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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MedDRA Classification |
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 evaluate the progression-free survival (PFS) in subjects receiving ofatumumab in addition to salvage chemotherapy (O-chemo) compared to subjects receiving rituximab in addition to salvage chemotherapy (R-chemo). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the following in subjects receiving O-chemo compared to subjects receiving R-chemo:
• PFS in the DHAP subgroup. • Overall response rate after salvage chemoimmunotherapy. • Overall response rate three months after ASCT. • Event-free survival. • Overall survival. • Number of subjects with inadequate mobilisation of autologous stem cells (<2.0 million CD34+ cells/kg) prior to administration of high dose therapy (HDT). • Changes in health-related quality of life (HRQL) measures • Incidence, severity of adverse events, serious adverse events and other safety parameters. • Time to neutrophil and platelet recovery after each cycle of therapy including HDT/ASCT. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. CD20 positive DLBCL. Biopsies performed after termination of first-line treatment must confirm CD20 positive DLBCL.
2. Refractory to, or relapsed following, first-line treatment with rituximab combined with anthracycline-based chemotherapy. Relapse is defined as biopsy confirmed CD20 positive DLBCL after a complete response.
Refractory disease must fulfill one of the following: • partial response (PR) after termination of first-line treatment. Subjects must have received at least 6 cycles of rituximab combined with anthracycline-based chemotherapy. Subjects with stage I/II disease will also be eligible if treated with at least 3 cycles of rituximab combined with anthracycline-based chemotherapy and definitive involved-field radiation therapy. Biopsy confirmation of CD20 positive DLBCL is required. • stable disease (SD) after termination of first-line treatment. Subjects must have received at least 3 cycles of rituximab combined with anthracycline-based chemotherapy. Biopsy confirmation of CD20 positive DLBCL is preferred but not required. • progressive disease (PD). Biopsy confirmation of CD20 positive DLBCL is preferred but not required. Disease response to first-line treatment should be determined according to Revised Response Criteria for Malignant Lymphoma [Cheson, 2007], or if PET scanning was not used, International Workshop Response criteria for NHL [Cheson, 1999].
3. Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites.
4. CT scan showing at least: • 2 or more clearly demarcated lesions/nodes with a largest diameter ≥1.5 cm and not previously irradiated OR • 1 clearly demarcated lesion/node with a largest diameter ≥2.0 cm and not previously irradiated.
5. Age ≥18
6. ECOG performance status 0, 1, or 2.
7. Eligible for high dose chemotherapy and ASCT.
8. Resolution of toxicities from first-line therapy to grade≤1.
9. Written informed consent. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Any previous cancer therapy for DLBCL, with the exception of: • First-line treatment with rituximab in combination with an anthracycline-based chemotherapy. • Radiotherapy as part of the first-line treatment plan or to a limited field at a maximum dose of ≤10Gy to control life-threatening symptoms.
2. Received any of the following treatments within 4 weeks prior to start of study therapy (unless otherwise stated): • Anti-cancer therapy (e.g. alkylating agents, anti-metabolites, purine analogues) • Radiotherapy unless it is to a limited field at a maximum dose of ≤10Gy to control life-threatening symptoms.
3. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study
4. Glucocorticoid use, unless given in doses ≤100mg/day hydrocortisone (or equivalent dose of other glucocorticoid-refer to the SPM for glucocorticoid equivalent doses) for <7 days for exacerbations other than lymphoma (e.g. asthma)
5. History of significant cerebrovascular disease or event with significant symptoms or sequelae.
6. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomisation, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.
7. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease.
8. Known DLBCL involvement of the CNS.
9. Known or suspected hypersensitivity to study treatments that, in the opinion of the investigator or GSKmedical Monitor, contraindicates their participation
10. Known HIV positivity.
11. Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive and HBsAb negative, a HB DNA test will be performed and if positive the subject will be excluded. Note: If HBcAb positive and HBsAb positive, which is indicative of a past infection, the subject can be included.
12. Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result.
13. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis and tuberculosis.
14. Other past or current malignancy. However, subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
15. Prior treatment with anti-CD20 monoclonal antibodies with the exception of rituximab or treated with other monoclonal antibodies within 3 months prior to start of study therapy.
16. Screening laboratory values: • platelets <50 x 10^9/L (unless due to DLBCL involvement of the bone marrow) • neutrophils <1.0 x 10^9/L (unless due to DLBCL involvement of the bone marrow) • creatinine >2.0 times upper normal limit (unless normal creatinine clearance) • total bilirubin >1.5 times upper normal limit (unless due to DLBCL involvement of liver or a known history of Gilbert’s disease) • ALT >2.5 times upper normal limit (unless due to DLBCL involvement of liver) • alkaline phosphatase >2.5 times upper normal limit (unless due to DLBCL involvement of the liver or bone marrow)
17. Subjects known or suspected of being unable to comply with the study protocol.
18. Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening.
19. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
20. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS). Progression-free survival is defined as the time from randomization until stable disease after two cycles of salvage chemoimmunotherapy, progression or death, whichever occurs first. |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
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) | 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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 | Information not present in EudraCT |
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 |
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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 end of the trial is not specified but the protocol states the follow-up of 5 years for all patients in section 3.1. The end of the trial will be Last Subject Last Visit after 5 years follow-up. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |