E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Indolent B-cell Non-Hodgkin’s Lymphoma |
|
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 establish effectiveness of ofatumumab in combination with bendamustine in patients with indolent B-cell NHL disease relapsed after rituximab therapy |
|
E.2.2 | Secondary objectives of the trial |
• To establish overall response rate, overall survival, time to and duration of response, and time to progression in subjects treated with ofatumumab (O) and bendamustine (B) combination therapy to those treated with bendamustine monotherapy • To evaluate and compare the safety and tolerability in subjects treated with O and B combination therapy to those treated with B alone • To evaluate ofatumumab pharmacokinetics when given with bendamustine • To evaluate and compare two treatment arms with respect to changes in subjects’ health-related quality of life • To evaluate and compare prognostic markers and their correlation with clinical responses in subjects treated with O and B compared to those treated with B monotherapy (i.e. ALC, FcR gamma 3, HACA) • To evaluate overall response rate to optional O monotherapy in subjects who are unresponsive to rituximab during or within 6 months of a rituximab-containing regimen who progress during or following single-agent bendamustine
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma and follicular lymphoma (FL) grades; 1, 2 and 3A defined according to WHO guidelines: • Tumor verified to be CD20+ positive from a previous or current lymph node biopsy • CT imaging in screening phase (based on local evaluation) showing 2 or more clearly demarcated lesions with a largest diameter ≥ 1.5 cm, or 1 clearly demarcated lesion with a largest diameter ≥ 2.0 cm. CT imaging performed at screening as baseline image 2. Indolent B-cell NHL that remains stable or unresponsive during or within 6 months of treatment with rituximab or a rituximab-containing regimen: • Maintaining stable disease or failure to achieve PR to rituximab-based therapy. (CT imaging will support this finding, and will be performed at least 60 days after the last dose of rituximab-based therapy) or, • Disease progression while on rituximab-based therapy (e.g., includes 4 weekly courses of rituximab given at 6-month intervals [Hainsworth, 2005]) or, • Disease progression in subjects with stable disease or better response to rituximab-based therapy <6 months of the last dose of rituximab Note: Subjects must have received minimum of 4 rituximab infusions as monotheray or 3 infusions as part of a rituximab containing combination regimens. 3. ECOG Performance Status of 0, 1, or 2 4. Age ≥ 18 years 5. Life expectancy of at least 6 months 6. Signed written informed consent prior to performing any study-specific procedures French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
|
|
E.4 | Principal exclusion criteria |
1. Grade 3b follicular lymphoma or evidence that the indolent lymphoma has transformed to aggressive lymphoma as verified by biopsy confirmation [e.g. constitutional symptoms, poor performance status, fast growing tumor or increasing lactate dehydrogenase (LDH) level]
2. Previous allogeneic stem cell transplant
3. Previous autologous stem cell transplant, fludarabine therapy, or radioimmunotherapy in the last 6 months
4. Previous external beam radiation therapy to the pelvis. Previous external beam radiation therapy for bony disease to the cranium, mediastinum, and axilla or to more than 3 vertebral bodies
5. High dose steroids ≥ 100 mg prednisone/day (or equivalent) for 7 consecutive days, given as concomitant medication, within 3 months prior to randomization. No more than 10 mg prednisone daily at the time of randomization
6. Prior bendamustine treatment within 1 year of randomization not resulting in a CR or PR for at least 6 months
7. Prior treatment with anti-CD20 monoclonal antibody, if 1st dose was administered within 60 days prior to randomization. Prior use of any monoclonal antibody (other than anti-CD20) within 3 months prior to randomization.
8. Known CNS involvement of indolent lymphoma
9. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of definitively treated non-melanoma skin cancer, or successfully treated in situ carcinoma, are eligible*
10. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, and active Hepatitis C
11. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from Visit 1, congestive heart failure, and arrhythmia requiring therapy, with the exception of extrasystoles or minor conduction abnormalities
12. History of significant cerebrovascular disease or event with significant symptoms or sequelae
13. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator or GSK medical Monitor contraindicates participation this study
14. 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**
15. Current active liver or biliary disease (subjects with Gilbert’s syndrome or asymptomatic gallstones, liver metastases related to indolent NHL or otherwise stable chronic liver disease per investigator assessment, are eligible) 16. Known HIV positive
17. Screening laboratory values: • platelets < 100 x 10^9/L (unless due to indolent lymphoma involvement of the bone marrow) • neutrophils < 1.5 x 10^9/L (unless due to indolent lymphoma involvement of the bone marrow) • Serum creatinine > 1.5 times the institution’s upper limit of normal (ULN); subjects with a serum creatinine > 1.5 ULN will be eligible if the calculated creatinine clearance [Cockcroft, 1976] or creatinine clearance from a 24-hour urine collection is > or = 40 mL/min. • Total bilirubin > 1.5 times ULN (unless due to liver involvement by FL or Gilbert’s disease) • Transaminases > 3 times ULN.
18. Known or suspected hypersensitivity to ofatumumab, bendamustine or mannitol
19. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half-lives or 4 weeks prior to Visit 1, whichever is longer or currently participating in any other interventional clinical study
20. Known or suspected inability to comply with study protocol
21. Lactating women, women with a positive pregnancy test at Visit 1 or women (of childbearing potential) as well as men with partners of childbearing potential, who are not willing to use adequate contraception from study start through one year following last treatment dose. Adequate contraception is defined as abstinence, oral hormonal birth control, hormonal birth control injections, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilization if male partner is sole partner for that subject. The double barrier method can be used in regions where considered acceptable and adequate (condom or occlusive cap plus spermicidal agent).
*Subjects can participate in the study if in the opinion of the investigator and medical monitor it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the data. ** If HBV DNA is negative, subject may be included but must undergo HBV DNA monitoring. Prophylactic antiviral therapy may be initiated at the discretion of the investigator.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Progression-free survival, defined as the time interval between randomization and disease progression or death |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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
| 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
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 |
|
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 will be the Last Subject Last Visit after 5 year follow up |
|
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 | 12 |
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 |