Clinical trial NCT04685616: Brentuximab Vedotin in Early Stage Hodgkin Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hodgkin Lymphoma
Keywords: PET-response adapted
Stage IA/IIA Hodgkin lymphoma
Brentuximab vedotin
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Takeda
name: University of Miami
name: European Organisation for Research and Treatment of Cancer - EORTC
name: Australasian Leukaemia and Lymphoma Group
name: Seagen Inc.
name: Canadian Cancer Trials Group
First posted: 2020-12-28
Enrollment: 1042
Sex: ALL
Minimum age (years): 16
Maximum age (years): 69
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression free survival (PFS)
timeFrame: 3 years from end of treatment
Secondary outcomes:
measure: PET-CMR (complete metabolic response) rate
timeFrame: At the end of cycle 2 (each cycle is 28 days)
measure: Event-free survival (EFS)
timeFrame: 5 years from end of treatment
measure: Overall survival (OS)
timeFrame: 5 years from end of treatment
measure: Incidence of second cancers and cardiovascular disease
timeFrame: 5 years from end of treatment
measure: Safety and toxicity of ABVD and A2VD as described by CTCAE v5.0
timeFrame: From start of treatment to 30 days post treatment
Other outcomes:
measure: Prognostic power of PET after 1 and 2 cycles of ABVD/A2VD
timeFrame: Up to 5 years after end of treatment
measure: Prognostic and predictive power of baseline PET features
timeFrame: Up to 3 years after end of treatment
measure: Change in pulmonary function tests at end of treatment, 1 and 2 years
timeFrame: 3 months & 1 year after end of treatment
measure: Correlation between maximum tumour dimension at baseline and end of treatment with PFS
timeFrame: Up to 5 years after end of treatment
Locations:
city: Stanford
country: United States
facility: Stanford University - (Stanford Cancer Institute)
state: California
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Townsville
country: Australia
facility: Townsville University Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Box Hill
country: Australia
facility: Box Hill Hospital
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Darwin
country: Australia
facility: Royal Darwin Hospital
city: Liverpool
country: Australia
facility: Liverpool Hospital
city: Melbourne
country: Australia
facility: Sunshine Hospital (Western Health)
city: Sydney
country: Australia
facility: Concord Repatriation General Hospital
city: Sydney
country: Australia
facility: St George Hospital
city: Roeselare
country: Belgium
facility: AZ Delta Campus Rumbeke
state: West Flanders
city: Leuven
country: Belgium
facility: UZ Leuven
city: Namur
country: Belgium
facility: CHU-UCL Namur
city: Ottawa
country: Canada
facility: Ottowa Hospital Research Institute
city: Saint John
country: Canada
facility: Saint John Regional Hospital
city: Toronto
country: Canada
facility: University Health Network Princess Margaret Cancer Centre
city: Vancouver
country: Canada
facility: Vancouver Cancer Centre
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
city: Aarhus
country: Denmark
facility: Aarhus University Hospitak Skjeby
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC - location VUMC
city: Delft
country: Netherlands
facility: Reinier de Graafweg 3-11 - Postbus 5011 - 2625 AD Delft
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Haaglanden
country: Netherlands
facility: NL 331 - Haaglanden Medisch Centrum (HMC) - Haaglanden MC
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center Nijmegen
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
state: Lancashire
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital, Newcastle
state: Newcastle
city: Glasgow
country: United Kingdom
facility: Lanarkshire
state: Scotland
city: London
country: United Kingdom
facility: St George's Hospital
state: Tooting
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Bodelwyddan
country: United Kingdom
facility: Glan Clwyd Hospital
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales, Cardiff & Vale University Local Health Board
city: Colchester
country: United Kingdom
facility: Colchester Hospital, ESNEFT
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: Liverpool
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHSFT, 65 Pembroke Place
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust (UCLH)
city: London
country: United Kingdom
facility: Royal Marsden Hospital Chelsea
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHST
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
city: Torquay
country: United Kingdom
facility: Torbay Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
Study officials:
affiliation: University of Manchester / Christie Hospital, Manchester
name: John Radford
role: PRINCIPAL_INVESTIGATOR
References: