Pulse Radiotherapy to Overcome Metastatic Immune System Evasion in Lung Cancer (PROMISE)

Pulse Radiotherapy to Overcome Metastatic Immune System Evasion in Lung Cancer (PROMISE) - Phase I Trial

This phase I study aims to evaluate the safety and effectiveness of adaptive pulsed radiotherapy combined with immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) resistant to immune checkpoint inhibitors. The primary goal is to assess treatment-related toxicity, while secondary objectives include progression-free survival, overall survival, and quality of life. The study will enroll 32 patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Non Small Cell Lung Cancer; Metastatic Lung Cancer
• Intervention / Treatment: Radiation: Pulse radiotherapy

Detailed Description

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is a leading cause of cancer-related death globally. Despite the success of immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, many patients develop resistance to these therapies, either at the start (primary resistance) or over time (secondary resistance). This resistance leads to disease progression during or after treatment, posing a major clinical challenge. Recent studies suggest that combining ICIs with radiotherapy may improve treatment outcomes. Advances in pulsed radiotherapy, including stereotactic radiation cycles, have shown promising results in overcoming ICI resistance in metastatic disease.

Objective: This phase I prospective study aims to evaluate the safety (primary objective) and efficacy of pulsed radiotherapy in combination with PD(L)-1 inhibitors (with or without chemotherapy) in patients with polymetastatic NSCLC who have developed systemic resistance. The hypothesis is that this combination approach could improve patient outcomes by directly reducing tumor burden and enhancing the immune response, while maintaining an acceptable toxicity profile.

Methods: This single-arm phase I study will enroll 32 patients with NSCLC who show disease progression in ≥ 5 extracranial sites while on PD(L)-1 inhibitors (with or without chemotherapy). Pulsed radiotherapy will be delivered in up to 3 cycles, targeting 2 to 5 progressive lesions per cycle. Eligible participants must be 18 years or older, with systemic progression of NSCLC in ≥ 5 sites during treatment with ICIs, and an ECOG performance status of 0-2. Brain metastases are permitted but will not be included in the lesion count.

The primary endpoint is dose-limiting toxicity (DLT), defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, focusing on grade 3-5 adverse events related to radiotherapy within 180 days of treatment. Secondary endpoints include the development of a clinical workflow for adaptive pulsed radiotherapy, progression-free survival (PFS), overall survival (OS), local recurrence, time to the next systemic treatment, and patient-reported quality of life.

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Houda Bahig, MD PhD; Phone Number: 514-890-8254; Email: houda.bahig.med@ssss.gouv.qc.ca

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada
      • Centre Hospitalier de l'Université de Montréal
      • Contact: Mom Phat; Phone Number: 514-890-8254; Email: mom.phat.chum@ssss.gouv.qc.ca
      • Principal Investigator: Houda Bahig, MD PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participants must be ≥ 18 years old
• Ability to provide written informed consent
• Actively receiving PD(L)-1 inhibitors
• Progressive disease defined as per RECIST criteria 1.1 on CT metrics as a greater than 20% increase in the sum measurement of lesions, non-target unequivocal progressive disease or a new lesion on CT.
• Radiological progression to ≥ 5 disease sites. Progression at the primary tumor site should be counted within the total number of progressive lesions. For patients with lymph node metastases, each node is counted as one site of metastasis.
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Patients with brain metastasis are allowed and should be treated as per standard of care
• All sites of disease can, in the opinion of the investigator, be safely treated and targetable with high-to-intermediate or low dose radiotherapy (taking into account prior local therapy, organ function and underlying medical condition such as inflammatory bowel disease, pulmonary fibrosis, etc.)
• Patients with prior metastases that have been treated with ablative therapies (e.g. radiotherapy, surgery or radiofrequency ablation) before their current line of systemic therapy, are eligible.
• Patients receiving additional systemic therapy agents such as chemotherapy are eligible, provided the other systemic agents are temporarily halted during radiation treatment.

Exclusion Criteria:

• Pregnant or breastfeeding individuals are excluded.
• Medical conditions that would hinder the safe administration of radiotherapy or follow-up.
• Patients who are ineligible for immunotherapy.
• Patients with a history of pneumonitis are excluded.
• Presence of an active autoimmune disease.

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: Pulse Radiotherapy; Pulsed radiotherapy combined with PD(L)-1 inhibitors targeting 2 to 5 progressive extracranial lesions per cycle	Radiation: Pulse radiotherapy; Pulsed radiotherapy combined with PD(L)-1 inhibitors targeting 2 to 5 progressive extracranial lesions per cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	Grade 3-5 toxicity as per Common Terminology Criteria for Adverse Events, version 4.0.	Within 180 days of radiotherapy completion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Time from the start of adaptive pulse radiotherapy to the first documented disease progression or death from any cause.	2 years post radiotherapy
Overall Survival (OS)	Time from the start of treatment to death from any cause.	2 years post radiotherapy
Quality of Life (QoL)	Measured using validated patient-reported outcome questionnaires, such as the EORTC QLQ-C30, at baseline, during treatment, and every 6 months.	until 2 years after radiotherapy
Long term toxicity	Grade 3-5 toxicity, based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	More than 180 days post-treatment up to 2 year post treatment

Collaborators and Investigators

• Sponsor: Houda Bahig
• Collaborators: Varian, a Siemens Healthineers Company

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: September 21, 2024
• First Submitted That Met QC Criteria: September 30, 2024
• First Posted (Actual): October 2, 2024

Study Record Updates

• Last Update Posted (Actual): October 2, 2024
• Last Update Submitted That Met QC Criteria: September 30, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Radiotherapy; Non small cell lung cancer; Metastatic lung cancer; Immunotherapy resistance; Progressive disease; Polymetastatic; Pulse radiotherapy
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: PROMISE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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