A phase II study of obinutuzumab monotherapy in rituximab-refractory follicular lymphoma

Given the preclinical data demonstrating superior antibody-dependent cellular
cytotoxicity (ADCC) and direct cell death induction with obinutuzumab when
compared with rituximab, it is hypothesized that obinutuzumab can provide
clinical benefit in rituximab-refractory patients. This will be the first study
to assess the response rate of obinutuzumab monotherapy in patients with
rituximab-refractory follicular lymphoma.
In addition we will investigate immuno-PET with 89Zr -obinutuzumab as a
potential predictive imaging biomarker to select patients who will benefit from
obinutuzumab, in an early stage. This study will provide insight in the
feasibility of 89Zr-obinutuzumab PET and provide information for future studies
with 89Zr-obinutuzumab.

The primary objective is:
* To determine the overall response rate (ORR) of 4 weekly infusions of
obinutuzumab monotherapy (Induction I) in patients with rituximab-refractory
follicular lymphoma.
The secondary objectives are:
* To determine the efficacy (defined as progression free survival, overall
survival, duration of response, duration of stable disease, time to next
treatment) of obinutuzumab monotherapy given as 4 weekly infusions to
rituximab-refractory follicular lymphoma patients
* To determine the efficacy (defined as ORR, progression free survival, overall
survival, duration of response, duration of stable disease, time to next
treatment) of obinutuzumab monotherapy given as 4 monthly infusions (Induction
II) to rituximab-refractory follicular lymphoma patients responding to 4 weekly
infusions of obinutuzumab monotherapy
* To determine the efficacy (defined as progression free survival, overall
survival, duration of response, duration of stable disease, time to next
treatment) of obinutuzumab maintenance given as bimonthly infusions (up to a
maximum of 2 years) to rituximab-refractory follicular lymphoma patients
responding to 4 weekly infusions of obinutuzumab monotherapy (Induction I),
followed by 4 monthly infusions of obinutuzumab monotherapy (Induction II).
* To investigate the relationship between tumour uptake on immuno-PET and
tumour response to obinutuzumab
* To compare tumour uptake using immuno-PET as a novel imaging biomarker to
*standard imaging technique* (18F-FDG-PET/CT)
* To determine the value of 18F-FDG-PET-CT scanning in response assessment of
follicular lymphoma patients
* To investigate the biodistribution and dosimetry in normal tissue of
89Zr-obinutuzumab
* To assess safety data by monitoring all adverse and serious adverse events
(AEs/SAEs) according to the NCI CTCAE v.4.

Phase II, single-cohort, non-blinded, single-agent, interventional single
center study. The Simon two-stage design will be used: 12 to 25 eligible
patients will be included in the study, according to the number of responses
observed. The total study duration is approximately 37 months.

Induction I: treatment with obinutuzumab:
- week 1day 0 (100mg)
- week 1 day 1 (900 mg) + 10mg 89Zr-obinutuzumab
- week 2 day 1(1000mg)
- week 3 day 1 (1000mg)
- week 4 day 1 (1000mg)

For patients with clinical benefit of study treatment (defined as complete
remission, partial remission or stable disease on PET-CT in week 10-12):
Induction II: treatment with obinutuzumab
- month 3 (1000mg)
- month 4 (1000mg)
- month 5 (1000mg)
- month 6 (1000mg)

For patients with ongoing clinical benefit of study treatment (defined as
complete remission, partial remission or stable disease on PET-CT in month 6,
CT in month 9 and 12)
Maintenance treatment with 1000mg obinutuzumab bimonthly, for a maximum of 2
years.

Upon enrollment of this study a baseline FDG-PET-CT scan will be obtained.
Patients are scheduled for 5 treatment visits, where obinutuzumab will be
administered intravenously. Patients with clinical benefit of study treatment
are eligible for continuation of study treatment. During therapy and follow-up,
patients are scheduled for standard laboratory analysis and PET/CT scans on
visits to the outpatient clinic. The exposure to ionizing radiation is
non-neglible, but patients may have clinical benefit by study treatment.