Avelumab in the Frontline Treatment of Advanced Classical Hodgkin Lymphoma - a Window Study (AVENuE)

• ClinicalTrials.gov Identifier: NCT03617666
• Recruitment Status: Active, not recruiting
• First Posted: August 6, 2018
• Last Update Posted: May 11, 2022
• Sponsor: University College, London
• Collaborator: Pfizer
• Information provided by (Responsible Party): University College, London

Study Description

Brief Summary:

This is a phase II, non-randomised, multicentre study to assess the safety and efficacy of the PD-L1 inhibitor, avelumab, in a previously untreated fit population of high risk stage II, stage III and stage IV classical Hodgkin lymphoma.

Condition or disease	Intervention/treatment	Phase
Hodgkin Lymphoma	Drug: Avelumab	Phase 2

Detailed Description:

This phase II study investigates the safety and efficacy of the PD-L1 inhibitor, avelumab, in a previously untreated fit population of high risk stage II, stage III and stage IV classical Hodgkin lymphoma.

Patients with newly diagnosed high risk stage II, stage III or stage IV cHL staged by 18FDG-PET/CT will receive 4 doses of single agent avelumab every 2 weeks. After the 4th dose of avelumab patients will have a PET-CT scan. All patients will then receive 2 cycles of ABVD followed by a PET-CT scan and further treatment will be guided in a risk-adapted manner based on the results of the RATHL. That is, patients who achieve PET CMR (defined as Deauville score 1-3) will receive 4 cycles of AVD and will undergo a CT scan. Patients with Deauville score 4-5 will receive 4 cycles of BEACOPP-14 or 3 cycles of escalated BEACOPP (at Investigators discretion and as per standard local policy) and will then undergo a further PET scan. Patients who are Deauville score 1-3 at this point will receive 2 further cycles of BEACOPP-14 or 1 cycle of escalated BEACOPP (at Investigators discretion and as per standard local policy). Patients who are Deauville score 4-5 at this point will receive further treatment at Investigators discretion and as per standard local policy. Radiotherapy to sites of residual avidity, initial bulk or as part of salvage treatment, is recommended (but not mandated).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 49 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: AVENuE - Avelumab in the Frontline Treatment of Advanced Classical Hodgkin Lymphoma - a Window Study
• Actual Study Start Date: September 27, 2019
• Estimated Primary Completion Date: July 1, 2022
• Estimated Study Completion Date: November 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Avelumab; Patients with newly diagnosed cHL will receive single agent avelumab in 2 cycles	Drug: Avelumab; Patients with newly diagnosed cHL will receive 4 doses of single agent avelumab 10 mg/kg intravenously given every 2 weeks.; Other Name: Bavencio

Outcome Measures

Primary Outcome Measures :

1. Overall response rate [ Time Frame: 2 months (after first dose of avelumab) ]
   Overall response rate (complete metabolic response (CMR) and partial metabolic response (PMR)) after 2 months (4 doses) of single agent avelumab treatment

Secondary Outcome Measures :

1. Progression free survival [ Time Frame: 1 year (from date of registration) ]
   Progression free survival will be calculated from the date of registration until the date of progression.
2. Overall survival [ Time Frame: 1 year (from date of registration) ]
   Overall survival time will be calculated from the date of registration until the date of death.
3. Rates of adverse events with avelumab [ Time Frame: 3 months (after first dose of avelumab) ]
   Safety and toxicity of avelumab, particularly autoimmune toxicity, as assessed by CTCAE v5.0
4. Rates of adverse events with ABVD/BEACOPP [ Time Frame: 7 months (after commencing ABVD/BEACOPP) ]
   Safety and toxicity of subsequent ABVD/BEACOPP based chemotherapy, as assessed by CTCAE v5.0
5. Complete metabolic response rate [ Time Frame: 2 months (after commencing ABVD) ]
   Complete metabolic response rate following 2 cycles of ABVD
6. Partial metabolic response rate [ Time Frame: 2 months (after commencing ABVD) ]
   Partial metabolic response rate following 2 cycles of ABVD
7. Treatment compliance [ Time Frame: 9 months (from the date of registration) ]
   Proportion of patients completing chemotherapy without delays/dose modifications and proportion of patients who have chemotherapy dose delay/modification.

Other Outcome Measures:

1. Correlate PET positive disease [ Time Frame: End of trial (3 years) ]
   Correlate PET positive disease with histological evidence of disease on biopsy to establish biopsy negative PMR rate (subject to patient consent)
2. Correlate disease response [ Time Frame: End of trial (3 years) ]
   Correlate disease response, as assessed by FDG-PET and histology, with serological markers, including serum TARC
3. Correlation between response to avelumab and biological parameter [ Time Frame: End of trial (3 years) ]
   Evaluate the correlation between response to avelumab and biological parameters e.g. PD-1 expression on Reed Sternberg cells

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 60 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Previously untreated classical Hodgkin lymphoma
• High risk stage II (defined as stage IIB, presence of bulky disease, 3 or more sites of disease), stage III or IV as assessed by FDG-PET/CT
• ECOG performance status 0-1
• Adequate bone marrow function (Hb >80g/l, Platelets >75 x 10^9/l, neutrophils >1.0 x 10^9/l)
• Adequate liver function tests (ALT/AST <2.5 x ULN, total serum bilirubin level <1.5 x ULN)
• Creatinine clearance >50ml/min calculated by Cockroft-Gault formula
• Written informed consent
• Willing to comply with the contraceptive requirements of the trial
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion Criteria:

• Nodular lymphocyte predominant Hodgkin lymphoma
• Compressive symptoms due to disease (which may or may not be bulky). If there is evidence of compression of vital structures radiologically but the patient is asymptomatic, the case must be discussed with the TMG.
• Requirement for urgent treatment due to life-threatening complications of the disease
• Women who are pregnant or breastfeeding
• History of colitis, inflammatory bowel disease or pneumonitis
• Patients with autoimmune disorders excluding patients with vitiligo, diabetes mellitus type 1, hypo- and hyperthyroidism, coeliac disease not requiring immunosuppressive therapy
• Immunosuppressive therapy within the last 2 months, apart from inhaled, intranasal, topical corticosteroids or systemic corticosteroids at low doses (≤10mg prednisolone per day or equivalent - see steroid exception below)
• Prior history of solid organ or allogeneic haematopoietic stem cell transplant
• Positive serology for hepatitis B or C (unless due to vaccination), or hepatitis C RNA negative if hepatitis C antibody positive
• Known HIV infection
• Administration of a live vaccine within 30 days prior to study entry
• History of allergy to monoclonal antibodies, anaphylaxis or uncontrolled allergy
• Chemo- or radiotherapy within 15 days prior to registration. Corticosteroids permitted for disease control but must be weaned down to ≤10mg prednisolone per day or equivalent at least 7 days prior to starting avelumab - steroids may only be started for disease control after the baseline PET-CT
• Persisting toxicity (of >grade 1) related to prior therapy, however, alopecia, sensory neuropathy Grade <2, or other grade <2 not constituting a safety risk based on investigator's judgement are acceptable
• Major surgery within 4 weeks prior to registration
• Active infection requiring systemic therapy
• Myocardial infarction, unstable angina, coronary artery bypass graft, cerebrovascular accident or transient ischaemic attack within the past 6 months
• Non-haematological malignancy within the past 3 years (some exceptions apply)
• Previously treated haematological malignancy
• Any uncontrolled medical condition which can impair delivery of planned immunochemotherapy
• Patient not deemed suitable for ABVD/AVD/escalated-BEACOPP/BEACOPP-14

Contacts and Locations

Locations

Australia, Victoria

Austin Health

Heidelberg, Victoria, Australia

United Kingdom

Heartlands Hospital

Birmingham, United Kingdom

Beatson Hospital

Glasgow, United Kingdom

Leicester Royal Infirmary

Leicester, United Kingdom

St George's Hospital

London, United Kingdom

Christie Hospital

Manchester, United Kingdom

Norfolk and Norwich University Hospital

Norwich, United Kingdom

Churchill Hospital

Oxford, United Kingdom

Derriford Hospital

Plymouth, United Kingdom

The Royal Marsden Hospital, Sutton

Sutton, United Kingdom

Sponsors and Collaborators

University College, London

Pfizer

Investigators

• Principal Investigator: Graham Collins; Churchill Hospital

More Information

• Responsible Party: University College, London
• ClinicalTrials.gov Identifier: NCT03617666
• Other Study ID Numbers: UCL /17/0192; 2018-002227-42 ( EudraCT Number )
• First Posted: August 6, 2018
• Last Update Posted: May 11, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by University College, London:

avelumab

Additional relevant MeSH terms:

Lymphoma; Hodgkin Disease; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Avelumab; Antineoplastic Agents, Immunological; Antineoplastic Agents