Treatment of Malignant Peritoneal Mesothelioma (MESOTIP)

Peritoneal Carcinomatosis Clinical Trial

— MESOTIP  

Official title:

Phase II Multicenter Randomized Trial Evaluating the Association of PIPAC and Systemic Chemotherapy Versus Systemic Chemotherapy Alone as 1st-line Treatment of Malignant Peritoneal Mesothelioma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03875144
• Other study ID #: PROICM 2019-03 MES
• Status: Recruiting
• Phase: Phase 2
• Start date: August 14, 2020
• Est. completion date: September 2028

Study information

• Verified date: January 2024
• Source: Institut du Cancer de Montpellier - Val d'Aurelle
• Contact: Olivia SGARBURA, MD
• Phone: 0467614586
• Email: Olivia.sgarbura[@]icm.unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

MESOTIP is a randomized trial evaluating the association of PIPAC and systemic chemotherapy versus systemic chemotherapy alone as 1st-line treatment of Malignant Peritoneal Mesothelioma In this study, patients in the experimental arm will be treated by 4 PIPAC (Cisplatine+Doxorubicine) alternating with 6 cycles of standard intravenous chemotherapy (Cisplatine+Pemetrexed). MESOTIP aim to show an improvement of the overall survival in the experimental arm.

Description:

Malignant peritoneal mesothelioma (MPM) is a rare tumoral disease characterized by the diffuse involvement of the peritoneal serosa. The incidence of all mesotheliomas is estimated quite differently in various reports with the highest rates in industrialized countries. In France, the estimated incidence is 300 cases/year. Three types of malignant mesotheliomas are described in the WHO classification: epithelioid, sarcomatoid and biphasic. The standard treatment of MPM is surgery. It has been shown that cytoreductive surgery (CRS) associated to hyperthermic intraperitoneal chemotherapy (HIPEC) improves prognosis resulting in a median overall survival of 29.5 months to 53 months and an 5 years overall survival rate ranging between 39 to 63%. Cytoreductive surgery should be complete or almost complete (CCR0/1) as macroscopic residual disease deteriorates prognosis. However some patients are not eligible for surgery due to the locoregional extension of the disease. Although debulking surgery may still be considered, its results are less encouraging than CRS and HIPEC. The neoadjuvant treatment combining Cisplatin and Pemetrexed became a routinely applied option for initially unresectable patients after the publication of an open-label study inspired by previous results of a randomized trial in pleural mesothelioma. This study showed a benefit in median survival of 5 months and an increase in the response rate of 10%. Ever since, other phase II studies were proposed but their benefit is still limited. Pleural mesothelioma which is more common and represents the model of choice for the treatment of peritoneal mesothelioma has also benefitted from phase III studies analyzing the addition of a targeted therapy (Bevacizumab) and phase II trials proposing immunotherapy. By contrast, peritoneal mesothelioma was the setting of choice for testing intraperitoneal administration of chemotherapy either as early postoperative intraperitoneal chemotherapy (EPIC) or as neoadjuvant intraperitoneal chemotherapy. Both studies offered promising results showing a sensitivity of MPM to intraperitoneal administration. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) has recently been developed and shows interesting results in the neoadjuvant context of several peritoneal carcinomatoses while producing little toxicity. PIPAC is a modality of repeated administration of intraperitoneal chemotherapy during laparoscopy using aerosols at the pressure of the capnoperitoneum (12mmHg). Data from ex-vivo, in-vivo and human studies demonstrated a higher local drug bioavailability when compared to liquid IP chemotherapy. PIPAC was tested in the setting of malignant mesothelioma showing encouraging results. In our study MESOTIP, patients in the experimental arm will be treated by 4 PIPAC (Cisplatine+Doxorubicine) alternating with 6 cycles of standard intravenous chemotherapy (Cisplatine+Pemetrexed). Although retrospective reports showing the interest of PIPAC in the neoadjuvant setting for different peritoneal carcinomatosis origins were published, MESOTIP would be the first study to combine PIPAC to systemic chemotherapy in the first-line of treatment and to only include patients not eligible for surgical treatment and proposing a complete cytoreductive surgery associated to HIPEC for patients converted to resectability. MESOTIP aim to show an improvement of the overall survival in the experimental arm.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. completion date: September 2028
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 years

2. PS (or WHO) <2

3. Histologically-confirmed diagnosis of peritoneal malignant mesothelioma

4. No previous line of treatment (both medical and surgical oncologic treatments) for this disease

5. Peritoneal Carcinomatosis Index (PCI)>27 or at least 4 on the small bowel with serosal involvement contraindicating the cytoreductive surgery because of the impossibility to preserve a length >=1.5 m of uninvolved small bowel

6. Written and dated informed consent

7. Affiliated to the French national social security system

Exclusion Criteria:

1. WHO performance status = 2

2. Any contraindication to chemotherapy and/or radiotherapy

3. Any contraindication to repeated laparoscopy

4. Symptomatic cardiac or coronary insufficiency

5. Severe renal insufficiency

6. Progressive active infection or any other severe medical condition

7. Intestinal occlusion non responsive to medical treatment

8. Other cancer treated within the last 2 years except in situ cervical carcinoma or basocellular/spinocellular carcinoma

