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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025320 |
E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
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:
• Overall and complete response rate after salvage chemoimmunotherapy.
• Overall and complete 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 completing 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 salvage
chemotherapy and time to engraftment after 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 an evaluable 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 concurrently with anthracycline- or anthracenedione-based chemotherapy.
Relapse is defined as:
• Biopsy (preferred) or FNA confirmed DLBCL or grade 3b FL after a complete response (CR) or unconfirmed complete response (CRu). 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. It is strongly recommended the lymphoma 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 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.
• 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.
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 >1.5cm and short axis ≥1.0cm
OR
• 1 clearly demarcated lesion/node with a long axis >2.0cm and short axis ≥1.0cm.
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 a grade that in the opinion of the
investigator does not contraindicate study participation.*
9. Signed 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 the lymphoma, with the exception of:
• First-line treatment with rituximab and an anthracycline- or anthracenedionebased 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.
• Radiotherapy to a limited field at a maximum dose of ≤10Gy to control lifethreatening symptoms.
• Prophylactic testicular radiotherapy for testicular lymphoma.
• Intrathecal chemotherapy for the prophylaxis of CNS disease.
2. Received any of the following treatments within two weeks prior to start of study therapy (unless otherwise stated):
• Anti-cancer cytotoxics (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 contraindicate participation in this study.
4. Planned post-randomisation glucocorticoid therapy, unless
• specified by the protocol
• 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 contraindicate
participation in the study.
6. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomisation, congestive heart failure (NYHA
III-IV), a current LVEF of <40%, 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 in the study.*
7. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study.
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 infection.
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 within 2 years prior to randomization unless in the opinion of the investigator it does not contraindicate participation in the study.
Subjects who have been free of malignancy for at least 2 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 <100x109/L (unless due to lymphoma involvement of the bone marrow)
• neutrophils <1.5x109/L (unless due to lymphoma involvement of the bone marrow)
• creatinine >2.0 times upper normal limit (unless due to lymphoma or unless creatinine clearance >60mL/min)
• total bilirubin >1.5 times upper normal limit (unless due to lymphoma or a known history of Gilbert’s disease)
• ALT >2.5 times upper normal limit (unless due to lymphoma)
• alkaline phosphatase >2.5 times upper normal limit (unless due to lymphoma )
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 adequatebcontraception 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) |
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.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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 97 |
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 |
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. 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 |