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

NCT02611024 | Completed Phase 1

• 1 other identifier: PM1183-A-014-15
• Study Type: interventional
• Target: 316
• Locations: 6 countries
• Sites: 23

Brief 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.

Conditions

Advanced Solid Tumors; Glioblastoma; Soft Tissue Sarcoma (Excluding GIST); Endometrial Carcinoma; Epithelial Ovarian Carcinoma; Mesothelioma; Gastroenteropancreatic Neuroendocrine Tumor; SCLC; Gastric Carcinoma; Pancreatic Adenocarcinoma; Colorectal Carcinoma; Neuroendocrine Tumors

Keywords

Lurbinectedin; PM01183; Tumors; Cancer; Pharma Mar; Sarcoma; SCLC; Neuroendocrine

Outcome Measures

Primary Outcomes (3)

• 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

  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

  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.

  At least six weeks after treatment initiation, up to 66 months

Secondary Outcomes (10)

• Safety evaluation

  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)

  66 months

• Area under the plasma concentration versus time curve (AUC)

  66 months

• Volume of distribution based on the terminal half-life (Vz)

  66 months

• Volume of distribution at steady state (Vss)

  66 months

Study Arms (3)

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)

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).

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.

Drug: Lurbinectedin; Drug: Irinotecan

Interventions

Lurbinectedin DRUG

lurbinectedin (PM01183) 4 mg vials

Also known as: PM01183

Intermediate Escalation Group; Irinotecan Escalation Group; Lurbinectedin Escalation Group

Irinotecan DRUG

irinotecan 40 mg, 100 mg or 300 mg vials

Intermediate Escalation Group; Irinotecan Escalation Group; Lurbinectedin Escalation Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• PharmaMar: lead

Study Sites (23)

Sarcoma Oncology Center

Santa Monica, California, 90403, United States

Location

Massachusetts General Hospital -

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Centre Léon Bérard

Lyon, 69373, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Helios Kilinikum Bad Saarow

Bad Saarow, 15526, Germany

Location

Helios Klinikum Berlin Buch

Berlin, 13125, Germany

Location

Campus Biomedico

Roma, 00128, Italy

Location

IRCCS Fondazione Candiolo (Turin)

Torino, 10060, Italy

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Univeristari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario Puerta de Hierro

Madrid, 28022, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitario Madrid Sanchinarro

Madrid, 28050, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, 39008, Spain

Location

Hospital Clínico Universitario de Santiago

Santiago de Compostela, 15706, Spain

Location

Hospital Virgen Del Rocio

Seville, 41013, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

Location

Inselspital Bern - Medizinische Onkologie

Bern, CH 3010, Switzerland

Location

Related Publications (1)

• Falcon 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.

  PMID: 40963055 DERIVED

MeSH Terms

Conditions

Glioblastoma; Sarcoma; Endometrial Neoplasms; Carcinoma, Ovarian Epithelial; Mesothelioma; Gastro-enteropancreatic neuroendocrine tumor; Stomach Neoplasms; Colorectal Neoplasms; Neuroendocrine Tumors; Neoplasms

Interventions

PM 01183; Irinotecan

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Connective and Soft Tissue; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Carcinoma; Ovarian Neoplasms; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Endocrine System Diseases; Gonadal Disorders; Adenoma; Neoplasms, Mesothelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Intestinal Neoplasms; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 5, 2015
• First Posted: November 20, 2015
• Study Start: May 6, 2016
• Primary Completion: July 1, 2025
• Study Completion: July 1, 2025
• Last Updated: July 9, 2025

Record last verified: 2025-07

Locations

DE (2); FR (2); US (4); IT (2); ES (12); CH (1)