Clinical trial NCT02194231: ATREUS - Phase II Study on the Activity of Trabectedin in Patients With Malignant Pleural Mesothelioma (MPM)
Official title: ATREUS Trial - A Phase II Study on the Activity of Trabectedin of Pretreated Epithelioid or Biphasic / Sarcomatoid Malignant Pleural Mesothelioma(MPM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malignant Pleural Mesothelioma
Keywords: Mesothelioma
MPM
Trabectedin
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
Collaborators: name: PharmaMar
First posted: 2014-07-18
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression Free Survival - PFS12w
timeFrame: 12 weeks
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 24 months
measure: Overall survival (OS)
timeFrame: 24 months
measure: Objective response rate
timeFrame: 24 months
measure: Trabectedin tolerability and safety
timeFrame: 24 months
measure: Pain Intensity (PI)
timeFrame: 24 months
measure: Pain type and characteristics
timeFrame: 24 months
measure: Antalgic treatments
timeFrame: 24 months
measure: microRNA (miRs) profile
timeFrame: 24 months
measure: High Mobility Group B1 (HMGB1) protein assessment
timeFrame: 24 months
measure: Blood Macrophages analysis
timeFrame: 24 months
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: Azienda ospedaliera ss. Antonio e Biagio e Cesare Arrigo
state: AL
city: Bergamo
country: Italy
facility: Cliniche Humanitas Gavazzeni
state: BG
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
state: Bo
city: Brescia
country: Italy
facility: P.O. Spedalli Civili
state: BS
city: Monza
country: Italy
facility: Azienda Ospedaliera S. Gerardo di Monza
state: MB
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Padova
country: Italy
facility: Istituto Oncologico Veneto - IOV
state: PD
city: Parma
country: Italy
facility: Azienda Ospedaliro-Universitaria di Parma
Study officials:
affiliation: Azienda Ospedaliera San Gerardo di Monza
name: Paolo Bidoli, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Istituto Di Ricerche Farmacologiche Mario Negri
name: Valter Torri, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.