Trial Information

A Phase 1, Dose Escalation Study of MGAH22 (Fc-Optimized Chimeric Anti-HER2 Monoclonal Antibody) in Patients With Refractory HER2 Positive Breast Cancer and Patients With Other HER2 Positive Carcinomas for Whom no Standard Therapy is Available

Background:

- HER-2/neu has proved to be an excellent target for cancer therapeutics with the success
of the monoclonal antibody, trastuzumab.

- While trastuzumab appears to alter growth factor receptor signaling leading to growth
inhibition or apoptosis, there is increasing evidence in laboratory animals and from
the clinic that an important mechanism of trastuzumab's action is induction of antibody
dependent cellular cytotoxicity (ADCC).

- Musolino et al. demonstrated that the FcGammaRIIIa (CD16A, an activating Fc receptor)
-158V/V genotype (significantly) and the FcGRIIa (CD32A, an activating Fc receptor)
-131H/H genotype (trend) were associated with superior outcome in patients treated with
trastuzumab-based therapy.

Because the higher affinity alleles of CD16A and CD32A are less frequent in the population
than the lower affinity alleles, these observations suggest that anti-HER2 antibodies, such
as MGAH22, engineered to have increased affinity for the activating Fc receptors and in
particular the low binding alleles of the activating Fc receptors may have increased
clinical activity and should be pursued.

Primary Objective:

-To determine the toxicity profile of four once-weekly intravenous (IV) doses of MGAH22.

Secondary Objectives:

- To determine the maximum tolerated dose (MTD) of four once-weekly doses of MGAH22

- To characterize the pharmacokinetics (PK) and immunogenicity of four once weekly doses
of MGAH22

- To describe any preliminary evidence of anti-tumor activity

- To evaluate the safety, definitive PK, immunogenicity, and preliminary efficacy in
patients treated with MGAH22 at the MTD dose/schedule

- To evaluate the feasibility, safety, immunogenicity, pharmacokinetics, and preliminary
activity of MGAH22 administered every 3 weeks at multiples of the MTD

- To explore the relationship between Fc receptor polymorphisms; changes in immune cell
subsets, serum cytokines, circulating HER2 levels, antibody dependent cellular
cytotoxicity (ADCC) activity, Fc receptor occupancy and the safety profile and activity
of MGAH22.

Eligibility:

- Histologically or cytologically confirmed carcinoma that over expresses HER2 by
immunohistochemistry (2+ or 3+ positivity by Hercep Test or equivalent).

- Progressive disease during or after last treatment regimen.

- Appropriate treatment history for histological entity.

Study Design:

- MGAH22 will be administered by IV infusion.

- All patients participating in the Dose Escalation and the MTD Cohort Expansion Segments
will receive MGAH22 once a week for 4 weeks during Cycle 1 (Study Days 1, 8, 15, and
22). Patients participating in the Intermittent Dosing Segment will receive MGAH22
every 3 weeks during Cycle 1 (Study Days 1 and 22).

- Disease status will be evaluated on Study Day 43 using computed tomography (CT)
techniques as well as physical examination.

- Patients with evidence of disease regression will be allowed to continue therapy.
Subsequent cycles, which should begin on Study Day 50, will be 28-day cycles with
antibody treatment on Study Days 1, 8, and 15 of each cycle (Dose Escalation and MTD
Cohort Expansion Segments) or 21-day cycles with antibody treatment on Day 1 of each
cycle (Intermittent Dosing Segment), with tumor evaluation every other cycle. Patients
with evidence of disease regression may receive continued antibody therapy until
evidence of progression of disease is documented.