Intrapleural Photodynamic Therapy in a Multimodal Treatment for Patients With Malignant Pleural Mesothelioma

NCT ID: NCT02662504

Last Updated: 2018-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-16
• Study Completion Date: 2018-03-13

Brief Summary

Malignant pleural mesothelioma (MPM) is an aggressive tumour with poor prognosis (median survival <13 months), and high resistance to chemotherapy. Extended pleurectomy/decortication (eP/D) is a debulking surgery of MPM but cannot be considered as a curative treatment. Therefore it has been suggested that eP/D may be of interest if combined with intra-operative treatment and adjuvant therapies.

Photodynamic Therapy (PDT) is an innovative treatment based on the rationale that tumour cells, if previously treated with photosensitizing drugs (Photofrin), will die when exposed to light at a particular wavelength. Interestingly PDT might also stimulate anti-tumour immune response through the release of tumour antigens and induced inflammation.

PDT was tested in phase I-II trials for MPM in combination with EPP or eP/D, and chemotherapy. US studies from J Friedberg et al found very promising survival results in MPM when combining eP/D, but not EPP, intra-operative PDT and chemotherapy (cisplatin-pemetrexed), with a median overall survival of 31.7 months.

However, the definitive value of intra-pleural PDT combined to eP/D in the treatment of MPM still need to be validated. The same multimodal treatment has been established in Lille, the French national expert centre for MPM, with the help of our american colleagues. Therefore, this phase II trial proposes to patients to benefit from the combination of eP/D, intra-operative PDT then chemotherapy by cisplatin-pemetrexed and prophylactic radiotherapy.

Primary endpoint is the feasibility for the patients to have the full multimodal treatment of MPM including intrapleural PDT without unacceptable or unexpected grade III-IV toxicities. Secondary endpoints are PFS, OS, ORR, and quality of life. If the feasibility of such treatment would be confirmed in France, a multicentric, randomized trial comparing this experimental treatment vs control arm (same multimodal treatment without PDT) is planned.

Detailed Description

phase II trial assessing the feasibility of an experimental multimodal treatment combining:

• surgery of the MPM: extended pleurectomy/decortication (eP/D)
• intra-operative (intrapleural) photodynamic therapy (PDT). Briefly, each patient will receive porfimer sodium (PHOTOFRIN®) (2 mg/kg) 24 hours before eP/D (IV injection on 3-5 minutes). Cutaneous light precautions will be instituted immediately and for the next 4 weeks.

then:

• prophylactic chest radiotherapy of surgical scars to prevent tumor seeding (3 x 7 Gray)
• adjuvant standard chemotherapy by (cis)platin 75 mg/m2 and pemetrexed 500 mg/m2 up to 6 cycles (1 cycle every 3 weeks), with oral folic acid (400 μg daily) and vitamin B12 (1000 μg Q9W) supplementation
• follow-up

Conditions

Malignant Pleural Mesothelioma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

multimodal treatment + intrapleural PDT

• surgery of the MPM: extended pleurectomy/decortication (eP/D)
• intra-operative (intrapleural) photodynamic therapy (PDT). Briefly, each patient will receive porfimer sodium (PHOTOFRIN®) (2 mg/kg) 24 hours before eP/D (IV injection on 3-5 minutes). Cutaneous light precautions will be instituted immediately and for the next 4 weeks.

then:

• prophylactic chest radiotherapy of surgical scars to prevent tumor seeding (3 x 7 Gray)
• adjuvant standard chemotherapy by (cis)platin 75 mg/m2 and pemetrexed 500 mg/m2 up to 6 cycles (1 cycle every 3 weeks), with oral folic acid (400 μg daily) and vitamin B12 (1000 μg Q9W) supplementation

Group Type: EXPERIMENTAL

photodynamic therapy (PDT)

Intervention Type: DEVICE

Intra-operative (intrapleural) photodynamic therapy (PDT): briefly, each patient will receive porfimer sodium (PHOTOFRIN®) (2 mg/kg) 24 hours before eP/D (IV injection on 3-5 minutes). Cutaneous light precautions will be instituted immediately and for the next 4 weeks.

