| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Classical Hodgkin Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| A type of cancer of lymph tissue |
|
| 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 |
|
| 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) |
|
| 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 |
|
| 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. 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 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).(25)
6. 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 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 were not acceptable methods of
contraception.)
7. 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.
8. Suitable venous access for the study-required blood sampling,
including PK sampling.
9. Clinical laboratory values as specified 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 was known HL marrow
involvement
• Total bilirubin < 1.5 the upper limit of normal (ULN)
unless the elevation was known to be due to Gilbert syndrome.
• ALT or AST < 3 the upper limit of the normal range. AST
and ALT could be elevated up to 5 times the ULN if their elevation can 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.
|
|
| E.4 | Principal exclusion criteria |
1. Nodular lymphocyte predominant Hodgkin lymphoma
2. 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
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 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.
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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Modified progression-free survival (PFS) per independent review facility (IRF) |
|
| 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 36 months and then every 6 months thereafter. The period of assessment will differ between patients. Analysis of the primary endpoint was completed in June 2017.
|
|
| E.5.2 | Secondary end point(s) |
|
| 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 36 months and then every 6 months thereafter. |
|
| 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 |
|
| 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 | 3 |
| 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 |
| China |
| Czech Republic |
| Denmark |
| France |
| Hong Kong |
| Hungary |
| Italy |
| Korea, Republic of |
| Norway |
| Poland |
| South Africa |
| Spain |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
| The final analysis of the mPFS endpoint was conducted when 263 mPFS events occured. Patients will be followed for survival until death or for a minimum of 10 years after enrollment of the last patient. The total study duration is approximately 14 years. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 9 |
| 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 |
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