Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02611024
Recruitment Status : Recruiting
First Posted : November 20, 2015
Last Update Posted : December 2, 2021
Sponsor:
Information provided by (Responsible Party):
PharmaMar

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.

Condition or disease Intervention/treatment Phase
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 Drug: Lurbinectedin Drug: Irinotecan Phase 1 Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
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
Actual Study Start Date : May 6, 2016
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : November 2023


Arm Intervention/treatment
Experimental: Lurbinectedin Escalation Group
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
lurbinectedin (PM01183) 4 mg vials
Other Name: PM01183

Drug: Irinotecan
irinotecan 40 mg, 100 mg or 300 mg vials

Experimental: Irinotecan Escalation Group
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
lurbinectedin (PM01183) 4 mg vials
Other Name: PM01183

Drug: Irinotecan
irinotecan 40 mg, 100 mg or 300 mg vials

Experimental: Intermediate Escalation Group
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
lurbinectedin (PM01183) 4 mg vials
Other Name: PM01183

Drug: Irinotecan
irinotecan 40 mg, 100 mg or 300 mg vials




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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.



Secondary Outcome Measures :
  1. 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 ]
    AEs will be graded according to the NCI-CTCAE v.4.

  2. Peak Plasma Concentration (Cmax) [ Time Frame: 66 months ]
    Pharmacokinetic Outcome Measures

  3. Area under the plasma concentration versus time curve (AUC) [ Time Frame: 66 months ]
    Pharmacokinetic Outcome Measures

  4. Volume of distribution based on the terminal half-life (Vz) [ Time Frame: 66 months ]
    Pharmacokinetic Outcome Measures

  5. Volume of distribution at steady state (Vss) [ Time Frame: 66 months ]
    Pharmacokinetic Outcome Measures

  6. Clearance (CL) [ Time Frame: 66 months ]
    Pharmacokinetic Outcome Measures

  7. Half-life (t1/2) [ Time Frame: 66 months ]
    Pharmacokinetic Outcome Measures

  8. 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 ]
    Evaluable and measurable as per RECIST v.1.1 or RANO for Glioblastoma patients

  9. 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. ]
    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.

  10. 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. ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Voluntarily signed and dated written informed consent prior to any specific-study procedure.
  2. Age ≥ 18 years.
  3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
  4. Life expectancy ≥ 3 months.
  5. 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:

    1. Glioblastoma.
    2. Soft-tissue sarcoma (excluding gastrointestinal stromal tumors [GIST]).
    3. Endometrial carcinoma.
    4. Epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas) regardless of platinum sensitivity.
    5. Mesothelioma.
    6. Gastroenteropancreatic neuroendocrine tumors (GEP-NET).
    7. Small cell lung cancer (SCLC).
    8. Pancreatic adenocarcinoma.
    9. Gastric carcinoma.
    10. Colorectal carcinoma (CRC).

    For the Intermediate Escalation Group:

    1. Endometrial carcinoma.
    2. SCLC.
    3. Other solid tumors may be included, if appropriate, after discussion between the Investigators and the Sponsor.

    For the Phase II expansion stage:

    1. Glioblastoma.
    2. Soft tissue sarcoma (including synovial sarcoma),
    3. Endometrial carcinoma.
    4. SCLC.
    5. Neuroendocrine tumors.

      • Group 1: NENs grade 3 (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 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.
  6. 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 NENs of gastroenteropancreatic origin or unknown primary site, excluding lung primary tumors), progression to first-line platinum-based chemotherapy; and
      • In Group 2 (patients with well differentiated P-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).

  7. Phase II expansion stage: Tumor-specific cohort(s) at the RD:

    1. 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.
    2. 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.
  8. At least three weeks since the last anticancer therapy (excluding immunotherapy that must be at least two weeks, provided that is not combined with chemotherapy), including 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:

    1. The patient has a new lesion outside of the radiotherapy field, or
    2. 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).

  9. Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days before inclusion in the trial):

    1. Platelet count ≥ 100 × 10^9/L, hemoglobin ≥ 9.0 g/dL and absolute neutrophil count (ANC) ≥ 2.0 × 10^9/L.
    2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN), even in the presence of liver metastases.
    3. Alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN if disease-related/in the case of liver metastases).
    4. Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN.
    5. International Normalized Ratio (INR) < 1.5 (except if patient is on oral anticoagulation therapy).
    6. Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (using Cockcroft-Gault formula).
    7. Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
    8. Albumin ≥ 3.0 g/dL
  10. 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).

Exclusion Criteria:

  1. Concomitant diseases/conditions:

    1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year.
    2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
    3. Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 × ULN in two different determinations performed one week apart).
    4. Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. Known Gilbert disease.
    5. Active uncontrolled infection.
    6. Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B.
    7. Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or sub-occlusion or paralysis.
    8. Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days.
    9. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study
    10. Active Coronavirus disease (COVID-19) (this includes positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR).
  2. 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
  3. Prior bone marrow or stem cell transplantation, or radiation therapy in more than 35% of bone marrow.
  4. 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.
  5. 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.
  6. Limitation of the patient's ability to comply with the treatment or follow-up protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02611024


Contacts
Layout table for location contacts
Contact: Pharma Mar Clinical Oncology clinicaltrials@pharmamar.com

Locations
Layout table for location information
United States, Massachusetts
Massachusetts General Hospital - Recruiting
Boston, Massachusetts, United States, 02114
Principal Investigator: Gregory Cote, MD, PhD         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Gregory Cote, MD, PhD         
Spain
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain, 28041
Principal Investigator: Luis Paz-Ares, Dr.         
Hospital Virgen Del Rocio Recruiting
Sevilla, Spain, 41013
Principal Investigator: Alejandro Falcon Gonzalez, Dr.         
Sponsors and Collaborators
PharmaMar
Layout table for additonal information
Responsible Party: PharmaMar
ClinicalTrials.gov Identifier: NCT02611024    
Other Study ID Numbers: PM1183-A-014-15
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: December 2, 2021
Last Verified: November 2021
Keywords provided by PharmaMar:
Lurbinectedin
PM01183
Tumors
Cancer
Pharma Mar
Ewing Sarcoma
Synovial Sarcoma
Sarcoma
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Neoplasms
Sarcoma
Glioblastoma
Mesothelioma
Neuroendocrine Tumors
Colorectal Neoplasms
Endometrial Neoplasms
Carcinoma, Ovarian Epithelial
Stomach Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Adenoma
Neoplasms, Mesothelial
Neoplasms by Site
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases