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Pharmacokinetic Study of PM01183 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. Identifier: NCT02611024
Recruitment Status : Recruiting
First Posted : November 20, 2015
Last Update Posted : June 9, 2020
Information provided by (Responsible Party):

Brief Summary:
Prospective, open-label, dose-ranging, uncontrolled phase I study with PM01183 in combination with irinotecan to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with irinotecan in patients with selected advanced solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Glioblastoma Soft Tissue Sarcoma Endometrial Carcinoma Ovarian Carcinoma Mesothelioma Gastroenteropancreatic Neuroendocrine Tumor SCLC Gastric Carcinoma Drug: lurbinectedin (PM01183) Drug: Irinotecan Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients with selected advanced solid tumors will be divided into two groups: the PM01183 Escalation Group and the Irinotecan Escalation Group. Each group will have a different dose escalation scheme.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I, Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination With Irinotecan in Pretreated Patients With Selected Advanced Solid Tumors
Actual Study Start Date : May 6, 2016
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2021

Arm Intervention/treatment
Experimental: PM01183 Escalation Group

PM01183 1.0 mg/m^2 D1 60 min (-5/+20 min) i.v. infusion q3wk

Irinotecan 75 mg/m^2 D1-8 90 min (-5/+30 min) i.v. infusion q3wk

Drug: lurbinectedin (PM01183)
lurbinectedin (PM01183) 4 mg vials

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

Experimental: Irinotecan Escalation Group

PM01183 3.0 mg/m^2 D1 60 min (-5/+20 min) i.v. infusion q3wk

Irinotecan 15 mg/m^2 D1-8 90 min (-5/+30 min) i.v. infusion q3wk

Drug: lurbinectedin (PM01183)
lurbinectedin (PM01183) 4 mg vials

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

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: 48 months ]
    The MTD for each group will be the lowest dose level explored during dose escalation which one third or more of evaluable patients develops DLT in Cycle 1.

  2. Recommended Dose (RD) [ Time Frame: 48 months ]
    The RD for each groupwill be the highest dose level explored during dose escalation in which fewer than one third of evaluable patients develop DLT during Cycle 1.

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: 48 months ]
    Pharmacokinetic Outcome Measures

  3. Area under the plasma concentration versus time curve (AUC) [ Time Frame: 48 months ]
    Pharmacokinetic Outcome Measures

  4. Volume of distribution based on the terminal half-life (Vz) [ Time Frame: 48 months ]
    Pharmacokinetic Outcome Measures

  5. Volume of distribution at steady state (Vss) [ Time Frame: 48 months ]
    Pharmacokinetic Outcome Measures

  6. Clearance (CL) [ Time Frame: 48 months ]
    Pharmacokinetic Outcome Measures

  7. Half-life (t1/2) [ Time Frame: 48 months ]
    Pharmacokinetic Outcome Measures

  8. Evaluation of antitumor response [ Time Frame: Start treatment until PD, other antitumor therapy, death or until 12 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs first. ]
    Evaluable and measurable as per RECIST v.1.1 or RANO for Gliobastoma 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 12 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 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 12 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

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

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. 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).
  6. Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types:

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

    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).

(*)Albumin transfusion to increase the blood level in order to fulfill the inclusion criterion is strictly forbidden.

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) infection. 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.
  2. Prior treatment with PM01183, 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. In SCLC, patients with brain metastases or leptomeningeal disease involvement 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.(*)
  6. Limitation of the patient's ability to comply with the treatment or follow-up protocol.

(*)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 three 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.

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 identifier (NCT number): NCT02611024

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Contact: Pharma Mar Clinical Oncology

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United States, Massachusetts
Massachusetts General Hospital - Recruiting
Boston, Massachusetts, United States, 02114
Principal Investigator: Gregory Cote, MD, PhD         
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: María José Flor Oncala, Dra.         
Sponsors and Collaborators
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Responsible Party: PharmaMar Identifier: NCT02611024    
Other Study ID Numbers: PM1183-A-014-15
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: May 2020
Keywords provided by PharmaMar:
Pharma Mar
Edwing Sarcoma
Synovial Sarcoma
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Endometrial Neoplasms
Stomach Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neoplasms, Mesothelial
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases