SMARTER: A Feasibility Study Evaluating Surgery for Mesothelioma After Radiation Therapy Using Extensive Pleural Resection

Sponsor

University Health Network, Toronto (Other)

Overall Status

Recruiting

CT.gov ID

NCT04028570

Collaborator

(none)

Enrollment

Location

Arm

66.9

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to find the maximum tolerated dose level for malignant pleural mesothelioma patients receiving background radiation + boost radiation, and surgery. Boost radiation is an experimental form of radiation that involves targeting non-uniform high doses of radiation to bulky pleural masses. We hypothesize the immunologic abscopal effect is an important component in controlling disease, and may be stimulated with highly hypofractionated doses. Doses will increase with every three patients who will be enrolled in the study until the background radiation reaches 1800 cGy or the maximum tolerated dose, whichever is lower.

Condition or Disease	Intervention/Treatment	Phase
Mesothelioma; Lung	Radiation: Varying Doses of Background and Boost RT	N/A

Detailed Description

This study aims to find the maximum tolerated dose level for mesothelioma patients receiving background radiation + boost radiation, and surgery. 3 patients will start with a background radiation therapy (RT) dose of 0 cGy, and boost RT of at least 2100 cGy. If the radiation is manageable (radiation related AEs grade < 4), the next set of 3 patients will be enrolled, and the background radiation dose will be increased by 600 cGy. This will continue until the background radiation dose reaches 1800 cGy. If 1 patient exhibits dose limiting toxicities (AEs grade 4 & 5), the dose level will repeat with the next 3 patients. If 2 or more patients exhibit DLTs, the previous dose level will be determined as the maximum tolerated dose level. Surgery will be scheduled to occur approximately 1-2 weeks after completing radiation therapy, and will subsequently be followed up as per study schedule.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Intervention Model Description:

3+3 radiation dose escalation3+3 radiation dose escalation

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Feasibility Study Evaluating Surgery for Mesothelioma After Radiation Therapy Using Extensive Pleural Resection

Actual Study Start Date :

Sep 5, 2019

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

Apr 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiation This study involves a 3+3 design. The starting cohort (n=3) will receive a neoadjuvant Background dose to the affected hemithorax (starting at 0 cGy) as well as concomitant Boost dose (of at least 2100 cGy) to a part of the gross tumour volume (GTV). The radiation will be delivered over 3 alternate days over 5-7 calendar days followed by macroscopically complete extensive pleural resection (either extra-pleural pneumonectomy or extended pleurectomy decortication, at the surgeon's discretion) after 7 to 14 days. If no dose limiting toxicities (DLTs) seen, then the Background RT dose will be increased by 600 cGy (up to 1800 cGy) and the cohort (n=3) for the next dose level will be accrued. If only 1 DLT seen, then an additional 3 patients will be treated on this dose level. If 2 or more DLTs seen at any given dose level, then the previous dose level will be defined as the maximum tolerated dose (MTD). Patients will be stratified by type of resection.	Radiation: Varying Doses of Background and Boost RT 3+3 radiation dose escalation model to see the maximum tolerated dose for background and boost radiation therapy.

Arm

Intervention/Treatment

Experimental: Radiation

This study involves a 3+3 design. The starting cohort (n=3) will receive a neoadjuvant Background dose to the affected hemithorax (starting at 0 cGy) as well as concomitant Boost dose (of at least 2100 cGy) to a part of the gross tumour volume (GTV). The radiation will be delivered over 3 alternate days over 5-7 calendar days followed by macroscopically complete extensive pleural resection (either extra-pleural pneumonectomy or extended pleurectomy decortication, at the surgeon's discretion) after 7 to 14 days. If no dose limiting toxicities (DLTs) seen, then the Background RT dose will be increased by 600 cGy (up to 1800 cGy) and the cohort (n=3) for the next dose level will be accrued. If only 1 DLT seen, then an additional 3 patients will be treated on this dose level. If 2 or more DLTs seen at any given dose level, then the previous dose level will be defined as the maximum tolerated dose (MTD). Patients will be stratified by type of resection.

Radiation: Varying Doses of Background and Boost RT

3+3 radiation dose escalation model to see the maximum tolerated dose for background and boost radiation therapy.

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose for Background Radiation [Up to five years]
AEs will be graded by CTCAE. Maximum tolerated dose is the dose level that do not result in fatal lung injury (grade 5 lung toxicity) or life-threatening or fatal treatment related toxicity (grade 4+).

Secondary Outcome Measures

Patient Morbidity [Up to five years]
NCI common toxicity scale
Local recurrence [Up to five years]
Documented radiographically
Patients' quality of life [Up to five years]
Short Form Health Survey-36 (SF-36) Form
Evaluating patients' pain [Up to five years]
Assess by using the Short Form (BPI-SF)
Evaluating patients' pain [Up to five years]
Assess by using The Hospital Anxiety and Depression Scale (HADS)
Evaluating patients' pain [Up to five years]
Assess by using the EuroQol EQ-5D-5L Questionnaire
Evaluating patients' pain [Up to five years]
Assess by using the Sensitivity to Pain Traumatization Scale (SPTS)
Evaluating patients' pain [Up to five years]
Assess by using the ID Pain form
Evaluating patients' pain [Up to five years]
Assess by using the Pain Catastrophizing Scale (PCS)
Evaluating patients' pain [Up to five years]
Assess by using the Post-traumatic Stress Disorder Checklist-Civilian version (PCL-C)
Evaluating patients' pain [Up to five years]
Assess by using a variety of standard instruments including the Injustice Experience Questionnaire (IEQ).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Good pulmonary function precluding radiation therapy (FEV1>1 L or >40% predicted or DLCO >45% predicted)
Any patient with a new histological diagnosis of malignant pleural mesothelioma (MPM). Sarcomatoid or biphasic histologies can be included but will be analyzed separately due to their poor prognosis.
Stage T1-3 N0-1 M0 according to the 8th edition of the tumor, node, and metastases (TNM) staging system based on conventional investigations and tests (Appendix 1). Note that the updated TNM staging system now categorizes ipsilateral mediastinal nodes as N1 disease.
Suitable for combined modality therapy
Informed consent.

Exclusion Criteria:

Age < 18 years.
Contralateral mediastinal nodal disease (N2)
Distant metastatic disease (M1).
Poor performance status ECOG 3-4.
Poor pulmonary function precluding radiation therapy (FEV1<1 L or <40% predicted or diffusion lung capacity for carbon monoxide (DLCO) <45% predicted)
Failure to provide informed consent.
Previous thoracic irradiation.
Serious non-malignant disease (e.g. cardiovascular, pulmonary, systemic lupus erythematosus (SLE), scleroderma) which would preclude definitive radiation treatment.
Previous chemotherapy for this or concurrent malignancy.
Previous or concomitant malignancies except for patients with non-melanoma skin cancer, contralateral non-invasive breast cancer, prostate cancer treated with curative intent or carcinoma in situ of any other site. In addition, patients with invasive cancers treated more than 3 years previously and without evidence of recurrence will be eligible.
Women who are currently pregnant or lactating.