9. Pregnant or breast-feeding woman

10. Previously operated patients where laparoscopy is not feasible

11. Persons deprived of liberty or under guardianship or incapable of giving consent

12. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule

Related Conditions & MeSH terms

• Carcinoma
• Mesothelioma
• Mesothelioma, Malignant
• Peritoneal Carcinomatosis
• Peritoneal Mesothelioma
• Peritoneal Neoplasms

Intervention

Procedure:
• PIPAC
Pressurized IntraPeritoneal Aerosol Chemotherapy of Cisplatin 10.5mg/m² + Doxorubicin 2.1 mg/m² every 6 weeks

Drug:
• Cisplatin
standard intravenous chemotherapy for mesothelioma (Cisplatin 75mg/m² + Pemetrexed 500mg/m²)
• Pemetrexed
standard intravenous chemotherapy for mesothelioma (Cisplatin 75mg/m² + Pemetrexed 500mg/m²)

Locations

Country	Name	City	State
France	Institut réginal du Cancer de Montpellier	Montpellier

Sponsors (1)

Lead Sponsor	Collaborator
Institut du Cancer de Montpellier - Val d'Aurelle

Country where clinical trial is conducted

France, 

References & Publications (7)

Alexander HR Jr, Li CY, Kennedy TJ. Current Management and Future Opportunities for Peritoneal Metastases: Peritoneal Mesothelioma. Ann Surg Oncol. 2018 Aug;25(8):2159-2164. doi: 10.1245/s10434-018-6337-5. Epub 2018 Feb 8. — View Citation

Baratti D, Kusamura S, Cabras AD, Bertulli R, Hutanu I, Deraco M. Diffuse malignant peritoneal mesothelioma: long-term survival with complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Eur J Cancer. 2013 Oct;49(15):3140-8. doi: 10.1016/j.ejca.2013.05.027. Epub 2013 Jul 4. — View Citation

Boffetta P. Epidemiology of peritoneal mesothelioma: a review. Ann Oncol. 2007 Jun;18(6):985-90. doi: 10.1093/annonc/mdl345. Epub 2006 Oct 9. — View Citation

Bossard N, Velten M, Remontet L, Belot A, Maarouf N, Bouvier AM, Guizard AV, Tretarre B, Launoy G, Colonna M, Danzon A, Molinie F, Troussard X, Bourdon-Raverdy N, Carli PM, Jaffre A, Bessaguet C, Sauleau E, Schvartz C, Arveux P, Maynadie M, Grosclaude P, Esteve J, Faivre J. Survival of cancer patients in France: a population-based study from The Association of the French Cancer Registries (FRANCIM). Eur J Cancer. 2007 Jan;43(1):149-60. doi: 10.1016/j.ejca.2006.07.021. Epub 2006 Nov 3. — View Citation

Helm JH, Miura JT, Glenn JA, Marcus RK, Larrieux G, Jayakrishnan TT, Donahue AE, Gamblin TC, Turaga KK, Johnston FM. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis. Ann Surg Oncol. 2015 May;22(5):1686-93. doi: 10.1245/s10434-014-3978-x. Epub 2014 Aug 15. — View Citation

Kim J, Bhagwandin S, Labow DM. Malignant peritoneal mesothelioma: a review. Ann Transl Med. 2017 Jun;5(11):236. doi: 10.21037/atm.2017.03.96. — View Citation

Yan TD, Deraco M, Baratti D, Kusamura S, Elias D, Glehen O, Gilly FN, Levine EA, Shen P, Mohamed F, Moran BJ, Morris DL, Chua TC, Piso P, Sugarbaker PH. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol. 2009 Dec 20;27(36):6237-42. doi: 10.1200/JCO.2009.23.9640. Epub 2009 Nov 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	overall survival	The overall survival is defined as the time from the date of randomization to the date of death from any cause	from randomization of first patient until the database cut-off
Secondary	Response to treatment using PFS	Progression free survival (PFS) defined as the time from the date of randomization to the date of any progression or death. PFS will be described with median PFS, 1 and 2y-PFS rate	week 10, week21,every 4 months during 2 years
Secondary	Adverse event	Safety according to CTCAE v5.0. Complications related to PIPAC will also be defined according to CTCAE v5.0 as recent publications in the field of peritoneal carcinomatosis suggest that this classification is more reliable when compared with the Clavien Dindo classification for the peritoneal carcinomatosis surgery	during treatment
Secondary	Feasibility of compliance	Feasibility rate of compliance defined as the percentage of patients who received 6 cycles of systemic chemotherapy and 4 PIPAC (for experimental arm).	Week 21
Secondary	Conversion to resectability	Conversion to resectability rate defined as the percentage of patients eligible for cytoreductive surgery and HIPEC at the end of the treatment out of the total number of patients. Patients are eligible for surgery if preservation of at least 1.5 m of small bowel and of at least 2 m of lower gastrointestinal tube is feasible in case of complete cytoreduction.	surgery
Secondary	Quality of life evaluation	Quality of life EORTC QLQ-C30 questionnaires according to EORTC Guidelines	baseline, week10, week21, FU every 4 months during 2 years