Stereotactic Body Radiotherapy for the Treatment of OPD (HALT)

Targeted Therapy With or Without Dose Intensified Radiotherapy for Oligo-progressive Disease in Oncogene-addicted Lung Tumours

HALT is a phase II, randomised multi-centre study with integrated seamless continuation to phase III trial following acceptable safety and feasibility assessment.

HALT aims to recruit 110 patients with mutation positive advanced NSCLC with oligoprogressive disease (OPD) following initial response to a Tyrosine Kinase Inhibitor (TKI).

Study Overview

• Status: Active, not recruiting
• Conditions: NSCLC
• Intervention / Treatment: Radiation: SBRT; Drug: TKI

Detailed Description

Eligible patients will be randomised to receive either SBRT or no SBRT at a ratio of 2:1 (SBRT : no SBRT), with all patients continuing to receive background treatment with TKI therapy as clinically indicated and as per standard care. Patients randomised to receive SBRT will receive a dose and fractionation schedule dependent on OPD lesion site and proximity to critical normal tissues. All patients will be seen 8 weeks post randomisation, then 3 monthly in line with routine care.

HALT aims to assess whether in patients with mutation positive advanced NSCLC the use of SBRT to ≤ 3 sites of OPD with continuation of TKI improves progression-free survival (PFS) compared with continuation of TKI alone.

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 94800
    • Institut Gustave Roussy
  • Toulouse, France, 31059
    • Institut Claudius Regaud
• Italy
  • Roma, Italy, 00128
    • Policlinico Universitario Campus Bio-Medico
  • Torino, Italy, 10043
    • Ospedale San Luigi Gonzaga - Universita Di Torino
• Spain
  • Barcelona, Spain, 08908
    • Institut Catala d'Oncologia
  • Barcelona, Spain, 08036
    • Hospital Clinic Universitari de Barcelona
  • Seville, Spain, 41013
    • University Hospital Virgen del Rocio
• Switzerland
  • Bellinzona, Switzerland, 6500
    • Oncology Institute of Southern Switzerland
  • Geneva, Switzerland
    • Hôpital Cantonal Universitaire de Genève
  • St. Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen
  • Zurich, Switzerland, 8091
    • UniversitätsSpital Zürich
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Belfast City Hospital
  • Bristol, United Kingdom, BS2 8ED
    • Bristol Haematology and Oncology Centre
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Centre
  • Hull, United Kingdom, HU16 5JQ
    • Castle Hill Hospital
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
  • London, United Kingdom, SE1 9RT
    • Guy'S Hospital
  • London, United Kingdom, EC1A 7BE
    • St Bartholomew's Hospital
  • London, United Kingdom, NW1 2PG
    • University College London Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham City Hospital
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital
  • Sheffield, United Kingdom, S10 2SJ
    • Weston Park Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton University Hospital
  • Wirral, United Kingdom, CH63 4JY
    • Clatterbridge Cancer Centre
  • England
    • Sutton, England, United Kingdom, SM2 5PT
      • Royal Marsden Hosital
  • London
    • Chelsea, London, United Kingdom, SW3 6JJ
      • Royal Marsden Hospital
  • Surrey
    • Guildford, Surrey, United Kingdom, GU2 7XX
      • Royal Surrey County Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, ≥ 16 years of age
2. Established histological diagnosis of advanced NSCLC, not suitable for radical treatment, with defined actionable mutation receiving targeted TKI therapy
3. Clinical and/or radiologically confirmed response to TKI therapy (assessed locally usually 2-3 months post commencing TKI)
4. Confirmed OPD defined as ≤ 5 extracranial sites of progressive disease. All sites must be visible, imaging defined targets and suitable for treatment with SBRT as determined by the virtual multi-disciplinary team (MDT) and in accordance with the HALT Radiotherapy planning and delivery guidance document.
5. Adequate baseline organ function to allow SBRT to all relevant targets
6. Predicted life expectancy ≥ 6 months
7. Karnofsky Index ≥ 60% and ECOG 0-2
8. Provision of written informed consent

Exclusion Criteria:

