A Phase I Study of MGAH22 in Patients With Refractory HER2 Positive Cancers

Background:

- MGAH22 is an experimental drug that has been designed to target cancer cells that make too much of a protein called human epidermal growth factor receptor 2 (HER2). Too much of this protein can turn a normal cell into a cancer cell and cause the cancer to grow faster. Some treatments have been successful at targeting HER2-positive cancer cells, particularly HER2-positive breast cancer, but these treatments have not been as effective for other types of HER2-positive cancers. MGAH22 is being tested to see if it is a safe and effective potential treatment for HER2-positive cancers that have not responded to standard treatments.

Objectives:

- To evaluate the safety and effectiveness of MGAH22 in treating HER2-positive cancers that have not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with HER2-positive breast cancer or other HER2-positive cancers (such as bladder, ovarian, lung, and prostate cancer) that have not responded to standard treatments.

Design:

• Participants will be screened with a physical examination, medical history, blood tests to evaluate current HER2 levels, imaging studies, and an electrocardiogram (ECG) to evaluate heart function.
• Participants must have stopped treatment with surgery, radiation, chemotherapy, and other test drugs at least 4 weeks before the start of this study. Treatment with monoclonal antibodies must have stopped about 3 months before the start of the study.
• This study will last at least 11 weeks, with about 13 office visits to the study doctor. The duration of the study will depend on the participant's response and benefit to the therapy.
• Participants will receive one dose of MGAH22 once a week for 4 weeks (a 28-day cycle of treatment). Blood samples will be taken on days 1, 2, 4, 5, 8, 15, and 22; urine samples will be taken on days 1 and 22. An echocardiogram will be performed on days 8, 15, and 22.
• Participants will have follow-up visits on days 29, 36, 43, and 50. Participants will be asked about side effects, provide blood samples (days 36, 43, and 50), have an imaging scan and ECG to evaluate tumor size and heart function (day 43), and have a physical exam (day 50).
• Participants who respond to the treatment and have no serious side effects may be eligible to continue taking the drug.

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.

• Non-Small Cell Lung Neoplasms
• Prostate Neoplasms
• Bladder Neoplasms
• Ovarian Neoplasms
• Breast Neoplasms

• Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF, Allison DE, Sliwkowski MX, Lieberman G, Kelsey SM, Fyfe G. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol. 2005 Apr 10;23(11):2534-43. Epub 2005 Feb 7.
• Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 2003 Jan 15;21(2):283-90.
• Clamon G, Herndon J, Kern J, Govindan R, Garst J, Watson D, Green M; Cancer and Leukemia Group B. Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B. Cancer. 2005 Apr 15;103(8):1670-5.

• INCLUSION CRITERIA:
• Patients of all races and ethnic origins will be eligible.
• Both men and women and members of all races and ethnic groups are eligible for this trial.
• Histologically or cytologically confirmed carcinoma that overexpresses HER2 byimmunohistochemistry (2+ or 3+ positivity by HercepTest or equivalent).
• Progressive disease during or after last treatment regimen.
• Appropriate treatment history for histological entity.

EXCLUSION CRITERIA:

-Participants under the age of 18 will be excluded from the study because adverse event data are not available for this age group with this therapy.