E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Untreated patients with histologically confirmed CD30+ classical Hodgkin lymphoma (stage I/II), aged > or = 18 and < or = 60 years old, with at least one unfavourable clinical pronostic factor |
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E.1.1.1 | Medical condition in easily understood language |
Patients from 18 to 60 years old, with Hodgkin lymphoma CD30+, with one unfavourable clinical pronostic factor |
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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 | LLT |
E.1.2 | Classification code | 10020328 |
E.1.2 | Term | Hodgkin's lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of the combination AVD+brentuximab vedotin in untreated patients with stage I/II unfavourable Hodgkin lymphoma, as measured by the rate of PET negativity after two cycles of immuno chemotherapy, PET assessment based on central review. |
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E.2.2 | Secondary objectives of the trial |
To assess the efficacy and safety of AVD+brentuximab vedotin as measured by:
• Secondary efficacy endpoints:
- CR rate (according to Cheson 2007) at the end of treatment
- Progression-free survival
- Overall survival
• Secondary safety endpoint:
- Toxicity of Brentuximab vedotin in combination with combined modality treatment will be assessed.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Analysis on tumor tissue biopsy to determine factors that influence treatment response based on PET scan assessment and prognosis |
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E.3 | Principal inclusion criteria |
• Histologically confirmed CD30+ classical Hodgkin lymphoma according to local evaluation
• Supradiaphragmatic Ann Arbor clinical stage I or II
• Previously untreated
• PET scan without IV contrast at diagnosis available for central review with at least one hypermetabolic lesion
• Unfavourable (U) characteristics according to the classic EORTC/LYSA clinical prognostic factors. Unfavourable (U) subset includes patients with at least one of the following factors:
o CSII ≥ 4 nodal areas
o age ≥ 50 yrs
o M/T ratio ≥ 0.35
o ESR ≥ 50 (without B-symptoms) or ESR ≥ 30 with B-symptoms
• ECOG performance status 0-2
• Life expectancy > 6 months
• Age 18 to 60 years (≥ 18 years to ≤ 60 years)
• Patients must be available for periodic blood sampling, study-related assessments, and management of toxicity at the treating institution.
• Female patients who:
o Are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile,
OR
o 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 completely abstain from heterosexual intercourse
• Male patients, even if surgically sterilized (ie, status postvasectomy), who:
o 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 completely abstain from heterosexual intercourse.
• Patients must give written informed consent. A copy of the informed signed consent form will be retained in the patient’s chart.
• Required baseline laboratory data:
o Absolute neutrophil count ≥ 1,500/µL
o Platelet count ≥ 75,000/ µL
o Hemoglobin ≥ 8g/dL
o Serum total bilirubin ≤ 1.5 X ULN unless the elevation is known to be due to Gilbert syndrome.
o Serum creatinine ≤ 2.0 mg/dL and/or calculated creatinine clearance > 40 mL/minute (Cockcroft-Gault formula or MDRD)
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN
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E.4 | Principal exclusion criteria |
• Histological diagnosis different from classical Hodgkin Lymphoma. Nodular lymphocyte predominant subtypes (nodular paragranuloma or Poppema paragranuloma) are excluded.
• Known cerebral or meningeal disease of any etiology, including signs or symptoms of PML
• Any sensory or motor peripheral neuropathy ≥ Grade 2
• Known history of any of the following cardiovascular conditions
o Myocardial infarction within 2 years of randomization
o New York Heart Association (NYHA) Class III or IV heart failure (see Appendix 14)
o 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
o Recent evidence (within 30 days before first dose of study drug) of a left-ventricular ejection fraction <50%
• Unstable diabetes mellitus (to avoid uninterpretable FDG-PET scan).
• Known HIV positive
• HCV positive
• HBV positive. This means:
o HBsAg positive
o HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA
o Note:
Patients who are HBsAg negative and viral DNA negative are eligible
Patients who are seropositive due to a history of hepatitis B vaccine are eligible.
• Any history of cancer during the last 5 years, with the exception of non-melanoma skin tumors. Carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Dementia or altered mental status that would preclude compliance with drug delivery
• Pregnancy or breastfeeding. Females of childbearing potential having a positive β-HCG pregnancy test result during screening or a positive pregnancy test (urinary or blood) within 1 day before start of treatment.
• Previous treatment with any anti-CD30 antibody.
• Known hypersensitivity to any excipients contained in the brentuximab vedotin formulation or known contra-indication to any drug contained in the chemotherapy regimens (for ex.: pulmonary or neurological disease grade ≥ 2)
• Treatment with corticosteroids before baseline PET scan (PET 0)
• Patients with known active viral, bacterial, or fungal infection requiring treatment with antimicrobial therapy or with untreated known active Grade 3 viral, bacterial, or fungal infection, within 2 weeks prior to the first dose of brentuximab vedotin
• Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy or immune-chemotherapy
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the PET response rate according to the Deauville criteria based on central review assessed after 2 cycles of chemotherapy or immuno-chemotherapy (ABVD or AVD/Brentuximab vedotin). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The categorization of the patients according to PET results will be performed as follows:
- 1, 2 or 3: PET negative = Responder
- 4- 5: PET positive =Non-responder.
- Missing PET evaluation (for whatever reason) : Non-responder
As sensitivity analysis will be performed on the Evaluable Set. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are the efficacy and the safety |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints will include:
• COMPLETE RESPONSE RATES ACCORDING TO PET RESPONSE AT END OF TREATMENT
Disease response evaluation at end of treatment (after radiotherapy) will be used to determine the Response Rate.
• PET RESPONSE RATE (ACCORDING TO DEAUVILLE CRITERIA) AT END OF TREATMENT
PET evaluation will be performed at end of treatment.
• PROGRESSION FREE SURVIVAL (PFS)
PFS is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. If a subject has not progressed or died, PFS will be censored at the time of last visit assessment.
• OVERALL SURVIVAL (OS)
Overall survival will be measured from date of randomization into the study to the date of death from any cause. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
To assess the rate of PET negativity after two cycles of immunochemotherapy |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 110 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 end of the study is defined as the last patient's last visit and will occur approximately 6 years and 8 months (80 months) after the first patient is enrolled to allow patients to have a minimum of 5 years of follow-up post treatment. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |