectedin that may help explain individual variability in main PK parameters.
Phase I: Preliminary information on the clinical antitumor activity of the combination. 28 months Preliminary antitumor activity in the phase I stage will be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable) at least 6 weeks after treatment initiation in all patients with measurable disease.
Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Clinical benefit ≥3 months. 38 months During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).
Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Overall survival (OS). 38 months During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).
Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Progression-free survival (PFS). 38 months During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).
Both Stages: Safety profile and feasibility of lurbinectedin in combination with pembrolizumab in patients with relapsed SCLC. 38 months Patients will be evaluable for safety if they have received at least one partial infusion of lurbinectedin. AEs will be graded according to the NCI-CTCAE v.5. Additionally, treatment compliance, in particular dose reduction requirements, skipped doses and/or cycle delays due to AEs, will be described.
Both stages: Characterize the plasma pharmacokinetics (PK) of lurbinectedin in this combination and to detect major drug-drug PK interactions. 38 months PK parameters (CMax) will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).
Both stages: Pharmacogenomic (PGx) analysis in tumor samples of patients exposed to lurbinectedin and pembrolizumab in order to assess potential markers of response and/or resistance. 38 months The mutational status of factors involved in DNA repair mechanisms, or related to the mechanism of action of PM01183 or pembrolizumab, will be evaluated from available prior paraffin-embedded tumor tissue samples obtained at diagnosis or relapse. mRNA and/or protein expression levels of these factors might be also analyzed, if relevant. Potentially whole exome sequencing will also be analyzed. Their correlation with the clinical response and outcome after treatment will be assessed.
Trial Locations
- Locations (5)
Hospital Vall D´Hebrón
🇪🇸Barcelona, Spain
ICO - Instituto Catalán de Oncología
🇪🇸Barcelona, Spain
START - Phase I Unit - HN San Chinarro
🇪🇸Madrid, Spain
Start - Unidad Fase I - Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hospital Gregorio Marañon
🇪🇸Madrid, Spain