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

Malignant Pleural Mesothelioma Clinical Trial

— ATREUS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02194231
• Other study ID #: IRFMN-MPM-6077
• Secondary ID: 2011-006330-16
• Status: Completed
• Phase: Phase 2
• Start date: July 2013
• Est. completion date: December 12, 2019

Study information

• Verified date: January 2020
• Source: Mario Negri Institute for Pharmacological Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: December 12, 2019
• Est. primary completion date: December 12, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Malignant Pleural Mesothelioma
• Mesothelioma

Intervention

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

Locations

Country	Name	City	State
Italy	Azienda ospedaliera ss. Antonio e Biagio e Cesare Arrigo	Alessandria	AL
Italy	Cliniche Humanitas Gavazzeni	Bergamo	BG
Italy	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi	Bologna	Bo
Italy	P.O. Spedalli Civili	Brescia	BS
Italy	Azienda Ospedaliera S. Gerardo di Monza	Monza	MB
Italy	Istituto Oncologico Veneto - IOV	Padova	PD
Italy	Azienda Ospedaliro-Universitaria di Parma	Parma
Italy	Istituto Clinico Humanitas	Rozzano	MI

Sponsors (2)

Lead Sponsor	Collaborator
Mario Negri Institute for Pharmacological Research	PharmaMar

Country where clinical trial is conducted

Italy, 

References & Publications (6)

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. — View 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. Review. — View 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 — View 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, Gómez J, Park YC, Le Cesne A. Efficacy and safety of trabectedin in patients with advanced or metastatic — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Overall survival (OS)		24 months
Secondary	Objective response rate	Responses will be assessed according to Modified RECIST criteria for Malignant Pleural Mesothelioma	24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Antalgic treatments	Evaluation of type and dosage of any pain medication administered to the patient at the moment of the study visit	24 months
Secondary	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
Secondary	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
Secondary	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

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