Brentuximab Vedotin in Early Stage Hodgkin Lymphoma (RADAR)

A Randomised Phase III Trial With a PET Response Adapted Design Comparing ABVD +/- ISRT With A2VD +/- ISRT in Patients With Previously Untreated Stage IA/IIA Hodgkin Lymphoma

RADAR is a multicentre, international, randomised, open-label phase III clinical trial composed of 2 trials running in parallel. Trial 1 will be led and sponsored by University College London (UCL) and conducted in Europe and Australia/New Zealand. Trial 2 will be led by the Canadian Cancer Trials Group (CCTG) and conducted in North America, with CCTG the regulatory sponsor in Canada, and University of Miami the regulatory sponsor and IND holder in the US. Datasets from Trial 1 and Trial 2 will be combined to achieve the total sample size. Data analysis will be performed by UCL and therefore UCL is responsible for the clinicaltrials.gov entry.

Eligible patients will be randomised to receive either ABVD or A2VD chemotherapy.

An interim PET-CT scan will be performed after 2 cycles of treatment, which will be used to adapt subsequent treatment. Patients will receive a total of 3-4 cycles of chemotherapy and may also receive involved site radiotherapy as consolidation.

Patients will be followed up for a minimum of 5 years after treatment.

Study Overview

• Status: Recruiting
• Conditions: Hodgkin Lymphoma
• Intervention / Treatment: Radiation: Involved site radiotherapy; Drug: Doxorubicin; Drug: Bleomycin; Drug: Vinblastine; Drug: Dacarbazine; Drug: Brentuximab vedotin; Drug: Haematopoietic growth factor

Detailed Description

Eligible patients will be randomised to receive either ABVD chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine) or A2VD chemotherapy (doxorubicin, brentuximab vedotin, vinblastine and dacarbazine, with growth factor support).

If patients agree, they will have a PET-CT scan after 1 cycle (PET1). The result of this scan will be blinded and used for exploratory endpoints only. Treatment will not be influenced by the result of this scan.

All patients will have a PET-CT scan after 2 cycles of treatment (PET2) which will be centrally reviewed. The Deauville score from central review will be used to risk adapt subsequent therapy as follows:

• Patients with Deauville score 1-3 will have one further cycle of their randomised chemotherapy and then enter follow up.
• Patients with Deauville score 4 will have two further cycles of their randomised chemotherapy followed by involved site radiotherapy
• Patients with Deauville score 5 will be withdrawn from trial treatment. They will have further treatment at their treating clinician's discretion and will enter follow up for the trial.

Patients with Deauville score 4 on PET2 will have a final PET-CT scan to confirm adequate treatment response.

Patients will be followed up for a minimum of 5 years after completing treatment.

• Study Type: Interventional
• Enrollment (Estimated): 1042
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: RADAR Trial Coordinator; Phone Number: +44(0)207 679 9860; Email: ctc.radar@ucl.ac.uk

