E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Classical Hodgkin Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
A type of cancer originating from White Blood Cells |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025319 |
E.1.2 | Term | Lymphomas Hodgkin's disease |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare 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 (HL) |
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E.2.2 | Secondary objectives of the trial |
Overall survival rate
To determine if A+AVD improves overall survival (OS) versus that obtained with ABVD |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients 18 years or older.
2. Treatment-naïve, HL patients with Ann Arbor Stage III or IV disease (refer to Section 15.1).
3. Patients must have 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]).
4. ECOG performance status ≤ 2 (refer to Section 15.2).
5. Patients must have 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).(25)
6. Female patients who:
• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree 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
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
• Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, OR
• Agree to practice true abstinence, when this is 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 are not acceptable methods of contraception.)
7. Voluntary written consent must be given 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.
8. Suitable venous access for the study-required blood sampling, including PK sampling.
9. Clinical laboratory values as specified below within 7 days before the first dose of study drug:
• Absolute neutrophil count ≥ 1,500/μL unless there is known HL marrow involvement
• Platelet count ≥ 75,000/μL unless there is known HL marrow involvement
• Total bilirubin must be 1.5 the upper limit of normal (ULN) unless the elevation is known to be due to Gilbert syndrome.
• ALT or AST must be 3 the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of HL in liver.
• Serum creatinine must be 2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance 40 mL/minute (refer to Section 15.3).
• Hemoglobin must be 8 g/dL.
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E.4 | Principal exclusion criteria |
• 1. Nodular lymphocyte predominant Hodgkin lymphoma
2. Female patients who are both lactating and breastfeeding or who have a positive serum pregnancy test during the screening period or a positive pregnancy test on Day 1 before first dose of study drug
3. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
4. Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of PML
5. Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
6. Any sensory or motor peripheral neuropathy
7. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to first study drug dose
8. Prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy (eg, immunoglobulin replacement, other monoclonal antibody therapies) within 12 weeks of first study drug dose
9. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin or any component of ABVD
10. Known human immunodeficiency virus (HIV) positive
11. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
12. Diagnosed or treated for another malignancy within 3 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
13. 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Modified PFS per IRF assessment using the Revised Response Criteria for Malignant Lymphoma’ |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Screening
•After Cycle 2: On C2D25 (± 1 day). This corresponds to 10 days (± 1 day) after the 4th dose (after C2D15) of study drug administration
• At End of Treatment Visit, following last dose of frontline therapy (usually Cycle 6): 30 ± 7 days following last dose of frontline therapy. In addition, patients who switch therapy prior to completion of frontline therapy must have a scan performed prior to the first dose of alternative treatment.
•During the follow-up period: every 3 months for the first year and then every 6 months thereafter.
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Screening
• Days 1 & 15 of each treatment cycle (safety endpoints)
• Day 1 of each treatment cycle and Days 8 & 15 of Cycles 1 & 3 (PK endpoints)
• Day 1 of treatment cycles 1, 2 & 6 (antibodies endpoint)
• After Cycle 2: On C2D25 (± 1 day). This corresponds to 10 days (± 1 day) after the 4th dose (after C2D15) of study drug administration
• At End of Treatment Visit, following last dose of frontline therapy (usually Cycle 6): 30 +/- 7 days following last dose of frontline therapy. In addition, patients who switch therapy prior to completion of frontline therapy must have a scan performed prior to the first dose of alternative treatment.
• During the follow-up period: every 3 months for the first year and then every 6 months thereafter. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity and biomarker analysis |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 79 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Brazil |
Canada |
Czech Republic |
Denmark |
France |
Hong Kong |
Hungary |
Italy |
Korea, Republic of |
Norway |
Poland |
Russian Federation |
South Africa |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will last approximately 60 months to reach the final analysis of the mPFS endpoint (approximately 36 months of enrollment plus 24 months of additional follow-up after the last patient is randomized). Patients will be followed for survival until death or the end of posttreatment follow-up (when 112 deaths occur, approximately 4 years from the date of the last patient randomized), whichever occurs first. The total study duration is approximately 7 years. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 3 |