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ATREUS - Phase II Study on the Activity of Trabectedin in Patients With Malignant Pleural Mesothelioma (MPM) (ATREUS)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02194231
Recruitment Status : Completed
First Posted : July 18, 2014
Last Update Posted : January 23, 2020
Sponsor:
Collaborator:
PharmaMar
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research

Tracking Information
First Submitted Date  ICMJE July 16, 2014
First Posted Date  ICMJE July 18, 2014
Last Update Posted Date January 23, 2020
Study Start Date  ICMJE July 2013
Actual Primary Completion Date December 12, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
Progression Free Survival - PFS12w [ Time Frame: 12 weeks ]
Proportion of patients free from progression or death at the second CT scan assessment performed at 12 weeks (Progression Free Survival - PFS12w) from the date of treatment start
Original Primary Outcome Measures  ICMJE
 (submitted: July 16, 2014)
Progression Free Survival (PFS) [ Time Frame: 12 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
  • Progression Free Survival (PFS) [ Time Frame: 24 months ]
    PFS will be evaluated by CT scans every 6 weeks from the date of first treatment until week 12 and subsequently every 8-9 weeks
  • Overall survival (OS) [ Time Frame: 24 months ]
  • Objective response rate [ Time Frame: 24 months ]
    Responses will be assessed according to Modified RECIST criteria for Malignant Pleural Mesothelioma
  • Trabectedin tolerability and safety [ Time Frame: 24 months ]
    Safety will be evaluated based on reported AEs, clinical laboratory assessments, vital signs and physical examinations. Adverse events will be encoded using the Medical Dictionary for Regulatory Activities (MedDRA) and graded using NCI-CTCAE ver 4
  • Pain Intensity (PI) [ Time Frame: 24 months ]
    Pain intensity will be evaluated by using an 11 points Numerical Rating Scale (NRS), where 0 indicates no pain and 10 indicates the worst pain one can imagine. Patients will be requested to evaluate the PI related to the 24 hours preceding the visit and indicating the score for the average, worst and least PI
  • Pain type and characteristics [ Time Frame: 24 months ]
    With special reference to the presence of neuropathic pain, evaluation shall be carried out using the DN4 questionnaire. The global score on this 10 item instrument allows to diagnose the presence of neuropathic pain (total score ≥4)
  • Antalgic treatments [ Time Frame: 24 months ]
    Evaluation of type and dosage of any pain medication administered to the patient at the moment of the study visit
  • microRNA (miRs) profile [ Time Frame: 24 months ]
    miRs profile evaluation will be performed with the aim of characterising the tumour biological features associated to the different response patterns. Since recent published studies suggests that trabectedin modulates the expression of some miRs in cancer cells exposed to the drug and, also, the resistance to anticancer drugs seems to be well correlated to the expression of some specific miRs, the evaluation of miRs expression may become a powerful prognostic and predictive marker. miRNA landscape in both plasma and tumour tissues will be profiled using commercially available oligo arrays platforms.
  • High Mobility Group B1 (HMGB1) protein assessment [ Time Frame: 24 months ]
    Recent data indicate that the high mobility group B1 (HMGB1) is implicated in the transformation of meshothelial cells and is strongly secreted in sera of patients with mesothelioma. These findings provide the rationale for considering HMGB1 as a potential useful marker to monitor therapeutic effectiveness in patients with mesothelioma. HMGB1 will be determined in plasma of patients at the same time points previously indicated for the assessment of miR profiles by using an ELISA essay
  • Blood Macrophages analysis [ Time Frame: 24 months ]
    We propose to analyse the effects of trabectedin on the number of circulating monocytes and the plasma levels of selected biological mediators. A decrease in the number of circulating monocytes could be a surrogate marker of a biological effect of trabectedin on the precursor cells of tumour macrophages. We propose to collect the number of circulating monocytes during the first 3 treatment cycles, immediately before and 7 days after trabectedin administration
Original Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2014)
Overall survival [ Time Frame: 24 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ATREUS - Phase II Study on the Activity of Trabectedin in Patients With Malignant Pleural Mesothelioma (MPM)
Official Title  ICMJE ATREUS Trial - A Phase II Study on the Activity of Trabectedin of Pretreated Epithelioid or Biphasic / Sarcomatoid Malignant Pleural Mesothelioma(MPM)
Brief Summary The purpose of this study is to determine whether trabectedin is effective in the treatment of malignant pleural mesothelioma (MPM).
Detailed Description

There are no approved agents for second-line treatment of MPM in patients who failed first line pemetrexed plus platinum derivatives regimens. Chemotherapy options are limited and include gemcitabine, vinorelbine and other antifolate compounds. The role of second-line chemotherapy is therefore not yet established and second-line patient population is considered suitable for phase II studies with investigational agents.

