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

Primary Purpose

Malignant Pleural Mesothelioma

Status

Completed

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Trabectedin

About this trial

This is an interventional treatment trial for Malignant Pleural Mesothelioma focused on measuring Mesothelioma, MPM, Trabectedin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Azienda ospedaliera ss. Antonio e Biagio e Cesare Arrigo
Cliniche Humanitas Gavazzeni
Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
P.O. Spedalli Civili
Azienda Ospedaliera S. Gerardo di Monza
Istituto Clinico Humanitas
Istituto Oncologico Veneto - IOV
Azienda Ospedaliro-Universitaria di Parma

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Trabectedin

Arm Description

Patients will receive trabectedin treatment

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Overall survival (OS)

Objective response rate

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

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

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

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)

Antalgic treatments

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

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.

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

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

Full Information

NCT ID

NCT02194231

First Posted

July 16, 2014

Last Updated

January 22, 2020

Sponsor

Mario Negri Institute for Pharmacological Research

Collaborators

PharmaMar

1. Study Identification

Unique Protocol Identification Number

NCT02194231

Brief Title

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

Acronym

ATREUS

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

2. Study Status

Record Verification Date

January 2020

Overall Recruitment Status

Completed

Study Start Date

July 2013 (undefined)

Primary Completion Date

December 12, 2019 (Actual)

Study Completion Date

December 12, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mario Negri Institute for Pharmacological Research

Collaborators

PharmaMar

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malignant Pleural Mesothelioma

Keywords

Mesothelioma, MPM, Trabectedin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

145 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Trabectedin

Arm Type

Experimental

Arm Description

Patients will receive trabectedin treatment

Intervention Type

Drug

Intervention Name(s)

Trabectedin

Other Intervention Name(s)

Yondelis

Intervention Description

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

Primary Outcome Measure Information:

Title

Progression Free Survival - PFS12w

Description

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

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

Progression Free Survival (PFS)

Description

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

Time Frame

24 months

Title

Overall survival (OS)

Time Frame

24 months

Title

Objective response rate

Description

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

Time Frame

24 months

Title

Trabectedin tolerability and safety

Description

Time Frame

24 months

Title

Pain Intensity (PI)

Description

Time Frame

24 months

Title

Pain type and characteristics

Description

Time Frame

24 months

Title

Antalgic treatments

Description

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

Time Frame

24 months

Title

microRNA (miRs) profile

Description

Time Frame

24 months

Title

High Mobility Group B1 (HMGB1) protein assessment

Description

Time Frame

24 months

Title

Blood Macrophages analysis

Description

Time Frame

24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paolo Bidoli, MD

Organizational Affiliation

Azienda Ospedaliera San Gerardo di Monza

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Valter Torri, MD

Organizational Affiliation

Istituto Di Ricerche Farmacologiche Mario Negri

Official's Role

Study Chair

Facility Information:

Facility Name

Azienda ospedaliera ss. Antonio e Biagio e Cesare Arrigo

City

Alessandria

State/Province

Country

Italy

Facility Name

Cliniche Humanitas Gavazzeni

City

Bergamo

State/Province

Country

Italy

Facility Name

Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi

City

Bologna

State/Province

ZIP/Postal Code

40138

Country

Italy

Facility Name

P.O. Spedalli Civili

City

Brescia

State/Province

ZIP/Postal Code

25125

Country

Italy

Facility Name

Azienda Ospedaliera S. Gerardo di Monza

City

Monza

State/Province

ZIP/Postal Code

20900

Country

Italy

Facility Name

Istituto Clinico Humanitas

City

Rozzano

State/Province

ZIP/Postal Code

20089

Country

Italy

Facility Name

Istituto Oncologico Veneto - IOV

City

Padova

State/Province

ZIP/Postal Code

35128

Country

Italy

Facility Name

Azienda Ospedaliro-Universitaria di Parma

City

Parma

ZIP/Postal Code

43126

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

Yes

Citations:

PubMed Identifier

8873596

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.

Results Reference

result

PubMed Identifier

10500494

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.

Results Reference

result

PubMed Identifier

11165136

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.

Results Reference

result

PubMed Identifier

19652065

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.

Results Reference

result

PubMed Identifier

19556318

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.

Results Reference

result

PubMed Identifier

20647340

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.

Results Reference

result

Links:

URL

http://medicine.iupui.edu/flockhart/table.htm

Description

At this link you may find all the relevant Cytochrome P450 Drud interactions

Learn more about this trial

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

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