After complete macroscopic resection of the tumour, the thoracic surgeon and his team will set isoprobes (7 at least) in the "pleural" cavity to monitor by a dosimetry device the correct illumination of the cavity with a visible red light (wavelength of 630 nm; laser source). PDT-related postoperative considerations include light precautions, intensive focus on perioperative nutrition, and a greater than normal fluid requirement in the immediate postoperative period.

thoracic surgery Pleurectomy / extended Decortication

Intervention Type: PROCEDURE

extended P/D is intended to remove any macroscopic tumor including the parietal and visceral pleura when the diaphragm and / or the pericardium was resected

Adjuvant chemotherapy

Intervention Type: DRUG

Chemotherapy should begin up to three months after surgery. It consists of pemetrexed 500 mg / m2 followed 30 minutes later by cisplatin 75 mg / m2 (in the usual manner from the center to the chemotherapy) on day 1 (J1) of each cycle every 3 weeks, for up to 6 cycles.

Interventions

photodynamic therapy (PDT)

Intra-operative (intrapleural) photodynamic therapy (PDT): briefly, each patient will receive porfimer sodium (PHOTOFRIN®) (2 mg/kg) 24 hours before eP/D (IV injection on 3-5 minutes). Cutaneous light precautions will be instituted immediately and for the next 4 weeks.

After complete macroscopic resection of the tumour, the thoracic surgeon and his team will set isoprobes (7 at least) in the "pleural" cavity to monitor by a dosimetry device the correct illumination of the cavity with a visible red light (wavelength of 630 nm; laser source). PDT-related postoperative considerations include light precautions, intensive focus on perioperative nutrition, and a greater than normal fluid requirement in the immediate postoperative period.

Intervention Type: DEVICE

thoracic surgery Pleurectomy / extended Decortication

extended P/D is intended to remove any macroscopic tumor including the parietal and visceral pleura when the diaphragm and / or the pericardium was resected

Intervention Type: PROCEDURE

Adjuvant chemotherapy

Chemotherapy should begin up to three months after surgery. It consists of pemetrexed 500 mg / m2 followed 30 minutes later by cisplatin 75 mg / m2 (in the usual manner from the center to the chemotherapy) on day 1 (J1) of each cycle every 3 weeks, for up to 6 cycles.

Intervention Type: DRUG

Other Intervention Names

Photofrin; pemetrexed / cisplatin

Eligibility Criteria

Inclusion Criteria

• histologically-proved epithelioid malignant pleural mesothelioma (MPM) on biopsies obtained before eP/D surgery
• tumor stage: no tumor extension to controlateral lung, mediastinum, peritoneum or myocardium (<T4); mediastinal lymph nodes extension: cN2 but no bulky N2 or N3), no metastasis (M0)
• Performance status WHO PS 0-1
• patients fit to have surgery (eP/D) and chemotherapy (cisplatin-pemetrexed), based on clinical examination, complete normal biological work-up, full assessment by cardiac and pulmonary function tests. Predicted post-surgical values should be sufficient for normal daily life: FEV1>40%; pre-surgical DLCO>50% predicted value and VO2max >15 ml/min/kg; (left ventricular) cardiac function >50% and no significant pulmonary artery hypertension
• written informed consent must be obtained before inclusion and randomization

Exclusion Criteria

• Another histologic subtype than epithelioid MPM at the time of diagnosis
• Bulky N2, N3 and/or M1 stage (UICC/IMIG 1995)
• prior chemotherapy for mesothelioma
• prior radiotherapy of thorax, neck or upper abdomen
• other malignancy treated within 5 years, except basal cell carcinoma or in situ carcinoma of the cervix
• contra-indication for MPM surgery or chemotherapy (cisplatin and pemetrexed): cardiac failure, pulmonary hypertension, liver or kidney dysfunction (GFR<60 ml/min), uncontrolled infection, previous major neurotoxicity or ototoxicity,... or other severe condition according to the investigator
• pregnancy or breast feeding
• contra-indication for porfimer sodium (Photofrin): porphyria or known hypersensitivity to porphyrins, severe hepatic impairment, tracheo-oesophageal or broncho-oesophageal fistula, suspected erosion of major blood vessels due to risk of massive, potentially fatal haemorrhage

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: collaborator

Région Nord-Pas de Calais, France

OTHER

Sponsor Role: collaborator

University Hospital, Lille

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Arnaud Scherpereel, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Lille

Locations

CHRU de Lille Hôpital Calmette

Lille, , France

Countries

France

Other Identifiers

2015-001554-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2014_01

Identifier Type: -

Identifier Source: org_study_id