Advanced Solid TumorsPhase 1/2NCT02611024
Pharmacokinetic Study of Lurbinectedin in Combination With Irinotecan in Patients With Selected Solid Tumors
A Phase 1/2 study testing Lurbinectedin and Irinotecan in people with Advanced Solid Tumors and Glioblastoma, run by PharmaMar at 23 sites in 6 countries.
Trial summary
Prospective, open-label, dose-ranging, uncontrolled phase I/II study of Lurbinectedin in combination with irinotecan. The study will be divided into two stages: a Phase I dose escalation stage and a Phase II expansion stage. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Solid Tumors, Glioblastoma, Soft Tissue Sarcoma (Excluding GIST)
- What is being tested?
- Lurbinectedin and Irinotecan
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 316 participants
- Where
- 23 sitesin 6 countries
- Study dates
- 6 May 2016to 1 Jul 2025
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Voluntarily signed and dated written informed consent prior to any specific-study procedure.
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
- Life expectancy ≥ 3 months.
- Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types:
- For the Lurbinectedin Escalation Group and the Irinotecan Escalation Group:
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- Glioblastoma.
- Soft-tissue sarcoma (excluding gastrointestinal stromal tumors [GIST]).
- Endometrial carcinoma.
- Epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas) regardless of platinum sensitivity.
- Mesothelioma.
- Gastroenteropancreatic neuroendocrine tumors (GEP-NET).
- Small cell lung cancer (SCLC).
- Pancreatic adenocarcinoma.
- Gastric carcinoma.
- Colorectal carcinoma (CRC).
- For the Intermediate Escalation Group:
- Endometrial carcinoma.
- SCLC.
- Other solid tumors may be included, if appropriate, after discussion between the Investigators and the Sponsor.
- For the Phase II expansion stage:
- Glioblastoma.
- Soft tissue sarcoma (including synovial sarcoma),
- Endometrial carcinoma.
- SCLC.
- Neuroendocrine tumors.
- Group 1: Poorly differentiated grade 3 NEC (Ki-67 >20%) according to the 2019 WHO classification of tumors of the digestive system, of gastroenteropancreatic origin or unknown primary site (lung primary tumors will be excluded).
- Group 2: Well differentiated grade 2 (Ki-67 3-20%) or grade 3 (Ki-67 21-55%) GEP-NETs according to the 2019 WHO classification of tumors of the digestive system.
- The number of prior lines of therapy allowed per patient will be as follows:
- For the Phase I Escalation Stage:
- No more than two prior lines of cytotoxic-containing chemotherapy regimens for advanced disease
- For the Phase II Lurbinectedin Expansion Stage:
- For SCLC, one prior line of platinum-containing chemotherapy with/without antibodies against programmed cell death protein-1 (PD-1) or programmed death ligand-1 (PD-L1).
- For NENs,
- In Group 1 (patients with poorly differentiated NEC of gastroenteropancreatic origin or unknown primary site, excluding lung primary tumors), one prior line of platinum-based chemotherapy; and
- In Group 2 (patients with well differentiated GEP-NETs), no more than three prior lines of systemic therapy (that may include somatostatin analogues, chemotherapy, everolimus and/or sunitinib).
- For all other tumor types, no more than two prior lines of cytotoxic-containing chemotherapy regimens for advanced disease.
- There is no limit for prior targeted therapy, hormonal therapy and immunotherapy (such as nivolumab).
- Phase II expansion stage: Tumor-specific cohort(s) at the RD:
- Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. For patients with glioblastoma: Measurable disease according to RECIST v.1.1 and Response Assessment in Neuro-Oncology (RANO) criteria.
- Documented disease progression per RECIST v.1.1 during or immediately after last therapy according to any of the aforementioned criteria. For patients with glioblastoma: Documented disease progression per RECIST v.1.1 and RANO criteria.
- At least three weeks since the last anticancer therapy, (including immunotherapy, investigational drugs and radiotherapy), and at least six weeks since nitrosoureas and mitomycin C (systemic).
- For biological/investigational anticancer therapies given orally, the aforementioned period of at least three weeks could be changed for one of at least five half-lives (whichever occurred first), provided that the therapy is given as single agent and not combined with other drugs. If this is not the case, this exception will not be acceptable.
