Ofatumumab versus Rituximab Salvage Chemoimmunotherapyfollowed by ASCT in Relapsed or Refractory DLBCL
试验速览
- 阶段
- 3 期
- 状态
- Other
- 入组人数
- 380
- 试验地点
- 4
- 主要终点
- ofatumumab in addition to salvage chemotherapy (O-chemo) compared to
研究概览
简要总结
This is a Phase III, parallel group, open label, active comparator, randomised (1:1),
intended registration trial of ofatumumab versus rituximab in addition to salvage
chemotherapy. Two salvage regimens, DHAP and DVD, will be included in the protocol.
HOVON centres will enter subjects into the DVD subgroup, all other centres will enter
subjects into the DHAP subgroup. Changes to this policy may be made subject to the
approval of the study management. Recruitment will continue until at least 280 subjects
are randomised into the DHAP subgroup. A maximum of 100 subjects will be recruited
into the DVD subgroup.
Subjects must be refractory to, or have relapsed following, first-line treatment with
rituximab in combination with an anthracycline- or anthracenedione- containing
chemotherapy regimen, and be eligible for ASCT. The following disease responses will
be deemed refractory: 1) progressive disease during first-line treatment, 2) stable disease
after at least 3 cycles of first-line treatment, and 3) PR after at least 6 cycles of first-line
treatment, or in the case of stage I/II disease at least 3 cycles of treatment and definitive
involved field radiotherapy. Subjects will be randomised to receive either rituximab or
ofatumumab in addition to salvage chemotherapy.
Ofatumumab or rituximab infusions will be administered on Day 1 and Day 8 of cycle 1,
and then on Day 1 of cycles 2 and 3. The dose of ofatumumab will be 1000mg and
rituximab will be administered at a dose of 375mg/m
- Cycle 2 and 3 will be delayed forhematological toxicity for a maximum of 2 weeks, thereafter the subject must be
withdrawn if neutrophil and platelet counts are not adequate for dosing.
Disease assessments, including CT and PET scans, will be performed at screening. After
the second cycle of salvage therapy, a CT scan will be performed and subjects not
achieving CR or PR will be considered treatment failures and will not receive any further
protocol therapy. According to local policy, during the second and/or third cycle of
salvage therapy, stem cells will be mobilized and harvested. CT and PET scans will be
performed after the third cycle of salvage therapy. Revised Response Criteria for
Malignant Lymphoma (RRCML) [
Cheson, 2007], modified as in Section 6.2.3, will beused for disease assessment. Provided that subjects have CR, PR or SD, they will receive
high dose chemotherapy followed by autologous stem cell transplantation. Success of
engraftment will be assessed. Response will be assessed at 3 months post ASCT with CT
and PET scans.
From 9 months post-randomisation, subjects will be assessed every 3 months until two
years post randomisation, then every 6 months during years 3 and 4, and then at the end
of year 5. CT scans will be performed at 1 and 2 years post-randomisation or if clinically
indicated to exclude disease relapse.
Patient reported outcomes (PRO) will be collected using the FACT-Lym subscale,
FACT-G, EQ-5D and HCQ questionnaires at specified protocol visits. Paraffin blocks of
the original diagnostic biopsy and, when obtained, the biopsy following first-line
treatment will be submitted to central labs for pathological review and the production of
tissue microarrays (TMA) for subsequent prognostic marker analysis.
An interim analysis for futility of efficacy will be performed when 70 subjects in each
treatment group (O-chemo and R-chemo) have concluded salvage chemoimmunotherapy.
Adequacy of stem cell mobilization and safety will also be reviewed. If the results of the
interim analysis are satisfactory, the study will then complete recruitment Recruitment
will not be interrupted while the interim analysis is conducted. An IDMC will oversee the
conduct of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 55.00 Year(s)（—）
- 性别
- All
入选标准
- •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 concurrently with anthracycline- or anthracenedione-based chemotherapy 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 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 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] For guidance on the adequacy of dosing of rituximab during first-line therapy refer to the SPM 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.
排除标准
- •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 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 symptom 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) 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.
结局指标
主要结局
ofatumumab in addition to salvage chemotherapy (O-chemo) compared to
时间窗: Long Term Follow-up
subjects receiving rituximab in addition to salvage chemotherapy (R-chemo).
时间窗: Long Term Follow-up
To evaluate the progression-free survival (PFS) in subjects receiving
时间窗: Long Term Follow-up
次要结局
- To evaluate the following in subjects receiving O-chemo compared(to subjects receiving R-chemo:)
- Number of subjects completing ASCT.(3 Months Post ASCT Follow-up)
- Changes in health-related quality of life (HRQL) measures.(Long Term Follow-up)
- 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.)
- Overall survival.(Long Term Follow-up)
- Overall response rate after salvage chemoimmunotherapy(3-Months Follow-up)
- Overall response rate three months after ASCT.(3 Months Post ASCT Follow-up)
- Event-free survival.(Long Term Follow-up)
- Number of subjects with inadequate mobilisation of autologous stem cells (2.0(million CD34+ cells/kg) prior to administration of high dose therapy (HDT).)