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Recruiting
    • Royal Adelaide Hospital
    • Contact: Pratyush Giri
    • Principal Investigator: Pratyush Giri
  • Box Hill, Australia, VIC 3128
    • Recruiting
    • Box Hill Hospital
    • Contact: Denise Lee
    • Principal Investigator: Denise Lee
  • Brisbane, Australia, QLD 4006
    • Recruiting
    • Royal Brisbane and Women's Hospital
    • Principal Investigator: Nicholas Weber
    • Contact: Nicholas Weber
  • Darwin, Australia, NT 0810
    • Recruiting
    • Emma Palfreyman
    • Contact: Emma Palfreyman
    • Principal Investigator: Emma Palfreyman
  • Melbourne, Australia, VIC 3021
    • Recruiting
    • Sunshine Hospital (Western Health)
    • Contact: Michael Gilbertson
    • Principal Investigator: Michael Gilbertson
  • Sydney, Australia, NSW 2139
    • Recruiting
    • Concord Repatriation General Hospital
    • Contact: Nicole Wong Doo
    • Principal Investigator: Nicole Wong Doo
  • Sydney, Australia, NSW 2217
    • Recruiting
    • St George Hospital
    • Contact: Fernando Roncolato
    • Principal Investigator: Fernando Roncolato
  • New South Wales
    • Saint Leonards, New South Wales, Australia, 2065
      • Recruiting
      • Royal North Shore Hospital
      • Principal Investigator: Keith Fay
      • Contact: Keith Fay
• New Zealand
  • Auckland, New Zealand, 1023
    • Recruiting
    • Auckland City Hospital
    • Contact: Leanne Berkahn
    • Principal Investigator: Leanne Berkahn
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Recruiting
    • Aberdeen Royal Infirmary
    • Contact: Dominic Culligan
    • Principal Investigator: Dominic Culligan
  • Bodelwyddan, United Kingdom, LL18 5UJ
    • Recruiting
    • Glan Clwyd Hospital
    • Contact: Earnest Heartin; Email: earnest.heartin@wales.nhs.uk
    • Principal Investigator: Earnest Heartin
  • Bristol, United Kingdom
    • Recruiting
    • Bristol Haematology and Oncology Centre
    • Contact: Claire Burney
    • Principal Investigator: Claire Burney
  • Cardiff, United Kingdom, CF14 4XW
    • Recruiting
    • University Hospital of Wales, Cardiff & Vale University Local Health Board
    • Contact: Eve Gallop-Evans
    • Principal Investigator: Eve Gallop-Evans
  • Glasgow, United Kingdom, G12 0YN
    • Recruiting
    • Beatson West of Scotland Cancer Centre
    • Contact: Pam McKay
    • Principal Investigator: Pam McKay
  • Hull, United Kingdom, HU16 5JQ
    • Recruiting
    • Castle Hill Hospital
    • Contact: Russell Patmore
    • Principal Investigator: Russell Patmore
  • Leicester, United Kingdom, LE1 5WW
    • Recruiting
    • University Hospitals of Leicester NHS Trust
    • Contact: Sapna Ladani
    • Principal Investigator: Sapna Ladani
  • London, United Kingdom, EC1A 7BE
    • Recruiting
    • St Bartholomew's Hospital
    • Contact: Rifca Le Dieu
    • Principal Investigator: Rifca Le Dieu
  • London, United Kingdom, NW1 2BU
    • Recruiting
    • University College London Hospitals NHS Foundation Trust (UCLH)
    • Contact: Maria Marzolini
    • Principal Investigator: Maria Marzolini
  • Manchester, United Kingdom, M20 4BX
    • Recruiting
    • Christie Hospital
    • Contact: Beth Phillips
    • Principal Investigator: Beth Phillips
  • Norwich, United Kingdom, NR4 7UY
    • Recruiting
    • Norfolk & Norwich University Hospital
    • Contact: Nimish Shah
    • Principal Investigator: Nimish Shah
  • Nottingham, United Kingdom, NG51PB
    • Recruiting
    • Nottingham University Hospitals NHST
    • Contact: Emily Chernucha
    • Principal Investigator: Emily Chernucha
  • Oxford, United Kingdom, Ox3 7LE
    • Recruiting
    • Churchill Hospital
    • Contact: Graham Collins
    • Principal Investigator: Graham Collins
  • Plymouth, United Kingdom, PL6 8DH
    • Recruiting
    • Derriford Hospital
    • Contact: Patrick Medd
    • Principal Investigator: Patrick Medd
  • Torquay, United Kingdom, TQ2 7AA
    • Recruiting
    • Torbay Hospital
    • Contact: Deborah Turner
    • Principal Investigator: Deborah Turner
  • Truro, United Kingdom, TR1 3LJ
    • Recruiting
    • Royal Cornwall Hospital
    • Principal Investigator: Bryson Pottinger
    • Contact: Bryson Pottinger
  • Newcastle
    • Newcastle Upon Tyne, Newcastle, United Kingdom, NE7 7DN
      • Recruiting
      • Freeman Hospital, Newcastle
      • Contact: Wendy Osborne
      • Principal Investigator: Wendy Osborne
• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami School of Medicine
      • Contact: Safia Sawleh
      • Principal Investigator: Craig Moskowitz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 67 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males and females aged 16-69 years (inclusive) (age range is 18-69 in US and EU)
• Histologically confirmed classical Hodgkin lymphoma
• Stage I or II supradiaphragmatic disease with no mediastinal bulk disease (defined as greater than a third of the transthoracic diameter at any level of thoracic vertebra as determined by CT) or B symptoms. Bulky disease at other sites is acceptable. Extranodal disease (single extranodal site (stage I) or contiguous nodal extension (stage II)) is acceptable.
• ECOG performance status 0-2.
• No previous treatment for Hodgkin lymphoma
• Fit to receive anthracycline-based chemotherapy (patients with a history of ischaemic heart disease or hypertension should have a left ventricular ejection fraction of ≥50%)
• Creatinine clearance (measured or calculated >40ml/min
• Total bilirubin <1.5 x upper limit of normal, unless attributable to disease or known Gilbert's syndrome
• ALT or AST < 2 x upper limit of normal
• Adequate bone marrow function with neutrophils ≥1.0x10^9/l and platelets ≥100x10^9/l
• Haemoglobin ≥8g/dL
• Willing and able to comply with the requirements of the protocol, including contraceptive advice, where applicable
• Written informed consent