- For patients with glioblastoma: at least 12 weeks since the end of radiotherapy, except if:
- The patient has a new lesion outside of the radiotherapy field, or
- The patient has undergone brain surgery to remove the tumor before study entry, and progressive disease has been confirmed histologically.
- Note: washout periods will be referred to the day of first cycle administration (Day 1), not to the day of registration (Day 0).
- Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days before inclusion in the trial):
- Platelet count ≥ 100 × 10^9/L, hemoglobin ≥ 9.0 g/dL and absolute neutrophil count (ANC) ≥ 2.0 × 10^9/L.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN), even in the presence of liver metastases.
- Alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN if disease-related/in the case of liver metastases).
- Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN.
- International Normalized Ratio (INR) < 1.5 (except if patient is on oral anticoagulation therapy).
- Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (using Cockcroft-Gault formula).
- Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
- Albumin ≥ 3.0 g/dL*
- Recovery to grade ≤ 1 or to baseline from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral neuropathy and/or fatigue grade ≤ 2).
- Albumin transfusion to increase the blood level in order to fulfill the inclusion criterion is strictly forbidden.
Who cannot join
- Concomitant diseases/conditions:
- History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year.
- Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
- Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 × ULN in two different determinations performed one week apart).
- Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. Known Gilbert disease.
- Active uncontrolled infection.
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- Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B.
- Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or sub-occlusion or paralysis.
- Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days.
- Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study
- Active Coronavirus disease (COVID-19).
- Hypersensitivity to any of the study drugs or their excipients.
- Prior treatment with lurbinectedin, trabectedin (Yondelis®) or topoisomerase I inhibitors (irinotecan, topotecan, etc.). Prior topoisomerase inhibitors (e.g., irinotecan) are only allowed in patients with colorectal carcinoma or NENs.
- Prior bone marrow or stem cell transplantation, or radiation therapy in more than 35% of bone marrow.
- Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions (primary or locally advanced) are eligible. Exception: patients with brain metastases are eligible provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment (patients taking steroids in the process of already being tapered within two weeks prior to screening are allowed). Brain CT-scan or MRI results must be provided at baseline.
- Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception. Women of childbearing potential (WOCBP) must agree to use an effective contraception method to avoid pregnancy during the course of the trial (and for at least six months after the last infusion). Fertile male patients must agree to refrain from fathering a child or donating sperm during the trial and for four months after the last infusion.
- Limitation of the patient's ability to comply with the treatment or follow-up protocol.
Trial locations and contacts
23 sites in 6 countries.
23 sites in 6 countries
Spain12 sites
Hospital de la Santa Creu i Sant Pau
Barcelona, 08025
Hospital Univeristari Vall d'Hebron
Barcelona, 08035
Hospital Universitario Puerta de Hierro
Madrid, 28022
Hospital Universitario Ramon y Cajal
Madrid, 28034
Hospital Universitario Fundación Jiménez Díaz
Madrid, 28040
Hospital Universitario 12 de Octubre
Madrid, 28041
Hospital Universitario La Paz
Madrid, 28046
Hospital Universitario Madrid Sanchinarro
Madrid, 28050
Hospital Universitario Marqués de Valdecilla
Santander, 39008
Hospital Clínico Universitario de Santiago
Santiago de Compostela, 15706
Hospital Virgen Del Rocio
Seville, 41013
Hospital Universitario Miguel Servet
Zaragoza, 50009
United States4 sites
Massachusetts General Hospital -
Boston, Massachusetts, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Sarcoma Oncology Center
Santa Monica, California, 90403
France2 sites
Centre Léon Bérard
Lyon, 69373
Institut Gustave Roussy
Villejuif, 94800
Germany2 sites
Helios Kilinikum Bad Saarow
Bad Saarow, 15526
Helios Klinikum Berlin Buch
Berlin, 13125
Italy2 sites
Campus Biomedico
Roma, 00128
IRCCS Fondazione Candiolo (Turin)
Torino, 10060
About this study
Official title: Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin in Combination With Irinotecan in Pretreated Patients With Selected Advanced Solid Tumors
Prospective, open-label, dose-ranging, uncontrolled phase I/II study of Lurbinectedin in combination with irinotecan. The study will be divided into two stages: a Phase I dose escalation stage and a Phase II expansion stage.
