| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with relapsed CD20+ indolent NHL will be enrolled (Relapsed defined as; relapsed indolent lymphoma with documented history of response [CR, CRu, or PR) of≥6 months in duration from the completion of last rituximab containing regimen at some point in a patients treatment history). |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029547 |
| E.1.2 | Term | Non-Hodgkin's lymphoma |
|
| 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 investigate the overall response rate and safety data of RO5072759 (1000mg flat dose) given as monotherapy in patients with relapsed CD20+ indolent NHL compared with rituximab (375mg/m2) monotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To characterize the pharmacokinetics of RO5072759.
• To investigate if a shorter RO5072759 duration of infusion schedule is feasible (Phase II part of the study only).
• To investigate peripheral blood B-cell depletion and repletion with increasing doses of RO5072759.
• To obtain preliminary data on the anti-tumor efficacy of RO5072759 monotherapy compared with rituximab (375mg/m2) monotherapy (including the maintenance extended treatment regimen period) in patients with relapsed CD20+ indolent NHL by evaluating:
– overall response rate (ORR)
– progression- free survival (PFS)
– event-free survival (EFS)
• To investigate pharmacogenetic parameters (FcyRIIa and FcyRIIIa polymorphisms at baseline) and pharmacodynamic parameters (including but not limited to bcl-2 rearrangements, at baseline, during and after treatment) in relation to efficacy.
• To evaluate the feasibility of extended therapy with RO5072759.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients in the phase II (including those in the SDI) part of the study must meet the following criteria:
1. Have history of histologically confirmed CD20+, indolent B-cell NHL (any grade). This includes small lymphocytic lymphoma and marginal zone lymphoma but exclude B-CLL. For each patient, a prior biopsy demonstrating CD20 positivity of tumor cells must be available locally at the investigator site (review performed according to local standard procedures), prior to dosing, and will be further confirmed following central pathology review after dosing. A biopsy must be performed if transformation is suspected.
2. Have a clinical indication for treatment as determined by the investigator.
3. Relapsed disease with documented history of response (CR, CRu, or PR) of ≥6 months in duration from completion of last rituximab containing regimen. A rituximab-containing regimen is defined as rituximab as a single agent during induction and/or maintenance, or in combination with other agents during induction and/or maintenance.
4. All patients must have at least one bi-dimensionally measurable lesion (>1.5 cm in its largest dimension by computerized tomography [CT] scan). Note that all measurable and evaluable disease must be assessed and documented prior to initiation of RO5072759/rituximab treatment. Tumor response will be based on the status of all areas of disease.
5. ECOG performance status: of 0-2
All patients (Phase I and II) must also meet the following criteria to be eligible for study entry:
6. Able and willing to provide written informed consent and to comply with the study protocol
7. Age ≥18 years
8. Life expectancy of ≥12 weeks.
|
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from the study:
1. Prior use of any investigational monoclonal antibody within 6 months of study start.
2. Prior administration of rituximab within 56 days of study entry or 3 months for any radioimmunotherapy.
3. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products.
4. Central nervous system lymphoma or histological evidence of transformation to high grade or diffuse large B-cell lymphoma (if transformation is clinically suspected a re-biopsy is mandatory).
5. History of other malignancy which could affect compliance with the protocol or interpretation of results. Patients with a history of malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for ≥2 years prior to enrollment.
6. Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of symptomatic bronchospasm).
7. Known active bacterial, viral (including human immunodeficiency virus [HIV], ( HCV, HBV, HTLV I), fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (relating to the completion of the course of antibiotics) within 4 weeks of 1st dose of RO5072759 or rituximab.
8. Recent major surgery (within 4 weeks prior to screening), other than for diagnosis.
9. Unless clearly due to lymphoma any of the following abnormal laboratory values (Note 5% window allowed for inter-laboratory variation per protocol):
• Renal – Calculated creatinine clearance by Cockcroft-Gault formula ≤50 mL/min
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal.
• Platelet count <75 × 109/L.
• Neutrophils <1.5 × 109/L
• Hemoglobin <10g/dL
10. Presence of positive test results for any of the following: all of the first 5 tests should be done for all patients
• Human immunodeficiency virus (HIV)
• Hepatitis B (HB virus [B DNA], HB surface antigen [HBsAg], total HB core antibody [anti HB c])
• Hepatitis C [Hepatitis C virus [HCV] antibody serology testing.
• Human T-lymphotropic virus 1 [HTLV I] (in endemic countries only)
11. Women who are pregnant or lactating.
12. Fertile men or women of childbearing potential unless (1) surgically sterile or (2) using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly. Effective contraception is required throughout the study and (because of the long half-life of humanized monoclonal antibodies and the potential for prolonged lymphopenia) for at least 12 months after the last dose of RO5072759 or rituximab.
13. Ongoing corticosteroid use, with the exception of corticosteroid use for other indications, is permitted only up to a maximum dose of 30 mg/day prednisone or equivalent.
14. Treatment with an investigational agent or participation a clinical study 30 days prior to study day 1.
NOTE: Patients with cell counts below the thresholds listed above may be considered eligible if in the investigators opinion, the reason is believed to be due to bone marrow infiltration. Likewise patients may be considered for the study if liver or kidney function is impaired and this is believed to be due to lymphoma. The investigator will discuss the eligibility of such patients with the Sponsor and only upon approval (confirmed in writing) by the Sponsor will a patient be enrolled in the study.
Patients eligible for the exploratory SDI part of the study, must meet the entry criteria for Phase II (Please refer to Appendix 9 for more information).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for the phase II part of the study will be overall response rate. Overall response rate will be analyzed in frequency tables including 95% Pearson Clopper confidence intervals by dose group for the phase I part of the study and by treatment group for the phase II part of the study. (This is a secondary endpoint for the phase I part of the study.)
For the phase II part of the study, the hypothesis of no difference in overall response rate versus a larger overall response rate in RO5072759 over rituximab will be tested in the two randomized treatment arms using a one sided y2-test at an alpha level of 0.2 restricted to follicular NHL patients only.
|
|
| 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 | No |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploration of a Shorter RO5072759 Duration of Infusion (SDI). |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 | No |
| 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
|
| 2.5 years after the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
Print
