Tumor uptake of ofatumumab and rituximab, labeled with 89Zirconium, in patients with malignant lymphoma.

Rationale:

For patients with a diffuse large B cell lymphoma (DLBCL) the efficacy of the anti-CD20 monoclonal antibody rituximab combined with salvage chemotherapy in the second-line setting has decreased due to more effective first-line treatment with rituximab containing chemo-immunotherapy. We hypothesize that ofatumumab, a second generation anti-CD20 monoclonal antibody with a different binding site, has a better efficiency of tumor targeting and can overcome relative or complete rituximab resistance, improving response rates.



Objectives:

The primary objective is:

1. To compare the biodistribution and uptake in DLBCL of 89Zirconium (89Zr)-ofatumumab and 89Zr-rituximab (visual and quantitative).

The secondary objectives are:

1. To compare the biodistribution and uptake in DLBCL of 89Zr-ofatumumab and 89Zr-rituximab with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) (visual and quantitative);

2. To quantify biodistribution and dosimetry in normal tissue of 89Zr-ofatumumab and 89Zr-rituximab;

3. To investigate whether increased uptake in DLBCL on immuno-positron emission tomography (immuno-PET) is associated with clinical efficacy.



Study design:

Pilot study.



Study population:

45 patients with DLBCL, treated in or conform the OMB110928 study (15 in the ofatumumab arm, 30 in the rituximab arm). OMB 110928 study is a phase III, parallel group, randomised, registration trial of ofatumumab versus rituximab in addition to salvage chemotherapy.



Intervention:

Patients will be injected with 10 mg 89Zr-ofatumumab (74 MBq) or 10 mg 89Zr-rituximab (74 MBq) intravenously, on the first day of the second-line treatment with respectively ofatumumab or rituximab plus chemotherapy. Immuno-PET scans will be obtained at 1, 72 and 144 hours post injection. A 18F-FDG PET scan, conform the OMB 110928 protocol, will be performed within a maximum interval of 2 weeks before the first immuno-PET scan. Patients will undergo blood sampling for pharmocokinetic purposes.



Main study parameters/endpoints:

The primary endpoint is:

1. The detection of 89Zr-ofatumumab and 89Zr-rituximab in DLBCL tumor lesions:

A. Visual (present/absent);

B. Quantitative (measured in peak Standardized Uptake Value (SUVpeak)).

The secondary endpoints are:

1. The detection of FDG in DLBCL tumor lesions:

A. Visual (present/absent);

B. Quantitative (in SUVpreak).

2. The detection of 89Zr-ofatumumab and 89Zr-rituximab in normal tissue:

A. Visual: description of biodistribution;

B. Quantitative (% uptake (of total injected) 89Zr-ofatumumab and 89Zr-rituximab, calculated residence times and calculated organ absorbed doses for 89Zr-ofatumumab and 89Zr-rituximab).

3. Clinical outcome:

A. In categories: complete remission, partial remission, stable disease or relapsed/progressive disease, using the Revised Response Criteria for Malignant Lymphoma (RRMCML) for disease assessment, assessed by CT after the second cycle of therapy / by PET performed after the third cycle of therapy, conform OMB110928 study protocol.

Other study parameters:

1. Pharmacokinetics of 89Zr-ofatumumab and 89Zr-rituximab;

2. Assessment of (89Zr-ofatumumab SUVpeak / 18F-FDG SUVpeak) and (89Zr-rituximab SUVpeak / 18F-FDG SUVpeak ) for the five tumor lesions with the highest antibody uptake.



Nature and extent of the burden and risks associated with participation, and benefit:

Patients will be asked for 2 extra visits to obtain PET-scans and blood samples. The risk level according to the ICRP-62 model is stated as Category III “moderate”(effective doses greater than 10mSv (adults), while the social benefit is regarded as “substantial”. Patients do not require shielding after injection of 89Zr-labeled ofatumumab or rituximab.

For patients with a diffuse large B cell lymphoma (DLBCL) the efficacy of the anti-CD20 monoclonal antibody rituximab combined with salvage chemotherapy in the second-line setting has decreased due to more effective first-line treatment with rituximab containing chemo-immunotherapy. We hypothesize that ofatumumab, a second generation anti-CD20 monoclonal antibody with a different binding site, has a better efficiency of tumor targeting and can overcome relative or complete rituximab resistance, improving response rates.

Immuno-PET scans obtained 1 hour, 72 hours and 144 hours post injection of 89Zirconium-ofatumumab or 89Zirconium-rituximab.



CT after the second cycle of therapy / by PET performed after the third cycle of therapy, conform OMB110928 study protocol.

Patients will be injected with 10 mg 89Zr-ofatumumab (74 MBq) or 10 mg 89Zr-rituximab (74 MBq) intravenously, on the first day of the second-line treatment with respectively ofatumumab or rituximab plus chemotherapy. Immuno-PET scans will be obtained at 1, 72 and 144 hours post injection. A 18F-FDG PET scan, conform the OMB 110928 protocol, will be performed within a maximum interval of 2 weeks before the first immuno-PET scan. Patients will undergo blood sampling for pharmocokinetic purposes.