Read the detailed 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 poorly differentiated grade 3 neuroendocrine cancer (NEC) (Ki67 >20%) of gastroenteropancreatic origin or unknown primary site (excluding lung primary tumors) 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 grade 2 (Ki-67 3-20%) or grade 3 (Ki-67 21-55%) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 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 response evaluation at each tumor assessment necessary to derive 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.
- Conditions
- Advanced Solid Tumors, Glioblastoma, Soft Tissue Sarcoma (Excluding GIST), Endometrial Carcinoma, Epithelial Ovarian Carcinoma, Mesothelioma
- Being tested
- Lurbinectedin, Irinotecan
- Keywords
- Lurbinectedin, PM01183, Tumors, Cancer, Pharma Mar, Sarcoma, SCLC, Neuroendocrine
- Medical subject headings
- Glioblastoma, Sarcoma, Endometrial Neoplasms, Carcinoma, Ovarian Epithelial, Mesothelioma, Gastro-enteropancreatic neuroendocrine tumor, Stomach Neoplasms, Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LurbinectedinDrug
Also called PM01183
lurbinectedin (PM01183) 4 mg vials
IrinotecanDrug
irinotecan 40 mg, 100 mg or 300 mg vials
| Study group | Role | What they receive |
|---|---|---|
| Lurbinectedin Escalation Group | Experimental | Irinotecan 75 mg/m^2 as a 90-min (-5-min/+30-min) intravenous (i.v.) infusion, followed by Lurbinectedin with starting dose of 1.0 mg/m^2 as a 60-min (-5-min/+20-min) i.v. infusion followed by Irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min [-5-min/+30-min] i.v. infusion) Receives: Drug: Lurbinectedin; Drug: Irinotecan |
| Irinotecan Escalation Group | Experimental | Starting dose of Irinotecan 15 mg/m^2 as a 90-min (-5-min/+30-min) i.v. infusion, followed by Lurbinectedin 3.0 mg/m^2 as a 60-min (-5-min/+20-min) i.v. infusion followed by Irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min [-5-min/+30-min] i.v. infusion). Receives: Drug: Lurbinectedin; Drug: Irinotecan |
| Intermediate Escalation Group | Experimental | Starting dose of Irinotecan 50 mg/m^2 as a 90-min (-5-min/+30-min) i.v. infusion, followed by Lurbinectedin 2.6 mg/m^2 as a 60-min (-5-min/+20-min) i.v. infusion. No Irinotecan dose will be administered on Day 8 in this group. Receives: Drug: Lurbinectedin; Drug: Irinotecan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD)
The MTD will be the lowest dose level explored during dose escalation which one third or more of evaluable patients develops DLTs in Cycle 1. DLTs are related AEs during Cycle 1 fulfilling at least 1 of the criteria below:
- Grade 4 neutropenia lasting >3 days
- Febrile neutropenia of any duration or neutropenic sepsis
- Grade 4 thrombocytopenia/Grade 3 with clinically bleeding requiring a transfusion
- Grade 4 ALT/AST increase/Grade 3 lasting >14 days
- Grade≥2 increased ALT/AST concomitantly with total bilirubin increase ≥2.0×ULN and normal ALP
- Grade≥3 diarrhea lasting >5 days and despite adequate corrective treatment
- Grade≥3 CPK increase
- Grade≥3 non-hematological related AE, excluding nausea/vomiting, hypersensitivity reactions, extravasations, grade 3 fatigue lasting <1 week and nonclinically biochemical abnormalities
- Administration delay of Cycle 2 >15 days from the Day 22 due to any related AEs
- Failure to meet the Day-8 continuation criteria for irinotecan in Cycle 1
Measured: 66 months
Recommended Dose (RD)
The RD will be the highest dose level explored during dose escalation in which fewer than one third of patients develop DLTs during Cycle 1. DLTs are related AEs during Cycle 1 fulfilling at least 1 of the criteria below:
- Grade 4 neutropenia lasting >3 days
- Febrile neutropenia of any duration or neutropenic sepsis
- Grade 4 thrombocytopenia/Grade 3 with clinically bleeding requiring a transfusion
- Grade 4 ALT/AST increase/Grade 3 lasting >14 days
- Grade≥2 increased ALT/AST concomitantly with total bilirubin increase ≥2.0×ULN and normal ALP
- Grade≥3 diarrhea lasting >5 days and despite adequate corrective treatment
- Grade≥3 CPK increase
- Grade≥3 non-hematological related AE, excluding nausea/vomiting, hypersensitivity reactions, extravasations, grade 3 fatigue lasting <1 week and nonclinically biochemical abnormalities
- Administration delay of Cycle 2 >15 days from the Day 22 due to any related AEs
- Failure to meet the Day-8 continuation criteria for irinotecan in Cycle 1
Measured: 66 months
Response Rate
Phase II Expansion Stage: Efficacy Response rate is a percentage of patients with any response: partial response or complete response.
Antitumor activity will be measured according to RECIST v.1.1.
- An increase of ≥20% from the baseline or new lesion appears represents progressive disease.
- A decrease in the sum of target disease of ≥30% represents partial response.
- Stable disease lies between partial response and progressive disease.
- Complete response is the disappearance of all lesions with nodes measuring <10 mm and normal tumour markers
Patients included in the tumor-specific expansion cohort(s) at the RD for each group, and in the new cohort of patients with NENs, must be evaluable per RECIST v.1.1 (including ovarian cancer patients). Specifically, patients with glioblastoma must be evaluated per RECIST v.1.1 and RANO criteria. A patient evaluable for efficacy should have received at least one complete dose of lurbinectedin and irinotecan.
Measured: At least six weeks after treatment initiation, up to 66 months
Secondary outcomes (10)
Safety evaluation
AEs will be graded according to the NCI-CTCAE v.4.
Measured: Since start of the treatment until 30 days after the last administration of study treatment; or until start of a new antitumor therapy or death
Peak Plasma Concentration (Cmax)
Pharmacokinetic Outcome Measures
Measured: 66 months
Area under the plasma concentration versus time curve (AUC)
Pharmacokinetic Outcome Measures
Measured: 66 months
Volume of distribution based on the terminal half-life (Vz)
Pharmacokinetic Outcome Measures
Measured: 66 months
Volume of distribution at steady state (Vss)
Pharmacokinetic Outcome Measures
Measured: 66 months
Clearance (CL)
Pharmacokinetic Outcome Measures
Measured: 66 months
Half-life (t1/2)
Pharmacokinetic Outcome Measures
Measured: 66 months
Duration of response
Evaluable and measurable as per RECIST v.1.1 or RANO for Glioblastoma patients
Measured: Time from date when response criteria are fulfilled to the first date when progression disease, recurrence or death, until 18 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs
Progression-free Survival
Time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death has not occurred at the time of the analysis, the Progression-free Survival (PFS) will be censored on the date of last tumor evaluation.
Measured: From the date of first infusion of study treatment to the date of progression or death or until 18 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs first.
Overall Survival
Time from the date of first infusion of study treatment to the date of death (due to any cause). Patients with no documented death will be censored at the last date they are known to be alive.
Measured: From the date of first infusion of study treatment to the date or death or until 18 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs first.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2015 (estimated)
- Study start6 May 2016
- Primary completion1 Jul 2025
- Study completion1 Jul 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Advanced Solid TumorsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Patients with selected advanced solid tumors will be divided into 3 groups: the Lurbinectedin Escalation Group, the Irinotecan Escalation Group and the Intermediate Escalation group. Each group will have a different dose escalation scheme.
- Masking
- None (open label)
- Enrolment
- 316 participants (actual)
Sponsor and investigators
- Lead sponsor
- PharmaMar
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02611024
- Sponsor's protocol ID
- PM1183-A-014-15
- Status last verified
- Jul 2025
- First submitted
- 5 Nov 2015
- Last updated
- 9 Jul 2025
- Results posted
- No
- Data monitoring committee
- No
Publications
Falcon A, Cote GM, Molina-Cerrillo J, Le Cesne A, Rocha P, Bockorny B, Paez D, Martin-Broto J, Chawla SP, Martinez S, Kahatt C, Alfaro V, Siguero M, Jimenez J, Custodio A, Alonso-Orduna V, Lopez C, Kollar A, Soto-Castillo JJ, Paz-Ares L. Pooled safety analysis of lurbinectedin plus irinotecan in patients with advanced solid tumors. Invest New Drugs. 2026 May 4. doi: 10.1007/s10637-026-01616-0. Online ahead of print.