1. > 5 extracranial sites of progressive disease
2. Progressing or newly diagnosed brain metastases identified at the time of trial entry, not amenable to radical surgery or SRS. Previously treated brain metastases (i.e palliative radiotherapy or systemic therapy) which have remained clinically and radiologically stable for ≥ 6 months are permissible.
3. Prior radiotherapy near the oligoprogressive lesion precluding ablative SBRT. Suitability of lesions for ablative SBRT as part of the trial defined in section 4.1 of this document and will be determined by the HALT virtual MDT
4. Co-morbidities considered clinically precluding the safe use of SBRT (as detailed in the HALT radiotherapy planning and delivery guidelines).
5. Any psychological, sociological or geographical issue potentially hampering compliance with the study
6. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Continued TKI therapy alone; Continuation on the same background TKI treatment as prior to trial entry	Drug: TKI; Continued background TKI alone; Other Names: Tyrosine Kinase Inhibitor
Experimental: SBRT and continued TKI therapy; Patients will continue to receive background TKI treatment as prior to trial entry. Simultaneous administration (SBRT & TKI) or break in TKI during SBRT will be by centre preference and determined prior to commencing recruitment. Repeat SBRT will be permissible upon development of subsequent OPD lesions dependent on SBRT suitability and total progression lesion number at any one point remaining ≤ 5.	Radiation: SBRT; SBRT dose and fractionation dependent on site of metastasis and proximity to critical normal tissues.; Other Names: SABR; Stereotactic body radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	The primary outcome measure is progression free survival defined as the time from randomisation to the first of one of the following events or death from any cause: Clinically symptomatic progression requiring palliative tumour-specific oncological intervention (e.g. change in systemic therapy or localised non-SBRT radiotherapy) as determined by the treating physician.; New or existing intra-cranial lesions not amenable to radical surgery or Stereotactic radiosurgery (SRS).; Development of new extra-cranial lesions or progression of existing extra-cranial lesions not meeting the criteria for; SBRT treatment (e.g. size >7cm); Development of >5 new or progressing extra-cranial lesion at any one point in time (i.e. widespread progression)	Time from randomisation to the first of one of the above events or death. Assessed 8 weeks post-randomisation and 3-monthly thereafter (up to 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to next line of systemic therapy or palliative care		Time from randomisation to change in therapy or referral to palliative care due to clinical progression as determined by the treating physician, or death. Assessed 3-monthly until progression and 6-monthly thereafter (up to 24 months).
Overall survival		Time from randomisation until death from any cause. Assessed up to 24 months.
Patterns of disease progression identified from CT scans to further document natural history of oncogene-addicted NSCLC		Assessed 3-monthly up to 24 months.
Radiotherapy toxicities (acute events)	Acute events are defined as ≤ 90 days post SBRT start date (applicable for each subsequent course of SBRT where relevant) assessed using CTCAE v4.0.	Baseline, 8 weeks and 3-monthly intervals during follow-up (a minimum of 6 months).
Quality of Life (EQ-5D-5L)	Assessed using EQ-5D-5L	Baseline, 8 weeks and at the first 3 month visit.
Quality of Life (EORTC QLQ-C30)	Assessed using EORTC QLQ-C30	Baseline, 8 weeks and at the first 3 month visit.
Measurement of resistant sub-clones in Circulating tumour DNA (ctDNA)		Baseline, 8 weeks post-randomisation and 3-monthly intervals during follow-up (up to 24 months).
Time to failure of next line treatment		Time from randomisation to disease progression on next line of active systemic therapy. Assessed up to 24 months.
Radiotherapy toxicities (late events)	Late events are defined as > 90 days post SBRT start date (applicable for each subsequent course of SBRT where relevant) assessed using CTCAE v4.0.	Baseline, 8 weeks and 3-monthly intervals during follow-up (a minimum of 6 months).

Collaborators and Investigators

• Sponsor: Institute of Cancer Research, United Kingdom
• Investigators: Principal Investigator: Fiona McDonald, MD, Royal Marsden NHS Foundation Trust

Publications and helpful links

General Publications

• Lee J, Koom WS, Byun HK, Yang G, Kim MS, Park EJ, Ahn JB, Beom SH, Kim HS, Shin SJ, Kim K, Chang JS. Metastasis-Directed Radiotherapy for Oligoprogressive or Oligopersistent Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2022 Jun;21(2):e78-e86. doi: 10.1016/j.clcc.2021.10.009. Epub 2021 Nov 18.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2017
• Primary Completion (Actual): July 17, 2023
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: August 10, 2017
• First Submitted That Met QC Criteria: August 17, 2017
• First Posted (Actual): August 22, 2017

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; SBRT; TKI; Oligoprogressive disease
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tyrosine Protein Kinase Inhibitors
• Other Study ID Numbers: ICR-CTSU/2016/10061

Drug and device information, study documents

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