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Malignant Pleural MesotheliomaPhase 2ATREUSNCT02194231

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

A Phase 2 study testing Trabectedin in people with Malignant Pleural Mesothelioma, run by Mario Negri Institute for Pharmacological Research at 8 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to determine whether trabectedin is effective in the treatment of malignant pleural mesothelioma (MPM). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Malignant Pleural Mesothelioma
What is being tested?
Trabectedin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
145 participants
Where
8 sitesItaly
Study dates
Jul 2013to 12 Dec 2019
Phase
Phase 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

  • 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)
  • Age >18 years
  • Performance status 0-1 (ECOG)
  • Measurable disease (CT-PET) according to RECIST criteria modified for malignant pleural mesothelioma
  • Not more than one previous chemotherapy course (consisting of pemetrexed plus platinum derivative), excluded adjuvant therapy if PFS < 12 months
  • A minimum of 3 weeks since previous tumour directed therapy
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  • Recovery from toxic effects of previous therapies to NCI CTC AE Grade 0-1
  • Patients who have received palliative radiation are eligible if <30% of bone marrow was irradiated and normal haematological function was completely regained
  • Haematologic variables: haemoglobin ≥ 9 g/dL, Absolute neutrophil count (ANC) ≥ 1,500/μL and Platelet count ≥ 100,000/μL
  • Serum creatinine ≤1.5 mg/dL or creatinine clearance ≥ 30 mL/min
  • Creatinine phosphokinase (CPK) ≤ 2.5 ULN
  • 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
  • Signed informed consent
  • 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

Who cannot join

  • - Radiotherapy with curative intent to thoracic wall (concomitant with or prior to chemotherapy)
  • - Uncompensated diabetes mellitus or other condition absolutely contra-indicating dexamethasone (used as pre-medication)
  • - Patients enrolled in other study with experimental drugs
  • - Women of childbearing age/potential
  • - Prior exposure to trabectedin
  • - 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
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  • - Active viral hepatitis or chronic liver disease
  • - Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within one year before enrolment, uncontrolled arterial hypertension or arrhythmias
  • - Active major infection
  • - Other serious concomitant illness
  • - Brain / leptomeningeal involvement

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

Italy8 sites
  • Azienda ospedaliera ss. Antonio e Biagio e Cesare Arrigo

    Alessandria, AL

  • Cliniche Humanitas Gavazzeni

    Bergamo, BG

  • Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi

    Bologna, Bo, 40138

  • P.O. Spedalli Civili

    Brescia, BS, 25125

  • Azienda Ospedaliera S. Gerardo di Monza

    Monza, MB, 20900

  • Istituto Oncologico Veneto - IOV

    Padova, PD, 35128

  • Azienda Ospedaliro-Universitaria di Parma

    Parma, 43126

  • Istituto Clinico Humanitas

    Rozzano, MI, 20089

Other trials in Italy

About this study

Official title: ATREUS Trial - A Phase II Study on the Activity of Trabectedin of Pretreated Epithelioid or Biphasic / Sarcomatoid Malignant Pleural Mesothelioma(MPM)

The purpose of this study is to determine whether trabectedin is effective in the treatment of malignant pleural mesothelioma (MPM).

Read the 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.

Being tested
Trabectedin
Keywords
Mesothelioma, MPM, Trabectedin
Medical subject headings
Mesothelioma, Malignant, Mesothelioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TrabectedinDrug

    Also called Yondelis

    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

Study groups in NCT02194231
Study groupRoleWhat they receive
TrabectedinExperimentalPatients will receive trabectedin treatment
Receives: Drug: Trabectedin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival - PFS12w

    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

    Measured: 12 weeks

Secondary outcomes (10)
  1. Progression Free Survival (PFS)

    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

    Measured: 24 months

  2. Overall survival (OS)

    Measured: 24 months

  3. Objective response rate

    Responses will be assessed according to Modified RECIST criteria for Malignant Pleural Mesothelioma

    Measured: 24 months

  4. Trabectedin tolerability and safety

    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

    Measured: 24 months

  5. Pain Intensity (PI)

    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

    Measured: 24 months

  6. Pain type and characteristics

    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)

    Measured: 24 months

  7. Antalgic treatments

    Evaluation of type and dosage of any pain medication administered to the patient at the moment of the study visit

    Measured: 24 months

  8. microRNA (miRs) profile

    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.

    Measured: 24 months

  9. High Mobility Group B1 (HMGB1) protein assessment

    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

    Measured: 24 months

  10. Blood Macrophages analysis

    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

    Measured: 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jul 2014 (estimated)
  2. Study startJul 2013
  3. Primary completion12 Dec 2019
  4. Study completion12 Dec 2019

Resources

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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
145 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02194231
Sponsor's protocol ID
IRFMN-MPM-6077
Other IDs
2011-006330-16
Acronym
ATREUS
Status last verified
Jan 2020
First submitted
16 Jul 2014
Last updated
23 Jan 2020
Results posted
No
Data monitoring committee
No
Individual data sharing
Yes

Publications

  • Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry. 1996 Oct 15;35(41):13303-9. doi: 10.1021/bi960306b.

    PubMed 8873596
  • Bonfanti M, La Valle E, Fernandez Sousa Faro JM, Faircloth G, Caretti G, Mantovani R, D'Incalci M. Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. Anticancer Drug Des. 1999 Jun;14(3):179-86.

    PubMed 10500494
  • Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT, D'Incalci M. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer. 2001 Jan;37(1):97-105. doi: 10.1016/s0959-8049(00)00357-9.

    PubMed 11165136
  • Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009 Sep 1;27(25):4188-96. doi: 10.1200/JCO.2008.21.0088. Epub 2009 Aug 3.

    PubMed 19652065
  • Del Campo JM, Roszak A, Bidzinski M, Ciuleanu TE, Hogberg T, Wojtukiewicz MZ, Poveda A, Boman K, Westermann AM, Lebedinsky C; Yondelis Ovarian Cancer Group. Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer. Ann Oncol. 2009 Nov;20(11):1794-802. doi: 10.1093/annonc/mdp198. Epub 2009 Jun 25.

    PubMed 19556318
  • D'Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010 Aug;9(8):2157-63. doi: 10.1158/1535-7163.MCT-10-0263. Epub 2010 Jul 20.

    PubMed 20647340

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Trabectedin in people with Malignant Pleural Mesothelioma, run by Mario Negri Institute for Pharmacological Research at 8 sites in Italy.

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 14 inclusion and 11 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 23 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in Italy. 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 phase mean?

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?

Progression Free Survival - PFS12w (time frame: 12 weeks). 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 NCT02194231, which also lists 6 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 23 Jan 2020.

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