Reirradiation Dose Escalation in Thoracic Cancers (REPAIR)

A Safety and Efficacy Trial of Reirradiation Dose Escalation in Thoracic Cancers: Re-evaluating Previous Dose and Allowing Increasing Recovery (REPAIR)

This is a study involving patients with recurrence, metastasis, or new primary malignancies in the thorax requiring radiation and who have previously received radiotherapy to the thorax, where re-irradiation is expected to exceed the dose constraints used for de novo treatments.

Currently, when this group of patients needs another set of radiotherapy, there is a dose limitation based on a percentage of the previous treatment's dose. However, this dose often limits the effectiveness of repeated treatment, with little scientific support for such. Therefore, this study aims to determine the maximally tolerated dose of reirradiation in the thorax, with dose escalation implemented by sequentially increasing the normal tissue recovery factors (i.e. repair factors) to the previously delivered dose.

Using a recovery factor equation associated with a 35% or lower rate of grade 3-5 treatment-related toxicity occurring within 1 year of treatment, accrual will start at level 1 (recovery factor = 10% at 6 months + 0.75% per month thereafter). Patients will be assigned to recovery factors using the TITE-CRM model. The model will use all available information from previously accrued patients to assign the highest dose with a predicted risk of grade 3-5 toxicity of 35% or less.

Study Overview

• Status: Not yet recruiting
• Conditions: Esophageal Cancer; Lung Cancer; Thoracic Cancer
• Intervention / Treatment: Radiation: stereotactic body radiation therapy (SBRT)

Detailed Description

The REPAIR trial aims to identify the magnitude of radiation recovery in the thorax and enable safe reirradiation dose escalation. The trial will provide critical information to support shared-decision making and ensure the risk-benefit trade-offs of reirradiation align with each patient's wishes. In addition, the data from this study will be informative in guiding subsequent studies on the use of reirradiation for other sites (such as the brain, abdomen, and pelvis) and to inform future re-irradiation trials. The objective of this phase I study is to determine the safety of dose escalation via recovery factors applied against previously delivered doses for patients receiving thoracic reirradiation.

This study will use a time-to-event continual reassessment method (TITE-CRM). The study design is based on previous thoracic dose escalation trials.

The primary endpoint of this study is the maximally tolerated dose (MTD) of thoracic reirradiation, implemented by sequentially increasing the normal tissue recovery factors applied to the previously delivered dose. The MTD is the recovery factor equation associated with a ≤ 35% rate of grade 3-5 pre-specified treatment-related toxicity occurring within 1 year of treatment.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Taciano Rocha, PhD, ACRP-CP; Phone Number: 56609 5196858500; Email: taciano.rocha@lhsc.on.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of malignancy, with disease in the thorax requiring re-irradiation for any treatment intent. This may include primary lung cancer of any type, esophageal cancer, recurrences, and/or metastasis from any primary. The intrathoracic disease at the time of enrollment does not itself require a biopsy if a prior biopsy has been obtained at that location or another body site. If the risk of biopsy is unacceptable and there is no prior confirmation of malignancy even at the time of the initial course of radiation, enrollment is permitted provided that the case is discussed at a multidisciplinary tumor board or peer-review rounds.
• Must have received prior photon thoracic radiotherapy ≥ 6 months ago
• Life expectancy > 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Age ≥ 18 years
• The current radiation course, when added to the previous radiation doses, exceeds the normal tissue constraints used for de novo treatments for esophagus, heart, lungs, trachea, bronchus, great vessels, or brachial plexus. Forgiveness of the previous dose (i.e. reduction of the previous dose in the cumulative dose calculation) is required to meet constraints. Submission of a pre-plan summary showing the estimated accumulation of current and previously delivered doses is required for registration.

Exclusion Criteria:

• Persistent toxicity from previously delivered radiation therapy
• Prior development of symptomatic radiation pneumonitis or immunotherapy-related pneumonitis from previous treatment, even if resolved
• Cumulative radiation dose for all organs-at-risk is already below dose constraints without a recovery factor applied, or with a recovery factor less than the current dose level of the trial. This will be confirmed by the enrolling team after the planning is completed.
• The reirradiation dose-limiting structure is expected to be spinal cord, chest wall, and/or stomach.
• Any prior thoracic radiotherapy < 6 months ago; OR prior thoracic radiotherapy delivered twice daily (compensation for holiday breaks are OK), thoracic radiotherapy delivered by brachytherapy, radionuclides, proton beams, or electron beams.
• Plans for patient to receive daily adaptive radiotherapy in current plan (computed tomography or magnetic resonance based).
• Plans for the patient to receive other local therapy (including standard fractionated radiotherapy and/or surgery) while on this study, except at disease progression.
• Concurrent systemic therapy (i.e. on the same days as radiation) is not allowed, EXCEPT for patients being treated for intrathoracic lung cancer (NSCLC or SCLC) with curative intent.
• For other patients receiving systemic therapy, they are still eligible for enrollment as long as there is a break in systemic therapy during the course of radiation. For example, if a patient has been on palliative pemetrexed and is planning to continue, they can still be enrolled and would continue to receive pemetrexed; reirradiation would be delivered between cycles, possibly requiring a break in systemic therapy. See Section 6.9 for further details.
• Prior surgical intervention that has significantly changed the position of an organ-at-risk that is expected to be a dose-limiting structure.
• Pregnancy
• The following autoimmune and connective tissue diseases will be excluded: Scleroderma and Systemic lupus erythematosus.
• Patients with interstitial lung disease (ILD).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Recovery factor levels; Radiation therapy - recovery factor levels Level 1: 6 months (10%) and 0.75%/month Level 2: 6 months (15%) and 0.75%/month Level 3: 6 months (15%) and 1.00%/month Level 4: 6 months (20%) and 1.00%/month Level 5: 6 months (20%) and 1.25%/month Level 6: 6 months (25%) and 1.40%/month	Radiation: stereotactic body radiation therapy (SBRT); Patients will be assigned to treatment doses using the TITE-CRM model.; Other Names: Radiation therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximally tolerated dose (MTD)	MTD of radiotherapy for thoracic tumors. The MTD is the dose of radiotherapy associated with a <35% rate of grade 3-5 toxicity occurring within 1 year of treatment.	occurring within 1 year of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to progression	Progression of treated disease	1-5 years
Time to distant metastases	Time to distant metastases	1-5 years
Progression-Free Survival	Progression-Free Survival	1-5 years
Overall survival	Overall survival	1-5 years
Patient reported outcome	Functional Assessment of Cancer Therapy: Lung (FACT-L)	Before treatment and at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months
Quality of Life - EuroQol 5-dimension 5-level	EuroQol 5-dimension 5-level	Before treatment and at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Investigators: Principal Investigator: David Palma, MD,PhD,FRCPC, London Health Science Centre

Study record dates

Study Major Dates

• Study Start (Estimated): October 30, 2024
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): January 29, 2027

Study Registration Dates

• First Submitted: August 14, 2024
• First Submitted That Met QC Criteria: August 14, 2024
• First Posted (Actual): August 16, 2024

Study Record Updates

• Last Update Posted (Actual): August 16, 2024
• Last Update Submitted That Met QC Criteria: August 14, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Dose escalation; Oncology; Toxicity; Re-irradiation
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Thoracic Neoplasms
• Other Study ID Numbers: ReDA 14927

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No