PubMed 42081171Ponce S, Ruiz-Torres M, Falcon A, Cote GM, Bernabe R, Lin JJ, Coya JM, Jimenez-Munoz M, Fernandez-Puyuelo P, Sanchez A, Zugazagoitia J, Ucero A, Baena J, Bote de Cabo H, Herrera M, Torres-Jimenez J, Zurera M, Kahatt C, Lopez-Vilarino JA, Martinez S, Siguero M, Malumbres M, Ferrer I, Paz-Ares L. Combination of Lurbinectedin Plus Irinotecan: Preclinical and Early Clinical Results in Patients With Relapsed SCLC. J Thorac Oncol. 2026 Jul;21(7):103654. doi: 10.1016/j.jtho.2026.103654. Epub 2026 Mar 4.
PubMed 41791703Falcon A, Ponce S, Cote GM, Gil A, Lin JJ, Bockorny B, Martinez J, Kahatt C, Martinez S, Zubiaur P, Siguero M, Cullell-Young M, Jimenez J, Zugazagoitia J, Paz-Ares L. Phase I results on the efficacy, safety and pharmacokinetics of lurbinectedin and irinotecan in advanced solid tumors. Invest New Drugs. 2025 Aug;43(4):955-967. doi: 10.1007/s10637-025-01583-y. Epub 2025 Sep 18.
PubMed 40963055
Study at a glance
From the registry record, last updated by the sponsor on 9 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin in Combination With Irinotecan in Pretreated Patients With Selected Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT02611024
- Acronym / sponsor ID
- PM1183-A-014-15
- Conditions
- Advanced Solid Tumors, Glioblastoma, Soft Tissue Sarcoma (Excluding GIST), Endometrial Carcinoma, Epithelial Ovarian Carcinoma, Mesothelioma
- Keywords
- Lurbinectedin, PM01183, Tumors, Cancer, Pharma Mar, Sarcoma, SCLC, Neuroendocrine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 316 participants (actual)
- Lead sponsor
- PharmaMarIndustry (pharma, biotech, devices)
- Study start
- 6 May 2016 (actual)
- Primary completion
- 1 Jul 2025 (actual)
- Study completion
- 1 Jul 2025 (actual)
- First posted
- 20 Nov 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Prospective, open-label, dose-ranging, uncontrolled phase I/II study of Lurbinectedin in combination with irinotecan. The study will be divided into two stages: a Phase I dose escalation stage and a Phase II expansion stage.
Detailed 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 poorly differentiated grade 3 neuroendocrine cancer (NEC) (Ki67 >20%) of gastroenteropancreatic origin or unknown primary site (excluding lung primary tumors) 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 grade 2 (Ki-67 3-20%) or grade 3 (Ki-67 21-55%) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 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 response evaluation at each tumor assessment necessary to derive 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Patients with selected advanced solid tumors will be divided into 3 groups: the Lurbinectedin Escalation Group, the Irinotecan Escalation Group and the Intermediate Escalation group. Each group will have a different dose escalation scheme.
| Arm | Type | Receives |
|---|---|---|
| Lurbinectedin Escalation Group | Experimental | Drug: Lurbinectedin, Drug: IrinotecanIrinotecan 75 mg/m^2 as a 90-min (-5-min/+30-min) intravenous (i.v.) infusion, followed by Lurbinectedin with starting dose of 1.0 mg/m^2 as a 60-min (-5-min/+20-min) i.v. infusion followed by Irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min [-5-min/+30-min] i.v. infusion) |
| Irinotecan Escalation Group | Experimental | Drug: Lurbinectedin, Drug: IrinotecanStarting dose of Irinotecan 15 mg/m^2 as a 90-min (-5-min/+30-min) i.v. infusion, followed by Lurbinectedin 3.0 mg/m^2 as a 60-min (-5-min/+20-min) i.v. infusion followed by Irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min [-5-min/+30-min] i.v. infusion). |
| Intermediate Escalation Group | Experimental | Drug: Lurbinectedin, Drug: IrinotecanStarting dose of Irinotecan 50 mg/m^2 as a 90-min (-5-min/+30-min) i.v. infusion, followed by Lurbinectedin 2.6 mg/m^2 as a 60-min (-5-min/+20-min) i.v. infusion. No Irinotecan dose will be administered on Day 8 in this group. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (58 listed)
- Voluntarily signed and dated written informed consent prior to any specific-study procedure.