Exclusion Criteria:

• Previous treatment for Hodgkin lymphoma, excluding short courses of oral corticosteroids at a dose of 100mg prednisolone (or equivalent) for up to 7 days
• Infradiaphragmatic disease
• Nodular lymphocyte predominant Hodgkin lymphoma
• Absence of FDG-avid lesions on baseline PET scan
• Age 70 years or over or age 15 years or under
• Other cancer diagnosed with the last 5 years. Patients with completely excised carcinoma in situ of any type and basal or squamous cell carcinoma of the skin are not excluded
• Recurrent or persistent other cancer within last 5 years irrespective of date of initial diagnosis
• Pre-existing grade ≥1 sensory or motor neuropathy from any cause
• History of or current progressive multi-focal leukoencephalopathy or other chronic condition of the brain
• Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
• Infection with HIV, hepatitis C or active hepatitis B infection (surface antigen or DNA positive)
• Any active systemic viral, bacterial or fungal infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first trial drug dose
• Receiving or recently treated with any other investigational agent (within 4 weeks of trial entry)
• Pregnant or breastfeeding women
• Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin or any component of ABVD
• Known history of any cardiovascular or respiratory conditions that would preclude anthracycline or bleomycin administration
• Other significant medical or psychiatric comorbidity that in the opinion of the investigator would make administration of ABVD or A2VD hazardous

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: ABVD +/- ISRT; 2 x 28 day cycles of ABVD: Doxorubicin 25mg/m^2 IV days 1 & 15 Bleomycin 10000 IU/m^2 days 1 & 15 Vinblastine 6mg/m^2 days 1 & 15 Dacarbazine 375mg/m^2 days 1 & 15 PET-CT after 2 cycles will determine subsequent treatment: Deauville score 1-3 (PET CMR): 1 further cycle of ABVD then follow up Deauville score 4 (PET positive): 2 further cycles of ABVD followed by involved site radiotherapy (ISRT) Deauville score 5: withdraw from trial treatment; further treatment will be given at the treating clinician's discretion. Enter follow up for the trial.	Radiation: Involved site radiotherapy; Involved site radiotherapy as per International Lymphoma Radiation Oncology Group (ILROG) guidelines. Recommended dose 30Gy; Drug: Doxorubicin; See arm description; Drug: Bleomycin; See arm description; Drug: Vinblastine; See arm description; Drug: Dacarbazine; See arm description
Experimental: A2VD +/- ISRT; 2 x 28 day cycles of A2VD: Doxorubicin 25mg/m^2 IV days 1 & 15 Brentuximab vedotin 1.2mg/kg (max 120mg) days 1 & 15 Vinblastine 6mg/m^2 days 1 & 15 Dacarbazine 375mg/m^2 days 1 & 15 Filgrastim (or equivalent haematopoietic growth factor) for 5-7 days from day 2 and day 16 (or single dose of peg-filgrastim on days 2 & 16) PET-CT after 2 cycles will determine subsequent treatment: Deauville score 1-3 (PET CMR): 1 further cycle of A2VD then follow up Deauville score 4 (PET positive): 2 further cycles of A2VD followed by involved site radiotherapy (ISRT) Deauville score 5: withdraw from trial treatment; further treatment will be given at the treating clinician's discretion. Enter follow up for the trial.	Radiation: Involved site radiotherapy; Involved site radiotherapy as per International Lymphoma Radiation Oncology Group (ILROG) guidelines. Recommended dose 30Gy; Drug: Doxorubicin; See arm description; Drug: Vinblastine; See arm description; Drug: Dacarbazine; See arm description; Drug: Brentuximab vedotin; See arm description; Drug: Haematopoietic growth factor; See arm description; Other Names: Filgrastim; G-CSF; Pegfilgrastim