Trabectedin is an originally natural marine product, now obtained by a semisynthetic process, that induces a delay in S phase progression and a blockade in G2 phase of the cell cycle by a mode of action that seems different from that of other DNA-damaging agents (see citations). Although the exact mechanism of action of trabectedin has not been fully elucidated yet, it appears to be unique compared to other anticancer agents (see citations). Trabectedin binds to N2 of guanines in the minor groove of DNA, causing a bending of the minor groove towards the major groove.

In the randomised clinical trials in metastatic leiomyosarcoma or liposarcoma and in recurrent platinum-sensitive ovarian cancer, trabectedin is infused at 1.5 mg/m2 as a 24-hour infusion or 1.3 mg/m2 as a 3 hour infusion every 3 weeks (see citations). Balancing efficacy with safety the short infusion is preferable in clinical practice.

In soft tissue sarcoma the response rate did not exceed 10%, however, trabectedin has been shown to provide disease control, with progression arrest rates exceeding 50% and progression-free survival rates exceeding 20% at 6 months. In pre-treated ovarian cancer the objective response rate was 30% with a median time to disease progression of 5.7 months.

Trabectedin has not been extensively employed in MPM, however in phase I studies, some objective response in heavily pre-treated mesothelioma patients was seen.

The present study is aimed at evaluating the activity of trabectedin in MPM patients not candidate for radical surgery. This option is of particular interest due to lack of valid therapeutic options.

Translational studies will be performed to identify factors predictive of the activity of trabectedin in MPM.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malignant Pleural Mesothelioma
Intervention  ICMJE Drug: Trabectedin
Patients will receive 1.1 mg/m2 intravenous trabectedin infusion in 5% glucose via central venous catheter over 3 hours every 21 days. Trabectedin infusion will be preceded by 20 mg of intravenous dexamethasone
Other Name: Yondelis
Study Arms  ICMJE Experimental: Trabectedin
Patients will receive trabectedin treatment
Intervention: Drug: Trabectedin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 6, 2018)
145
Original Estimated Enrollment  ICMJE
 (submitted: July 16, 2014)
79
Actual Study Completion Date  ICMJE December 12, 2019
Actual Primary Completion Date December 12, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histologically proven unresectable MPM. In order to make a reproducible diagnosis, in particular regarding biphasic MPM, histology must derive from transthoracic biopsies (at least 3 representative samples) or from videothoracoscopy (at least 5 representative samples)
  2. Age >18 years
  3. Performance status 0-1 (ECOG)
  4. Measurable disease (CT-PET) according to RECIST criteria modified for malignant pleural mesothelioma
  5. Not more than one previous chemotherapy course (consisting of pemetrexed plus platinum derivative), excluded adjuvant therapy if PFS < 12 months
  6. A minimum of 3 weeks since previous tumour directed therapy
  7. Recovery from toxic effects of previous therapies to NCI CTC AE Grade 0-1
  8. Patients who have received palliative radiation are eligible if <30% of bone marrow was irradiated and normal haematological function was completely regained
  9. Haematologic variables: haemoglobin ≥ 9 g/dL, Absolute neutrophil count (ANC) ≥ 1,500/μL and Platelet count ≥ 100,000/μL
  10. Serum creatinine ≤1.5 mg/dL or creatinine clearance ≥ 30 mL/min
  11. Creatinine phosphokinase (CPK) ≤ 2.5 ULN
  12. Hepatic function variables: Total bilirubin ≤ ULN, Total alkaline phosphatase ≤ 2.5 ULN or if > 2.5 ULN alkaline phosphatase liver fraction or GGT or 5' nucleotidase must be determined and ≤ ULN, AST (serum aspartate transaminase [SGOT]) and ALT (serum alaninetransaminase [SGPT]) must be ≤ 2.5 x ULN, Albumin ≥ 25 g/L
  13. Signed informed consent
  14. Adequate contraceptive methods for male patients whose partner is of childbearing age/potential, during the study and for three months after the end of treatment

Exclusion Criteria:

  1. - Radiotherapy with curative intent to thoracic wall (concomitant with or prior to chemotherapy)
  2. - Uncompensated diabetes mellitus or other condition absolutely contra-indicating dexamethasone (used as pre-medication)
  3. - Patients enrolled in other study with experimental drugs
  4. - Women of childbearing age/potential
  5. - Prior exposure to trabectedin
  6. - History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse
  7. - Active viral hepatitis or chronic liver disease
  8. - Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within one year before enrolment, uncontrolled arterial hypertension or arrhythmias
  9. - Active major infection
  10. - Other serious concomitant illness
  11. - Brain / leptomeningeal involvement
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02194231
Other Study ID Numbers  ICMJE IRFMN-MPM-6077
2011-006330-16 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Mario Negri Institute for Pharmacological Research
Study Sponsor  ICMJE Mario Negri Institute for Pharmacological Research
Collaborators  ICMJE PharmaMar
Investigators  ICMJE
Principal Investigator: Paolo Bidoli, MD Azienda Ospedaliera San Gerardo di Monza
Study Chair: Valter Torri, MD Istituto Di Ricerche Farmacologiche Mario Negri
PRS Account Mario Negri Institute for Pharmacological Research
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP