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


- candidate number12234
- NTR NumberNTR3392
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR12-apr-2012
- Secondary IDs40422 / 2012-001597-29; ABR / EudraCT
- Public TitleTumor uptake of ofatumumab and rituximab, labeled with 89Zirconium, in patients with malignant lymphoma.
- Scientific TitleTumor uptake of 89Zirconium-ofatumumab and 89Zirconium-rituximab in diffuse large B cell lymphoma
- ACRONYM
- hypothesisFor 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.
- Healt Condition(s) or Problem(s) studiedDiffuse large B cell lymphoma
- Inclusion criteriaPatients to be included must be before initiation of second-line treatment in or conform OMB 110928 study, meeting the following criteria (conform the inclusion criteria of OMB 110928 study protocol):
1. Patients have refractory or relapsed (see protocol for definition) CD20 positive DLBCL during or after first line treatment with rituximab combined with anthracycline-based chemotherapy, confirmed by biopsy after first line treatment;
2. Age 18 years or older;
3. Baseline 18F-FDG PET scan with positive lesions, compatible with CT defined anatomical tumor sites;
4. CT-scan showing at least one or more clearly demarcated lesions with a largest diameter larger or equal to 1.5 cm, or 1 clearly demarcated lesion with a largest diameter larger or equal to 2.0 cm (not previously irradiated);
5. ECOG performance status 0,1 or 2
6. Patients must be eligible for high dose chemotherapy and autologous stem cell transplantation;
7. Resolution of toxicities from first-line therapy to grade 1 or below;
8. Patients must be able to adhere to the study appointments and other protocol requirements;
9. Patients must be capable of giving written informed consent and the consent must have been obtained prior to the study related procedures.
- Exclusion criteriaPatients are excluded if they meet the following criteria (conform the exclusion criteria of OMB 110928 study protocol):
1. Any previous therapy for DLBCL, with the exception of first-line treatment with rituximab in combination with anthracycline-based chemotherapy, or radiotherapy as part of the first-line treatment plan or to a limited field at a maximum dose equal to or less than 10Gy to control life-threatening symptoms;
2. Received any of the following treatments within 4 weeks prior to start of trial therapy (unless otherwise stated): Anti-cancer therapy, radiotherapy (unless limited field at a maximum dose equal to or less than 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 enrolment (whichever is longer) or currently participating in any other interventional clinical study, glucocorticoid use, unless given in doses equal to or less than 100 mg/day hydrocortisone (or equivalent dose of other glucocorticoids) for < 7 days for exacerbations other than lymphoma (e.g. asthma);
3. Significant cerebrovascular disease;
4. Chronic or active infections with systemic treatment with antibiotics, antifungal or antiviral medication;
5. Other malignancy;
6. Prior treatment with monoclonal antibodies, with the exception of rituximab, within 3 months prior to start of the study;
7. Pregnancy or lactation;
8. Women of childbearing potential or male subjects, unable or unwilling to adhere to the adequate contraception conform study protocol.
- mec approval receivedyes
- multicenter trialno
- randomisedno
- groupParallel
- Type2 or more arms, non-randomized
- Studytypeobservational
- planned startdate 1-jun-2012
- planned closingdate1-apr-2015
- Target number of participants45
- InterventionsPatients 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.
- Primary outcomeThe detection of 89Zr-ofatumumab and 89Zr-rituximab in DLBCL tumor lesions:
1. Visual (present/absent);
2. Quantitative (measured in peak Standardized Uptake Value (SUVpeak)).
- Secondary outcome1. The detection of 18F-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.
- TimepointsImmuno-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.
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESDrs. Y.W.S. Jauw
- CONTACT for SCIENTIFIC QUERIES J.M. Zijlstra
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
VU University Medical Center, GlaxoSmithKline
- PublicationsN/A
- Brief summaryRationale:
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.
- Main changes (audit trail)
- RECORD12-apr-2012 - 22-sep-2012


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