| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse large B-cell lymphoma (DLBCL) |
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| E.1.1.1 | Medical condition in easily understood language |
| Diffuse large B-cell lymphoma (DLBCL) |
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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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012820 |
| E.1.2 | Term | Diffuse large B-cell lymphoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067070 |
| E.1.2 | Term | Follicular B-cell non-Hodgkin's lymphoma |
| E.1.2 | System Organ Class | 100000004864 |
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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 assess the antitumor activity of brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone, as measured by the CR rate at the end of treatment per investigator assessment in treatment-naive patients with high-intermediate or high risk systemic DLBCL
To assess the safety profile of brentuximab vedotin administered at dose levels of 1.2 mg/kg versus 1.8 mg/kg in combination with RCHOP or brentuximab vedotin 1.8 mg/kg in combination with RCHP in treatment-naive patients with high-intermediate or high risk systemic DLBCL
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| E.2.2 | Secondary objectives of the trial |
To assess the antitumor activity of brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone, as measured by the objective response rate (ORR) at the end of treatment per investigator assessment
To assess the progression-free survival (PFS) associated with brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone
To assess survival associated with brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Treatment-naive patients with systemic de novo or transformed DLBCL, or follicular NHL grade 3b; patients must have high-intermediate or high risk disease based on standard IPI (score ≥3 for patients >60 years of age) or aaIPI (score 2 or 3 for patients ≤60 years of age), and stage IAX (bulk defined as single lymph node mass >10 cm in diameter), IB–IV disease
2.Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist
3.An Eastern Cooperative Oncology Group (ECOG) performance status ≤2
4.Age 18 years or older
5.Patients must have the following baseline laboratory data:
●bilirubin ≤1.5X upper limit of normal (ULN) or ≤3X ULN for patients with Gilbert's disease or documented hepatic involvement with lymphoma
●alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3X ULN or ≤5X ULN for patients with documented hepatic involvement with lymphoma
●serum creatinine ≤2X ULN
●absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow involvement with lymphoma)
●platelet count ≥50,000/µL (unless documented bone marrow involvement with lymphoma)
6.Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of brentuximab vedotin. Females of non-childbearing potential are those who are post menopausal for more than 1 year or who have had a bilateral tubal ligation or hysterectomy.
7.Females of childbearing potential and males who have partners of childbearing potential must agree to use 2 effective contraception methods during the study and for 12 months following the last dose of study drug
8.Patients or their legally authorized representative must provide written informed consent
9.Patients in Parts 2 and 3 must have histologically confirmed diagnosis of CD30-positive DLBCL |
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| E.4 | Principal exclusion criteria |
1.Previous history of treated indolent lymphoma. Newly diagnosed patients with DLBCL who are found to have small cell infiltration of the bone marrow or other diagnostic material (representing a discordant lymphoma) are eligible.
2.History of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has not been in remission for at least 3 years
3.History of progressive multifocal leukoencephalopathy (PML)
4.Cerebral/meningeal disease related to the underlying malignancy
5.Baseline peripheral neuropathy >/= Grade 2 (per the National Cancer Institute’s Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 4.03) or patients with the demyelinating form of Charcot-Marie-Tooth syndrome
6.Left ventricular ejection fraction less than 45% or symptomatic cardiac disease (including symptomatic ventricular dysfunction, symptomatic coronary artery disease, and symptomatic arrhythmias), or myocardial infarction within the past 6 months or previous treatment with complete cumulative doses of doxorubicin or other anthracyclines
7.Any active Grade 3 or higher (per the NCI CTCAE, Version 4.03) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study treatment
8.Current therapy with other systemic anti-neoplastic or investigational agents
9.Females who are breastfeeding
10.Known hypersensitivity to any excipient contained in any of the drug formulations of study treatments
11.Patients with known urinary outflow obstruction
12.Known human immunodeficiency virus (HIV) infection or known or suspected active hepatitis C infection. Patients with a positive hepatitis B polymerase chain reaction (PCR) assay who have also tested positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody; patients with a negative PCR assay are permitted with effective anti-viral prophylaxis.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Complete remission (CR) rate per investigator assessment following the completion of study treatment
- Type, incidence, severity, seriousness, and relatedness of adverse events and laboratory abnormalities
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
CR rate is defined as the proportion of patients with CR at the end of treatment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007), as assessed by the investigator.
The end of treatment response assessments are made 5 weeks after the last dose. |
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| E.5.2 | Secondary end point(s) |
- Objective response rate (ORR) per investigator
- Progression-free survival (PFS) per investigator
- Overall Survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The end of treatment response assessments are made 5 weeks after the last dose.
Survival is assessed 4 months after the last scan for 2 years, then every 6 months. |
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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 | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Czech Republic |
| Italy |
| Poland |
| Spain |
| 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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| For the primary efficacy analysis, it is LVLS (5 weeks after last dose of study drug). |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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