| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B-Cell Lymphoma (DLBCL) and grade 3b follicular lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
Lymphoma called diffuse large B-cell lymphoma (DLBCL) or grade 3b
follicular lymphoma that has been treated before. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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). |
|
| 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).
• NUmber of subjects completeing ASCT.
• Changes in patient 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. |
|
| 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 or grade 3b follicular lymphoma (FL) at original diagnosis. If a biopsy or fine needle aspiration (FNA) is performed prior to enrolment to the study it must confirm CD20 positive DLBCL or grade 3b FL. Note: If evidence
emerges that the binding of the immunohistochemical antibody to CD20 can be blocked by rituximab, demonstration of CD20 positivity in the repeat biopsy/FNA will not be required.
2. Refractory to, or relapsed following, first-line treatment with rituximab concurrentlywith anthracycline-or anthracenedione based chemotherapy.
Relapse is defined as:
•Biopsy (preferred) or FNA confirmed DLBCL or grade 3b FL after a complete response (CR). However, for subjects relapsing during first-line treatment, biopsy/FNA reconfirmation of the lymphoma is recommended but not mandatory.
Subjects must have received rituximab concurrently with at least 6 cycles of chemotherapy. However, subjects with stage I/II disease will be eligible if they have received rituximab concurrently with at least 3 cycles of chemotherapy and definitive involved-field radiation therapy.
Refractory disease must fulfill one of the following:
•continuing partial response (PR) from termination of first-line treatment. The lymphoma should be reconfirmed by biopsy (preferred) or FNA, however, if these procedures are deemed to be inappropriate, then HOVON may determine eligibility following review of the imaging results and disease history.
Subjects must have received of rituximab concurrently with at least 6 cycles of chemotherapy. However, subjects with stage I/II disease will be eligible if they have received concurrently with at least 3 cycles of chemotherapy and definitive involved-field radiation therapy.
•continuing stable disease (SD) from termination of first-line treatment. Reconfirmation of the lymphoma by biopsy (preferred) or FNA is recommended but not mandatory.
Subjects must have received rituximab concurrently with at least 3 cycles of chemotherapy
•progressive disease (PD). Biopsy or FNA reconfirmation of the lymphoma is recommended but not mandatory.
Note: Disease response to first-line treatment should be determined according to Revised Response Criteria for Malignant Lymphoma [Cheson, 2007] or 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 long axis>1.5 cm and short axis >1.0 cm
OR
•1 clearly demarcated lesion/node with a long axis>2.0 cm and short axis >1.0 cm
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 that in the opinion of the investigator does not contraindicate study participation
9. Written informed consent. |
|
| 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 lymphoma, with the exception of:
• First-line treatment with rituximab and anthracycline or antracenedione-based chemotherapy.
•Monotherapy rituximab, dosed prior to first line rituximab combined with chemotherapy or as maintenance therapy
• 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 2 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 unless in the opinion of the investigator it does not contrainidicate particpation.
4. planned post randomised glucocorticoid, unless administered in doses ≤1mg/kg/day prednisolone (or equivalent dose of other glucocorticoid-refer to the SPM for glucocorticoid equivalent doses)
administered as inhalation therapy for mild COPD or asthma
5. History of significant cerebrovascular disease or event with significant symptoms or sequelae unless in the opinion of the investigator it does not contrainidicate participation
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 unless in the opinion of the investigator it does not contraindicate participation
7. Significant concurrent, uncontrolled medical condition unless in opinion of the investigator it does not contraindicate participation
8. Known lymphoma involvement of the CNS.
9. Known or suspected hypersensitivity to study treatments that, in the opinion of the investigator , 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 (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
12. Active hepatitis C infections
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 unless investigator considers it does not contrainidcate participation in the study. e.g 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.
16. Screening laboratory values:
• platelets <100x 10^9/L (unless due to lymphoma involvement of the bone marrow)
• neutrophils <1.5 x 10^9/L (unless due to lymphoma 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 lymphoma involvement of liver or a known history of Gilbert’s disease)
• ALT >2.5 times upper normal limit (unless due to lymphoma involvement of liver)
• alkaline phosphatase >2.5 times upper normal limit (unless due to lymphoma 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. |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS is defined as the time from randomisation until stable disease after
two cycles of salvage chemoimmunotherapy,
lymphoma progression or death from any cause. Maximum follow-up per
subject is 5 years post randomisation. |
|
| E.5.2 | Secondary end point(s) |
• Overall response and complete response rates at two timepoints
• Overall Survival (OS)
• Event Free Survival (EFS)
• Ability to mobilize ≥ 2x106 CD34+ cells/ kg from the peripheral blood
• Number of subjects completing ASCT
• Incidence, severity, of adverse
events (AE), serious adverse events (SAE) and other safety parameters
• Time to neutrophil and platelet recovery after each cycle of therapy
including HDT/ASCT
• Changes in health-related quality of life (HRQL) measures |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Overall response & complete response rates will be reviewed after the
completion of salvage chemotherapy
• The frequency and proportion of
subjects yielding at least 2 million CD34+ cells/kg from peripheral blood
will be compared by the CMH test.
• The frequency and proportion of
subjects completing ASCT will be compared by the CMH test.
•AEs will be collected from the start of salvage
• SAEs will be collected from the start
of salvage
• Neutrophil and platelet recovery after HDT/ASCT is defined as 3 consecutive days when the Absolute Neutrophil count is ≥ 0.5 x 109/L and an unsupported platelet count of 20 x 109/L.
• HRQL will be collected at all study visits both during treatment and all follow-up visits. |
|
| 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.8.2.4 | 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 | 18 |
| 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 |
| Argentina |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| Thailand |
| 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 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| 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 |
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