Brentuximab Vedotin in Early Stage Hodgkin Lymphoma
- Conditions
- Hodgkin Lymphoma
- Interventions
- Radiation: Involved site radiotherapyDrug: Haematopoietic growth factor
- Registration Number
- NCT04685616
- Lead Sponsor
- University College, London
- Brief Summary
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.
- 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* Patients with Deauville score 5 will be withdrawn from trial treatment.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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1042
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ABVD +/- ISRT Involved site radiotherapy 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. A2VD +/- ISRT Involved site radiotherapy 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. A2VD +/- ISRT Haematopoietic growth factor 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. ABVD +/- ISRT Doxorubicin 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. ABVD +/- ISRT Bleomycin 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. ABVD +/- ISRT Vinblastine 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. ABVD +/- ISRT Dacarbazine 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. A2VD +/- ISRT Doxorubicin 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. A2VD +/- ISRT Brentuximab vedotin 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. A2VD +/- ISRT Vinblastine 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. A2VD +/- ISRT Dacarbazine 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.
- Primary Outcome Measures
Name Time Method Progression free survival (PFS) 3 years from end of treatment Time from randomisation to first date of progression or death
- Secondary Outcome Measures
Name Time Method PET-CMR (complete metabolic response) rate At the end of cycle 2 (each cycle is 28 days) Proportion of patients who have Deauville score 1-3 on PET-CT scan
Overall survival (OS) 5 years from end of treatment Time from randomisation to death
Incidence of second cancers and cardiovascular disease 5 years from end of treatment Proportion in each arm who develop a second cancer or cardiovascular disease
Event-free survival (EFS) 5 years from end of treatment Time from randomisation to first date of progression, death or a positive PET2 scan (whichever occurs first)
Safety and toxicity of ABVD and A2VD as described by CTCAE v5.0 From start of treatment to 30 days post treatment 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
Trial Locations
- Locations (58)
Stanford University - (Stanford Cancer Institute)
🇺🇸Stanford, California, United States
University of Miami School of Medicine
🇺🇸Miami, Florida, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Royal North Shore Hospital
🇦🇺Saint Leonards, New South Wales, Australia
Townsville University Hospital
🇦🇺Townsville, Queensland, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, Australia
Box Hill Hospital
🇦🇺Box Hill, Australia
Royal Brisbane and Women's Hospital
🇦🇺Brisbane, Australia
Royal Darwin Hospital
🇦🇺Darwin, Australia
Liverpool Hospital
🇦🇺Liverpool, Australia
Sunshine Hospital (Western Health)
🇦🇺Melbourne, Australia
Concord Repatriation General Hospital
🇦🇺Sydney, Australia
St George Hospital
🇦🇺Sydney, Australia
AZ Delta Campus Rumbeke
🇧🇪Roeselare, West Flanders, Belgium
UZ Leuven
🇧🇪Leuven, Belgium
CHU-UCL Namur
🇧🇪Namur, Belgium
Ottowa Hospital Research Institute
🇨🇦Ottawa, Canada
Saint John Regional Hospital
🇨🇦Saint John, Canada
University Health Network Princess Margaret Cancer Centre
🇨🇦Toronto, Canada
Vancouver Cancer Centre
🇨🇦Vancouver, Canada
CancerCare Manitoba
🇨🇦Winnipeg, Canada
Aarhus University Hospitak Skjeby
🇩🇰Aarhus, Denmark
Amsterdam UMC - location VUMC
🇳🇱Amsterdam, Netherlands
Reinier de Graafweg 3-11 - Postbus 5011 - 2625 AD Delft
🇳🇱Delft, Netherlands
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
NL 331 - Haaglanden Medisch Centrum (HMC) - Haaglanden MC
🇳🇱Haaglanden, Netherlands
Radboud University Medical Center Nijmegen
🇳🇱Nijmegen, Netherlands
Auckland City Hospital
🇳🇿Auckland, New Zealand
Hospital Del Mar
🇪🇸Barcelona, Spain
Institut Catala d'Oncologia
🇪🇸Barcelona, Spain
Complejo Hospitalario de Navarra
🇪🇸Pamplona, Spain
Blackpool Victoria Hospital
🇬🇧Blackpool, Lancashire, United Kingdom
Freeman Hospital, Newcastle
🇬🇧Newcastle Upon Tyne, Newcastle, United Kingdom
Lanarkshire
🇬🇧Glasgow, Scotland, United Kingdom
St George's Hospital
🇬🇧London, Tooting, United Kingdom
Aberdeen Royal Infirmary
🇬🇧Aberdeen, United Kingdom
Glan Clwyd Hospital
🇬🇧Bodelwyddan, United Kingdom
Bristol Haematology and Oncology Centre
🇬🇧Bristol, United Kingdom
University Hospital of Wales, Cardiff & Vale University Local Health Board
🇬🇧Cardiff, United Kingdom
Colchester Hospital, ESNEFT
🇬🇧Colchester, United Kingdom
University Hospital Coventry
🇬🇧Coventry, United Kingdom
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, United Kingdom
Castle Hill Hospital
🇬🇧Hull, United Kingdom
University Hospitals of Leicester NHS Trust
🇬🇧Leicester, United Kingdom
The Clatterbridge Cancer Centre NHSFT, 65 Pembroke Place
🇬🇧Liverpool, United Kingdom
St Bartholomew's Hospital
🇬🇧London, United Kingdom
University College London Hospitals NHS Foundation Trust (UCLH)
🇬🇧London, United Kingdom
Royal Marsden Hospital Chelsea
🇬🇧London, United Kingdom
Christie Hospital
🇬🇧Manchester, United Kingdom
Norfolk & Norwich University Hospital
🇬🇧Norwich, United Kingdom
Nottingham University Hospitals NHST
🇬🇧Nottingham, United Kingdom
Churchill Hospital
🇬🇧Oxford, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Sunderland Royal Hospital
🇬🇧Sunderland, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom
Torbay Hospital
🇬🇧Torquay, United Kingdom
Royal Cornwall Hospital
🇬🇧Truro, United Kingdom