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
- Life expectancy ≥ 3 months.
- Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types:
Key exclusion criteria (17 listed)
- Concomitant diseases/conditions:
- Prior treatment with lurbinectedin, trabectedin (Yondelis®) or topoisomerase I inhibitors (irinotecan, topotecan, etc.). Prior topoisomerase inhibitors (e.g., irinotecan) are only allowed in patients with colorectal carcinoma or NENs.
- Prior bone marrow or stem cell transplantation, or radiation therapy in more than 35% of bone marrow.
- Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions (primary or locally advanced) are eligible. Exception: patients with brain metastases are eligible provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment (patients taking steroids in the process of already being tapered within two weeks prior to screening are allowed). Brain CT-scan or MRI results must be provided at baseline.
- Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception. Women of childbearing potential (WOCBP) must agree to use an effective contraception method to avoid pregnancy during the course of the trial (and for at least six months after the last infusion). Fertile male patients must agree to refrain from fathering a child or donating sperm during the trial and for four months after the last infusion.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LurbinectedinAlso: PM01183lurbinectedin (PM01183) 4 mg vials | Drug | Intermediate Escalation Group, Irinotecan Escalation Group, Lurbinectedin Escalation Group |
| Irinotecanirinotecan 40 mg, 100 mg or 300 mg vials | Drug | Intermediate Escalation Group, Irinotecan Escalation Group, Lurbinectedin Escalation Group |
Primary outcome
Maximum Tolerated Dose (MTD)
Time frame: 66 months
The MTD will be the lowest dose level explored during dose escalation which one third or more of evaluable patients develops DLTs in Cycle 1. DLTs are related AEs during Cycle 1 fulfilling at least 1 of the criteria below: * Grade 4 neutropenia lasting >3 days * Febrile neutropenia of any duration or neutropenic sepsis * Grade 4 thrombocytopenia/Grade 3 with clinically bleeding requiring a transfusion * Grade 4 ALT/AST increase/Grade 3 lasting >14 days * Grade≥2 increased ALT/AST concomitantly with total bilirubin increase ≥2.0×ULN and normal ALP * Grade≥3 diarrhea lasting >5 days and despite adequate corrective treatment * Grade≥3 CPK increase * Grade≥3 non-hematological related AE, excluding nausea/vomiting, hypersensitivity reactions, extravasations, grade 3 fatigue lasting <1 week and nonclinically biochemical abnormalities * Administration delay of Cycle 2 >15 days from the Day 22 due to any related AEs * Failure to meet the Day-8 continuation criteria for irinotecan in Cycle 1
Recommended Dose (RD)
Time frame: 66 months
The RD will be the highest dose level explored during dose escalation in which fewer than one third of patients develop DLTs during Cycle 1. DLTs are related AEs during Cycle 1 fulfilling at least 1 of the criteria below: * Grade 4 neutropenia lasting >3 days * Febrile neutropenia of any duration or neutropenic sepsis * Grade 4 thrombocytopenia/Grade 3 with clinically bleeding requiring a transfusion * Grade 4 ALT/AST increase/Grade 3 lasting >14 days * Grade≥2 increased ALT/AST concomitantly with total bilirubin increase ≥2.0×ULN and normal ALP * Grade≥3 diarrhea lasting >5 days and despite adequate corrective treatment * Grade≥3 CPK increase * Grade≥3 non-hematological related AE, excluding nausea/vomiting, hypersensitivity reactions, extravasations, grade 3 fatigue lasting <1 week and nonclinically biochemical abnormalities * Administration delay of Cycle 2 >15 days from the Day 22 due to any related AEs * Failure to meet the Day-8 continuation criteria for irinotecan in Cycle 1
Response Rate
Time frame: At least six weeks after treatment initiation, up to 66 months
Phase II Expansion Stage: Efficacy Response rate is a percentage of patients with any response: partial response or complete response. Antitumor activity will be measured according to RECIST v.1.1. * An increase of ≥20% from the baseline or new lesion appears represents progressive disease. * A decrease in the sum of target disease of ≥30% represents partial response. * Stable disease lies between partial response and progressive disease. * Complete response is the disappearance of all lesions with nodes measuring <10 mm and normal tumour markers Patients included in the tumor-specific expansion cohort(s) at the RD for each group, and in the new cohort of patients with NENs, must be evaluable per RECIST v.1.1 (including ovarian cancer patients). Specifically, patients with glioblastoma must be evaluated per RECIST v.1.1 and RANO criteria. A patient evaluable for efficacy should have received at least one complete dose of lurbinectedin and irinotecan.
