RADAR: Brentuximab Vedotin in Early Stage Hodgkin Lymphoma

• Sponsor: University College, London (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04685616
• Collaborator: Takeda (Industry), Canadian Cancer Trials Group (Other)
• Enrollment: 1,042
• Locations: 7
• Arms: 2
• Anticipated Duration (Months): 124.6
• Patients Per Site: 148.9
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hodgkin Lymphoma	Radiation: Involved site radiotherapy; Drug: Doxorubicin; Drug: Bleomycin; Drug: Brentuximab vedotin; Drug: Vinblastine; Drug: Dacarbazine; Drug: Haematopoietic growth factor	Phase 3

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• Patients with Deauville score 5 will be withdrawn from trial treatment.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 Design

• Study Type: Interventional
• Anticipated Enrollment: 1042 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 14, 2022
• Anticipated Primary Completion Date: Sep 1, 2030
• Anticipated Study Completion Date: Sep 1, 2032

Arms and Interventions

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: Brentuximab vedotin; See arm description; Drug: Vinblastine; See arm description; Drug: Dacarbazine; See arm description; Drug: Haematopoietic growth factor; See arm description; Other Names: Filgrastim G-CSF Pegfilgrastim

Outcome Measures

Primary Outcome Measures

1. Progression free survival (PFS) [3 years from end of treatment]

   Time from randomisation to first date of progression or death

Secondary Outcome Measures

1. 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

2. 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)

3. Overall survival (OS) [5 years from end of treatment]

   Time from randomisation to death

4. 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

5. 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

Other Outcome Measures

1. Prognostic power of PET after 1 and 2 cycles of ABVD/A2VD [Up to 5 years after end of treatment]

   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

2. Prognostic and predictive power of baseline PET features [Up to 3 years after end of treatment]

   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

3. Change in pulmonary function tests at end of treatment, 1 and 2 years [3 months & 1 year after end of treatment]

   Change from baseline pulmonary function test (DLCO/TLCO percentage of normal) will be compared

4. Correlation between maximum tumour dimension at baseline and end of treatment with PFS [Up to 5 years after end of treatment]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 69 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males and females aged 16-69 years (inclusive

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
2	Castle Hill Hospital	Hull		United Kingdom	HU16 5JQ
3	Christie Hospital	Manchester		United Kingdom	M20 4BX
4	Norfolk & Norwich University Hospital	Norwich		United Kingdom	NR4 7UY
5	Churchill Hospital	Oxford		United Kingdom	OX3 7LE
6	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH
7	Royal Cornwall Hospital	Truro		United Kingdom	TR1 3LJ

Sponsors and Collaborators

• University College, London
• Takeda
• Canadian Cancer Trials Group

Investigators

• Principal Investigator: John Radford, University of Manchester / Christie Hospital, Manchester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University College, London
• ClinicalTrials.gov Identifier: NCT04685616
• Other Study ID Numbers: UCL/15/0105; 2020-005160-65; IISR X25041
• First Posted: Dec 28, 2020
• Last Update Posted: May 25, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University College, London: PET-response adapted; Stage IA/IIA Hodgkin lymphoma; Brentuximab vedotin
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Doxorubicin; Bleomycin; Dacarbazine; Brentuximab Vedotin; Vinblastine; Mitogens

Study Results

No Results Posted as of May 25, 2022