A phase Ib, multicenter, open-label study of HCD122 administered intravenously in combination with bendamustine in patients with CD40+ follicular lymphoma who are refractory to rituximab

Follicular lymphoma (FL) is the most common indolent non-Hodgkin*s lymphoma
(NHL) and the second most common form of NHL worldwide
Therapy options for symptomatic patients after initial diagnosis include
chemotherapy, rituximab monotherapy, rituximab and chemotherapy, or
radioimmunotherapy (National Comprehensive Cancer Network [NCCN] guidelines
v.1.2010).
Upon clinical relapse or for nonresponsive disease, second-line treatment
options include rituximab plus chemotherapy (e.g. R-CHOP, R-CVP),
fludarabine-based chemotherapy, bendamustine, or high-dose chemotherapy with
autologous or allogeneic stem-cell rescue.
The anti-CD20 monoclonal antibody, rituximab, has been a valuable addition to
the treatment of B-cell NHL and has improved response rates in FL. However,
50% of patients with relapsed or refractory CD20-positive FL do not respond to
initial therapy with rituximab, and approximately 60% of patients who were
previously treated with rituximab no longer benefit from retreatment (Tay et al
2010). The alkylating agent, bendamustine, was recently approved as a single
agent for rituximab-refractory NHL, and is an effective treatment option for
indolent B-cell NHLs that are refractory to rituximab (Friedberg et al 2008a,
Kahl et al 2010). In the first-line setting, preliminary studies with
bendamustine plus rituximab demonstrate improved progression free survival
(PFS) and complete response (CR) rates compared with R-CHOP (Rummel et al 2009).
Although the introduction of these new agents and regimens for the treatment of
NHL has resulted in improved CR rates and survival rates in some settings, the
lack of any significant improvement in overall survival indicates a continued
need for novel drugs and interventions (Tay et al 2010).

Objective
Primary
Dose escalation phase only: To determine the MTD of HCD122 when administered in
combination with bendamustine
Dose expansion phase only: To assess the safety and tolerability of HCD122 in
combination with bendamustine

Secondary
Dose escalation phase only: To assess the safety and tolerability of HCD122 in
combination with bendamustine
To assess the preliminary anti-tumor activity of HCD122 in combination with
bendamustine
To characterize the PK profile of HCD122 and bendamustine
To assess the immunogenicity of HCD122

Exploratory
To assess Fc*RIIIa polymorphism status
To assess CD40 expression levels
Dose expansion phase only: To characterize CD40 occupancy of HCD122 on
peripheral CD19+ B cells
To investigate candidate markers predictive of response found in blood and
malignant lymphoid tissue
To investigate if post-treatment pharmacodynamic changes in blood inflammatory
and immune markers correlate with clinical response
To explore candidate pharmacodynamic markers, cellular response markers, and
gene expression changes in malignant lymphoid tissue pre- and post-treatment

This phase Ib, multicenter, open-label study will investigate the safety,
pharmacokinetics, pharmacodynamics, and preliminary efficacy of HCD122 in
combination with bendamustine in patients with CD40+ FL that is refractory to
treatment with rituxmab.
In dose escalation (n=15-30), successive cohorts of newly enrolled patients
will receive increasing doses of HCD122 in combination with bendamustine until
the MTD of HCD122 is determined (Figure 3-1). Once the MTD has been
established, additional patients will be enrolled into the dose expansion phase
of the study to better characterize the safety, tolerability, and make a
preliminary assessment of anti-tumor activity of the combination. A minimum of
20 total patients (escalation + expansion) will be treated at the MTD.
DLTs that will primarily contribute to the determination of the MTD will be
identified during cycle 1 of dose escalation (Section 5.1.2.6). All patients
will remain on treatment until disease progression, unacceptable toxicity, or
patient withdrawal.

HCD122 infusion will be administered once every 14 days at the assigned dose
(during dose escalation) or at the MTD (during dose expansion). Bendamustine
infusion will be administered on the first two days of each 28-day combination
treatment cycle.

Toxicity of the combination-therapy and HCD122 Bendamustine
- Radiation exposure of CT scan / MRI
-Frequent visits and blood sampling
- (optional) tumorbiopsy
-Bone marrow punction (if necessary)

An overview of all visits during the procedure are given in Appendix B of the
patient information.
The side effects can be found in Appendix C of the patient information.
It is not certain that participation in the study will lead them directly
benefit the patient, the data can be useful for the future.
The burden on the patients is as expected from a Phase 1 study.