10 secondary outcomes
Safety evaluation
Time frame: Since start of the treatment until 30 days after the last administration of study treatment; or until start of a new antitumor therapy or death
Peak Plasma Concentration (Cmax)
Time frame: 66 months
Area under the plasma concentration versus time curve (AUC)
Time frame: 66 months
Volume of distribution based on the terminal half-life (Vz)
Time frame: 66 months
Volume of distribution at steady state (Vss)
Time frame: 66 months
Clearance (CL)
Time frame: 66 months
Half-life (t1/2)
Time frame: 66 months
Duration of response
Time frame: Time from date when response criteria are fulfilled to the first date when progression disease, recurrence or death, until 18 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs
Progression-free Survival
Time frame: From the date of first infusion of study treatment to the date of progression or death or until 18 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs first.
Overall Survival
Time frame: From the date of first infusion of study treatment to the date or death or until 18 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs first.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jul 2025.
- Derived from this study: PubMed 42081171Falcon A, Cote GM, Molina-Cerrillo J, Le Cesne A, Rocha P, Bockorny B, Paez D, Martin-Broto J, Chawla SP, Martinez S, Kahatt C, Alfaro V, Siguero M, Jimenez J, Custodio A, Alonso-Orduna V, Lopez C, Kollar A, Soto-Castillo JJ, Paz-Ares L. Pooled safety analysis of lurbinectedin plus irinotecan in patients with advanced solid tumors. Invest New Drugs. 2026 May 4. doi: 10.1007/s10637-026-01616-0. Online ahead of print.
- Derived from this study: PubMed 41791703Ponce S, Ruiz-Torres M, Falcon A, Cote GM, Bernabe R, Lin JJ, Coya JM, Jimenez-Munoz M, Fernandez-Puyuelo P, Sanchez A, Zugazagoitia J, Ucero A, Baena J, Bote de Cabo H, Herrera M, Torres-Jimenez J, Zurera M, Kahatt C, Lopez-Vilarino JA, Martinez S, Siguero M, Malumbres M, Ferrer I, Paz-Ares L. Combination of Lurbinectedin Plus Irinotecan: Preclinical and Early Clinical Results in Patients With Relapsed SCLC. J Thorac Oncol. 2026 Jul;21(7):103654. doi: 10.1016/j.jtho.2026.103654. Epub 2026 Mar 4.
- Derived from this study: PubMed 40963055Falcon A, Ponce S, Cote GM, Gil A, Lin JJ, Bockorny B, Martinez J, Kahatt C, Martinez S, Zubiaur P, Siguero M, Cullell-Young M, Jimenez J, Zugazagoitia J, Paz-Ares L. Phase I results on the efficacy, safety and pharmacokinetics of lurbinectedin and irinotecan in advanced solid tumors. Invest New Drugs. 2025 Aug;43(4):955-967. doi: 10.1007/s10637-025-01583-y. Epub 2025 Sep 18.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
23 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Lurbinectedin and Irinotecan in people with Advanced Solid Tumors and Glioblastoma, run by PharmaMar at 23 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 58 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in Spain, United States, France, Germany, Italy and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) (time frame: 66 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02611024, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2025.