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

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

Detailed Description
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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.

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

Conditions
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Malignant Pleural Mesothelioma

Intervention / Treatment
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* Drug: Trabectedin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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 Exclusion Criteria: - 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 - 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin<br>Patients will receive trabectedin treatment | Drug: Trabectedin<br>* 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<br>* Other names: Yondelis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 24 months | 
| Overall survival (OS) |  | 24 months | 
| Objective response rate | Responses will be assessed according to Modified RECIST criteria for Malignant Pleural Mesothelioma | 24 months | 
| 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 | 24 months | 
| 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 | 24 months | 
| 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) | 24 months | 
| Antalgic treatments | Evaluation of type and dosage of any pain medication administered to the patient at the moment of the study visit | 24 months | 
| 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. | 24 months | 
| 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 | 24 months | 
| 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 | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesothelioma, MPM, Trabectedin