Phase 3 Randomized Open-Label Trial Comparing Brentuximab Vedotin Plus AVD Versus ABVD in Advanced Classical Hodgkin Lymphoma Patients
- Trial ID
- 2023-506419-16-00
- Protocol
- C25003
Trial statistics
Objectives
The primary objective of this study is to compare the **modified progression-free survival** (mPFS) achieved with brentuximab vedotin (ADCETRIS®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) against that obtained with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) in the frontline treatment of patients with advanced classical Hodgkin lymphoma. This comparison is clinically relevant as it aims to determine the efficacy of A+AVD in delaying disease progression, which is crucial for improving patient outcomes in this aggressive form of lymphoma.
Secondary objectives include evaluating the overall survival rate to determine if A+AVD improves overall survival (OS) compared to ABVD. This is significant as it assesses the long-term benefits of the treatment, providing insights into its potential to extend patient lifespan beyond progression-free intervals.
Participants
The clinical trial involves a total of **886 participants** diagnosed with **Advanced Classical Hodgkin Lymphoma**. The study population includes both male and female subjects aged 18 years and older, with a focus on treatment-naïve patients presenting with Ann Arbor Stage III or IV disease. Participants were selected based on their histologically confirmed diagnosis of classical Hodgkin lymphoma, as per the World Health Organization Classification. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, ensuring they are capable of self-care and ambulatory activities. The study population is characterized by a requirement for bidimensional measurable disease, as documented by radiographic techniques. Participants are required to adhere to specific contraceptive measures if of childbearing potential, and must provide voluntary written consent prior to any study-related procedures. The trial does not specify particular lifestyle considerations such as diet or physical activity, but does require suitable venous access for blood sampling and specific clinical laboratory values within defined limits. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study aimed at evaluating the efficacy of brentuximab vedotin (ADCETRIS®) plus AVD (doxorubicin, vinblastine, and dacarbazine) compared to ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for the frontline treatment of **advanced classical Hodgkin lymphoma**. The primary endpoint is the modified progression-free survival (mPFS) assessed by an independent review facility (IRF) using the Revised Response Criteria for Malignant Lymphoma. Secondary endpoints include overall survival. The trial is expected to conclude by January 2026, with recruitment having commenced in October 2012.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease stage, and histological confirmation of classical Hodgkin lymphoma. The trial will include multiple follow-up visits to monitor treatment response and safety, with the end-of-study visit marking the completion of the participant's involvement. The total duration of participant involvement is anticipated to be up to 24 months, depending on individual treatment response and tolerability.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will employ intravenous administration of the investigational products, with dosing regimens tailored to the specific treatment arm. The trial will ensure that all products are appropriately labeled with trial-specific information. The study is not categorized as low intervention, reflecting the complexity and potential risks associated with the investigational treatments.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments for the frontline treatment of advanced classical Hodgkin lymphoma. The experimental medication, **Brentuximab Vedotin** (ADCETRIS®), is provided as a 50 mg powder for concentrate for solution for infusion. It is administered intravenously at a dosage of 1.2 mg/kg, with a maximum total dose of 14.4 mg/kg over a treatment period of 24 weeks. This medication is classified as an antibody-drug conjugate (ADC) and is produced by Takeda Pharma A/S. The administration schedule and participant compliance are monitored throughout the trial.
**Vinblastine Sulfate** is used in two formulations: Vinblastinsulfat Teva® 1 mg/ml injection and Vinblastine Sulfate 1 mg/ml solution for injection. Both are administered intravenously with a dosage of 6 mg/m², reaching a maximum total dose of 72 mg/m² over 24 weeks. These formulations are of chemical origin and are provided by TEVA GMBH and HOSPIRA UK LIMITED, respectively. The commercial products are re-labelled to include trial-specific information.
**Bleomycin** is administered in two forms: Bleomycin 15000 IU powder for solution for injection/infusion and Bleomedac®. Both are administered intravenously with a maximum daily dose of 10 IU and a total dose of 120 IU over 24 weeks. Bleomycin is classified as an antibiotic and is provided by NEON HEALTHCARE LIMITED and MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH.
**Dacarbazine** is provided in two formulations: Detimedac 200 mg powder for solution for injection/infusion and Dacarbazine medac 200 mg powder for solution for injection/infusion. Both are administered intravenously at a dosage of 375 mg/m², with a maximum total dose of 4500 mg/m² over 24 weeks. These formulations are of chemical origin and are provided by MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH. The commercial products are re-labelled to include trial-specific information.
**Doxorubicin Hydrochloride** is used in two formulations: Doxorubicinhydrochlorid Teva® 2 mg/ml concentrate for solution for infusion and Doxorubicin hydrochloride 2 mg/ml solution for infusion. Both are administered intravenously at a dosage of 25 mg/m², with a maximum total dose of 300 mg/m² over 24 weeks. These formulations are of chemical origin and are provided by TEVA GMBH and MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH. The commercial products are re-labelled to include trial-specific information.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the **modified progression-free survival (mPFS)** obtained with brentuximab vedotin (ADCETRIS®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma. The primary endpoint for evaluating efficacy is the modified PFS as assessed by an Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma. Additionally, overall survival will be considered as a secondary endpoint.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patients 18 years or older.
