Brentuximab Vedotin in Early Stage Hodgkin Lymphoma

Study Overview
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Brief Summary
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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
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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cycles of their randomised chemotherapy followed by involved site radiotherapy Patients with Deauville score 5 will be withdrawn from trial treatment.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.

Official Title
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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

Conditions
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Hodgkin Lymphoma

Intervention / Treatment
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* Radiation: Involved site radiotherapy
* Drug: Doxorubicin
* Drug: Bleomycin
* Drug: Brentuximab vedotin
* Drug: Vinblastine
* Drug: Dacarbazine
* Drug: Haematopoietic growth factor


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ABVD +/- ISRT<br>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<br>* Involved site radiotherapy as per International Lymphoma Radiation Oncology Group (ILROG) guidelines. Recommended dose 30Gy<br>Drug: Doxorubicin<br>* See arm description<br>Drug: Bleomycin<br>* See arm description<br>Drug: Vinblastine<br>* See arm description<br>Drug: Dacarbazine<br>* See arm description<br>|
| Experimental: A2VD +/- ISRT<br>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<br>* Involved site radiotherapy as per International Lymphoma Radiation Oncology Group (ILROG) guidelines. Recommended dose 30Gy<br>Drug: Doxorubicin<br>* See arm description<br>Drug: Brentuximab vedotin<br>* See arm description<br>Drug: Vinblastine<br>* See arm description<br>Drug: Dacarbazine<br>* See arm description<br>Drug: Haematopoietic growth factor<br>* See arm description<br>* Other names: Pegfilgrastim;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PET-response adapted, Stage IA/IIA Hodgkin lymphoma, Brentuximab vedotin