A phase III, parallel group, randomised, registration trial of ofatumumab versus rituximab in addition to salvage chemotherapy.
- CD20 positive DLBCL. Biopsies performed after termination of first-line treatment must confirm CD20 positive DLBCL.
- 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 tretament. 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].
- baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites.
- CT scan showing at least:
- 2 or more clearly demarcated lesions with a largest diameter ≥ 1.5 cm and not previously irradiated
- 1 clearly demarcated lesion/node with a largest diameter ≥ 2.0 cm and not previously irradiated.
- Age ≥18
- ECOG performance status 0, 1, or 2.
- Eligible for high dose chemotherapy and ASCT.
- Resolution of toxicities from first-line therapy to grade ≤ 1.
- Written informed consent
- 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.
- Received any of the following treatments within 4 weeks prior to start of trial 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.
- 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
- Glucocorticoid use, unless given in doses ≤100 mg/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)
- History of significant cerebrovascular disease or event with significant symptoms or sequelae.
- 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.
- Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease.
- Known DLBCL involvement of CNS.
- Known or suspected hypersensitivity to study treatments that, in the opinion of the investigator or GSK medical Monitor, contraindicates their participation.
- Known HIV positivity.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 liver involvement of DLBCL)
- alkaline phosphatase >2.5 times upper normal limit (unless due to DLBCL involvement of the liver or bone marrow))
- Subjects known or suspected of being unable to comply with the study protocol.
- Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test prior at screening.
- 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.
- Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.