E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CD30 positive diffuse large B-cell lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
CD30 positive diffuse large B-cell lymphoma patients refractory to first line chemotherapy or in first relapse |
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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 | PT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
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 |
Phase 1 part
- To identify the feasibility and RDL (recommended dose level) of brentuximab vedotin in combination with R-DHAP
Phase 2 part
- To evaluate the efficacy of the combination of brentuximab -vedotin and R-DHAP as salvage treatment in relapse/refractory DLBCL patients in terms of metabolic CR rate after the third cycle
- To establish the rate of CTCAE grade 3/4 non-hematological toxicity, including neurotoxicity after each cycle of brentuximab vedotin-R-DHAP |
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E.2.2 | Secondary objectives of the trial |
Phase 1 part
- To assess the toxicity of brentuximab vedotin in combination with R-DHAP
- To assess the success rate of autologous peripheral blood stem cell harvest after brentuximab vedotin-R-DHAP
Phase 2 part
-To asses the overall response rate (ORR) after 3 cycles and after ASCT
-To assess the toxicity profile of brentuximab vedotin in combination with R-DHAP
-To assess hematological recovery after each cycle of brentuximab vedotin-R-DHAP
-To assess the success rate of harvesting an autologous peripheral blood stem cell graft
-To assess the fraction of patients (CR/PR) eligible for ASCT who actually undergo ASCT
-To assess peripheral blood neutrophil and platelet recovery after ASCT
-To evaluate the progression free survival (PFS), event free survival (EFS), and overall survival (OS)
-To identify predictive factors for response, PFS, EFS and OS (exploratory analysis)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• CD30 positive DLBCL, i.e. more than 1% of DLBCL cells CD30 positive (central pathology review results not required to enter patient into the study), according to the WHO classification 2008:
- CD30 positive DLBCL, including EBV positive DLBCL
- CD30 positive primary mediastinal B-cell lymphoma
• Primary refractory to or in first relapse after first line therapy with R-CHOP or R-CHOP-like therapy (A rituximab biosimilar is permitted when it is registered for the indication of DLBCL)
• Age ≥ 18 years (upper age limit for ASCT at the discretion of the participating center)
• Measurable disease: on CT scan at least 1 lesion/node with a long axis of > 1.5 cm and at least one positive lesion on 18F-FDG PET scan
• WHO performance status 0-2 (see appendix C)
• Adequate hepatic function
• Adequate renal function
• Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5x10E9/L and platelet
count ≥ 100 x 10E9/L
• Hemoglobin must be ≥ 8 g/dL (5.0 mmol/L), transfusion is allowed
• Eligible for high-dose chemotherapy and ASCT
• Resolution of relevant toxicities from first-line therapy
• Life expectancy of > 3 months with treatment
• Negative pregnancy test at study entry, if applicable
• Female patient is either post-menopausal for at least 1 year before screening visit or surgically sterile or if of childbearing potential, agrees to practice 2 effective methods of contraception, at the same time, or agrees to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months after the last dose of study drug
• Male patients, even if surgically sterilized, (i.e. status post vasectomy) agree to practice effective barrier contraception, or agrees to completely abstain from heterosexual intercourse, during the entire study period and through 12 months after the last dose of study drug
• Written informed consent
• Patient is capable of giving informed consent
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E.4 | Principal exclusion criteria |
• Peripheral sensory or motor neuropathy grade ≥ 2
• Known cerebral or meningeal disease (NHL or any other etiology), including signs and symptoms of progressive multifocal leukoencephalopathy (PML)
• Symptomatic neurological disease compromising normal activities of daily living or requiring medications
• Transformed lymphoma
• DLBCL after organ transplantation
• Immunodeficiency-associated B-cell lymphoproliferative disease
• Use of other investigational agents within at least 5 half-lives of the most recent agent used prior to study entry
• Treatment with myelosuppressive chemotherapy or biological therapy ≤ 4 weeks before study entry
• Female patients who are breast feeding
• History of another malignancy less than 3 years before study inclusion, or previously diagnosed with another malignancy and have evidence of residual disease, with the exception of non-melanoma skin cancer, completely resected melanoma TNMpT1 and carcinoma in situ of the uterine cervix
• Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin
• Active hepatitis B or C infection as defined by positive serology and transaminitis. Non-active hepatitis B carriers or anti-HBc positive patients may be included if protected with lamuvidine or entecavir
• HIV positivity
• Radiation therapy within 8 weeks prior to start of protocol treatment. Emergency radiation therapy is allowed, as long as measurable disease (at non-irradiated sites) persists
• Patients with a serious psychiatric disorder that could, in the investigator's opinion, potentially interfere with the completion of treatment according to protocol
• Major organ dysfunction, unless NHL-related
• Patients who have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study
• Thyroid abnormalities when thyroid function cannot be maintained in the normal range by medication
• Current participation in another clinical trial interfering with this trial
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Claustrophobia to the extent that PET-CT is impossible
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1 part
• The rate of patients with serious toxicity during cycle 1-2 of the combination BV-R-DHAP
Phase 2 part
Primary efficacy endpoint
• Metabolic CR rate (PET-diagnostic CT) after the third cycle of BV-R-DHAP salvage therapy
Primary feasibility/toxicity endpoints
• Rate of grade 3/4 non-hematological toxicity, including neurotoxicity after each cycle of BV-R-DHAP
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 part:
The patients will be monitored closely for adverse events. The number of patients with serious toxicities (ST) will be determined at day 21 after start of cycle 1 or 2 , when 6 patients have been entered in a dose level.
Phase 2 part: the endpoints will be evaluated when data for 3 BV-R-DHAP cycles are available for all patients |
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E.5.2 | Secondary end point(s) |
Phase 1 part
- (Serious) Adverse Events during combination treatment
- Time to hematological recovery after each cycle of BV-R-DHAP
- Time to recovery from non-hematological toxicity after each cycle of BV-R-DHAP
- Administration of treatment: dose reductions, interval between cycles, discontinuation rate
- Rate of successful PBSC collection (≥ 2x106 CD34+ cells/kg) after the third cycle of BV-R-DHAP
Phase 2 part
Secondary efficacy endpoints
- Overall response rate (PR + CR) after the third cycle of BV-R-DHAP salvage therapy (based on the results of the FDG-PET/CT scan)
- Overall response rate (PR + CR) after ASCT (based on the results of the FDG-PET/CT scan)
- Metabolic CR rate (PET-CT) after ASCT
- Fraction of patients (CR/PR) eligible for ASCT who actually undergo ASCT
- Progression free survival (PFS), Event free survival (EFS), Overall survival (OS
Secondary feasibility/toxicity endpoints
- (Serious) Adverse Events during the combination treatment
- Time to hematological recovery after each cycle of BV + R-DHAP
- Administration of treatment: dose reductions, interval between courses, discontinuation rate
- Rate of successful PBSC collection (≥ 2 x106 CD34+ cells/kg) after the second or third cycle of BV-R-DHAP
- Time to hematological recovery after ASCT
- (Serious) Adverse Events after ASCT
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1 part
These endpoints will be evaluated when the relevant data for all patients are available in the phase 1
Phase 2 part
These endpoints will be evaluated when the relevant data for all patients are available |
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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 | 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 | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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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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 | 6 |
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 | 6 |