- Treatment-naïve, HL patients with Ann Arbor Stage III or IV disease
- Histologically confirmed classical HL according to the current World Health Organisation Classification (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted, or classical Hodgkin lymphoma, NOS [not otherwise specified]).
- ECOG performance status ≤ 2
- Patients must have had bidimensional measurable disease as documented by radiographic technique (spiral CT preferred) per the International Working Group Revised Criteria for Response Assessment for Malignant Lymphoma (Cheson 2007).
- Female patients who: •Were postmenopausal for at least 1 year before the screening visit, OR • Were surgically sterile, OR • If they were of childbearing potential, agreed to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 6 months after the last dose of study drug, or • Agreed to practice true abstinence, when this was in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal were not acceptable methods of contraception.) Male patients, even if surgically sterilized (ie, status postvasectomy), who: • Agreed to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, OR • Agreed to practice true abstinence, when this was in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal were not acceptable methods of contraception.)
- Voluntary written consent was required before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
- Suitable venous access for the study-required blood sampling, including PK sampling.
- Clinical laboratory values as specified within 7 days before the first dose of study drug: • Absolute neutrophil count ≥ 1,500/μL unless there was known HL marrow involvement • Platelet count ≥ 75,000/μL unless there was known HL marrow involvement • Total bilirubin < 1.5 X the upper limit of normal (ULN) unless the elevation was known to be due to Gilbert syndrome. • ALT or AST < 3 X the upper limit of the normal range. AST and ALT could be elevated up to 5 times the ULN if their elevation could be reasonably ascribed to the presence of HL in liver. • Serum creatinine < 2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance > 40 mL/minute (refer to Section 15.3). • Hemoglobin ≥ 8 g/dL.
Exclusion Criteria
- Nodular lymphocyte predominant Hodgkin lymphoma
- Female patients who were both lactating and breastfeeding or who had a positive serum pregnancy test during the screening period or a positive pregnancy test on Day 1 before first dose of study drug
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
- Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of PML
- Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
- Any sensory or motor peripheral neuropathy
- Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to first study drug dose
- Prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy (eg, immunoglobulin replacement, other monoclonal antibody therapies) within 12 weeks of first study drug dose
- 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 human immunodeficiency virus (HIV) positive
- Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
- Diagnosed or treated for another malignancy within 3 years before the first dose or previously diagnosed with another malignancy and had any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type were not excluded if they had undergone complete resection.
- Any of the following cardiovascular conditions or values within 6 months before the first dose of study drug: • A left-ventricular ejection fraction < 50% • Myocardial infarction within 2 years of randomization • New York Heart Association (NYHA) Class III or IV heart failure (see Section 15.4). • Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 17 Oct 2012 | 9 |
 Czechia | Not Recruiting | 17 Oct 2012 | 23 |
 Denmark | Not Recruiting | 17 Oct 2012 | 36 |
 France | Not Recruiting | 17 Oct 2012 | 18 |
 Hungary | Not Recruiting | 17 Oct 2012 | 57 |
 Italy | Not Recruiting | 17 Oct 2012 | 101 |
 Norway | Not Recruiting | 17 Oct 2012 | 12 |
 Poland | Not Recruiting | 17 Oct 2012 | 133 |
 Spain | Not Recruiting | 17 Oct 2012 | 59 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Doxorubicinhydrochlorid Teva® 2 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 25 | 24 | PRD4131412 |
Bleomycin 15000 IU Powder for solution for injection/infusion | Comparator | POWDER FOR SOLUTION FOR INJECTION/INFUSION | SOLUTION FOR INJECTION | 10 | 24 | PRD11145998 |
Detimedac 200 mg, Pulver zur Herstellung einer Injektions-/Infusionslösung | Comparator | PULVER ZUR HERSTELLUNG EINER INJEKTIONS-/INFUSIONSLÖSUNG | INTRAVENOUS USE | 375 | 24 | PRD504529 |
Doxorubicin hydrochloride 2 mg/ml solution for infusion | Comparator | SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 25 | 24 | PRD547262 |
ADCETRIS 50 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1.2 | 24 | PRD672059 |
Vinblastine Sulfate 1 mg/ml solution for injection | Comparator | SOLUTION FOR INJECTION | SOLUTION FOR INJECTION | 6 | 24 | PRD1178005 |
Dacarbazine medac 200 mg, powder for solution for injection/infusion | Comparator | POWDER FOR SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | 375 | 24 | PRD504674 |
Vinblastinsulfat Teva® 1 mg/ml Injektionslösung | Comparator | INJEKTIONSLÖSUNG | INTRAVENOUS USE | 6 | 24 | PRD789638 |
Bleomedac® | Comparator | SOLUTION FOR INJECTION | INTRAVENOUS USE | 10 | 24 | PRD573623 |