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	Time from randomisation to first date of progression or death	3 years from end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PET-CMR (complete metabolic response) rate	Proportion of patients who have Deauville score 1-3 on PET-CT scan	At the end of cycle 2 (each cycle is 28 days)
Event-free survival (EFS)	Time from randomisation to first date of progression, death or a positive PET2 scan (whichever occurs first)	5 years from end of treatment
Overall survival (OS)	Time from randomisation to death	5 years from end of treatment
Incidence of second cancers and cardiovascular disease	Proportion in each arm who develop a second cancer or cardiovascular disease	5 years from end of treatment
Safety and toxicity of ABVD and A2VD as described by CTCAE v5.0	Numbers of patients experiencing a grade 3+ adverse event of each type will be presented and compared between the arms. Only patients who start treatment will be included	From start of treatment to 30 days post treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic power of PET after 1 and 2 cycles of ABVD/A2VD	7A Associations between PET1 Deauville score (DS) and PET2 DS; 7B Associations between PET1 DS and EFS; 7C Associations between PET1 DS and OS; 7D Associations between PET1 DS and PFS; 7E Associations between PET2 DS and EFS; 7F Associations between PET2 DS and OS; 7G Associations between PET2 DS and PFS; 7H Associations between EORTC baseline stratification and PET1 DS; 7I Associations between EORTC baseline stratification and PET2 DS; 7J Associations between EORTC baseline stratification and EFS; 7K Associations between EORTC baseline stratification and OS; 7L Associations between EORTC baseline stratification and EFS; 7M Associations between GHSG baseline stratification and PET1 DS; 7N Associations between GHSG baseline stratification and PET2 DS; 7O Associations between GHSG baseline stratification and EFS; 7P Associations between GHSG baseline stratification and OS; 7Q Associations between GHSG baseline stratification and EFS	Up to 5 years after end of treatment
Prognostic and predictive power of baseline PET features	The association of baseline quantitative PET parameters such as total lesion glycolysis (TLG) and PFS/EFS/OS will be assessed. The ability to predict PET score (PET1 and PET2) and Hodgkin lymphoma events within 3 years will be compared: 8A Associations between baseline quantitative PET parameters such as total lesion glycolysis (TLG) and PFS; 8B Associations between baseline quantitative PET parameters such as total lesion glycolysis (TLG) and OS; 8C Associations between baseline quantitative PET parameters such as total lesion glycolysis (TLG) and EFS; 8D Associations between baseline quantitative PET parameters such as total lesion glycolysis (TLG) and PET1 DS; 8E Associations between baseline quantitative PET parameters such as total lesion glycolysis (TLG) and PET2 DS	Up to 3 years after end of treatment
Change in pulmonary function tests at end of treatment, 1 and 2 years	Change from baseline pulmonary function test (DLCO/TLCO percentage of normal) will be compared	3 months & 1 year after end of treatment
Correlation between maximum tumour dimension at baseline and end of treatment with PFS	The relationship between maximum tumour dimension at baseline and at end of treatment and PFS will be examined. This may also be analysed within the groups that achieve/do not achieve CMR after 2 cycles and may also be adjusted for the use of consolidation radiotherapy	Up to 5 years after end of treatment

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: University of Miami; Takeda; European Organisation for Research and Treatment of Cancer - EORTC; Canadian Cancer Trials Group; Seagen Inc.; Australasian Leukaemia and Lymphoma Group
• Investigators: Principal Investigator: John Radford, University of Manchester / Christie Hospital, Manchester

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2022
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): September 1, 2032

Study Registration Dates

• First Submitted: November 27, 2020
• First Submitted That Met QC Criteria: December 21, 2020
• First Posted (Actual): December 28, 2020

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Brentuximab vedotin; PET-response adapted; Stage IA/IIA Hodgkin lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Hodgkin Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immunoconjugates; Immunotoxins; Doxorubicin; Dacarbazine; Bleomycin; Brentuximab Vedotin; Vinblastine; Mitogens
• Other Study ID Numbers: RADAR; UCL/15/0105 (Other Identifier: UCL); 2020-005160-65 (EudraCT Number); IISR X25041 (Other Grant/Funding Number: Takeda Pharmaceutical Company Ltd); CCTG HD.12 (Other Identifier: CCTG); IRB number 20230081 (Other Identifier: University of Miami)

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