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A Neoadjuvant Phase II Trial of GW572016 in HER2 Overexpressing Breast Cancer Patients: Biologic Correlative Study


Phase 2
18 Years
N/A
Not Enrolling
Female
Breast Cancer

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Trial Information

A Neoadjuvant Phase II Trial of GW572016 in HER2 Overexpressing Breast Cancer Patients: Biologic Correlative Study


The EGFR/HER family of transmembrane type I receptor tyrosine kinases are enzymes that play
an important role in fundamental cell processes like cell proliferation, differentiation,
and survival. These receptor tyrosine kinases, which include HER1 (epidermal growth factor
receptor, EGFR), HER2 (HER2/neu, c-erbB2), HER3 and HER4 contain an extracellular domain and
intracellular protein tyrosine kinase core. Aberrant HER1 and HER2 signaling has been
causally associated with cancer cell proliferation and survival.

HER1 is expressed or over-expressed in many human solid tumors and plays an important role
in progression to invasion and metastases.. The association between HER2 overexpression and
poor prognosis in node-positive and advanced breast cancer has been shown by a number of
studies. Based on this association between the members of HER1/HER2 family and worse
clinical outcome, antibodies and small molecules that specifically target these receptor
tyrosine kinases were developed for their therapeutic efficacy.

Trastuzumab (Herceptin) is a highly purified recombinant DNA-derived humanized monoclonal
antibody that selectively binds with high affinity to the extracellular domain of the HER2
receptor. Pivotal multicenter efficacy trials in metastatic patients showed improved
response rates and disease-free survival in patients who received trastuzumab in addition to
chemotherapy. One of these studies was an open-labeled, multicenter, randomized phase III
study evaluating the addition of trastuzumab to standard first-line chemotherapy in
metastatic breast cancer. This study randomized 469 patients with metastatic disease to
chemotherapy with or without trastuzumab. Results of this study showed survival in patients
who received trastuzumab plus chemotherapy to be almost twice as long as chemotherapy alone
(7.2 vs. 4.5 months, p<0.0001).

As dimerization is important in signal transduction, therapies that target more than one
member of the HER family may have greater anti-tumor effect. Recently, data with trastuzumab
plus IMC-C224 in human ovarian cancer cells showed greater growth inhibition compared to
either monoclonal antibody alone. GW572016 is an orally active dual HER1/HER2 kinase
inhibitor that blocks signal transduction pathways. This dual inhibition is an attractive
therapeutic strategy for epithelial cancers, as ligand-induced HER1/HER2 dimerization
triggers off potent proliferative and survival signals. In vitro studies with GW572016 have
shown marked activity, leading to growth arrest and apoptosis in HER1 and HER2
overexpressing cell lines. GW572016 markedly reduced tyrosine phosphorylation of HER1 and
HER2, and activation of MAP kinase and Akt, the downstream effectors of proliferation and
survival, respectively. In vitro studies in HER-2 overexpressing cell lines have
demonstrated synergistic activity when GW572016 is combined with taxanes. Phase I studies
with GW572016 and taxanes have been completed, with results demonstrating that this small
molecule inhibitor may be safely combined with chemotherapy with no unanticipated side
effects.

The EGFR/HER family of transmembrane type I receptor tyrosine kinases are enzymes that play
an important role in fundamental cell processes like cell proliferation, differentiation,
and survival. These receptor tyrosine kinases, which include HER1 (epidermal growth factor
receptor, EGFR), HER2 (HER2/neu, c-erbB2), HER3 and HER4 contain an extracellular domain and
intracellular protein tyrosine kinase core. Aberrant HER1 and HER2 signaling has been
causally associated with cancer cell proliferation and survival.

Trastuzumab (Herceptin) is a highly purified recombinant DNA-derived humanized monoclonal
antibody that selectively binds with high affinity to the extracellular domain of the HER2
receptor. Results of this study showed survival in patients who received trastuzumab plus
chemotherapy to be almost twice as long as chemotherapy alone (7.2 vs. 4.5 months,
p<0.0001).

In vitro studies with GW572016 have shown marked activity, leading to growth arrest and
apoptosis in HER1 and HER2 overexpressing cell lines. GW572016 markedly reduced tyrosine
phosphorylation of HER1 and HER2, and activation of MAP kinase and Akt, the downstream
effectors of proliferation and survival, respectively. In vitro studies in HER-2
overexpressing cell lines have demonstrated synergistic activity when GW572016 is combined
with taxanes. Phase I studies with GW572016 and taxanes have been completed, with results
demonstrating that this small molecule inhibitor may be safely combined with chemotherapy
with no unanticipated side effects.

As the type I tyrosine kinases are involved in various aspects of cell growth and survival,
a potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecule (GW572016) against HER1
and HER2 was developed which showed potent in vitro inhibition of HER1 and HER2 in tumor
cell lines. Mouse xenograft models of BT474 and HN5 cell lines also showed growth inhibition
in a dose-responsive manner. In addition, GW572016 caused a reduction in HER1 and HER2
autophosphorylation, indicating interference of this signaling pathway. GW572016 not only
inhibited baseline activation of HER1 and HER2, but also has been shown to interrupt
downstream activation of Erk1/2 MAP kinases and Akt.

HER1 is expressed or over-expressed in many human solid tumors and plays an important role
in progression to invasion and metastases.. The association between HER2 overexpression and
poor prognosis in node-positive and advanced breast cancer has been shown by a number of
studies. Based on this association between the members of HER1/HER2 family and worse
clinical outcome, antibodies and small molecules that specifically target these receptor
tyrosine kinases were developed for their therapeutic efficacy.

Trastuzumab (Herceptin) is a highly purified recombinant DNA-derived humanized monoclonal
antibody that selectively binds with high affinity to the extracellular domain of the HER2
receptor. Pivotal multicenter efficacy trials in metastatic patients showed improved
response rates and disease-free survival in patients who received trastuzumab in addition to
chemotherapy. One of these studies was an open-labeled, multicenter, randomized phase III
study evaluating the addition of trastuzumab to standard first-line chemotherapy in
metastatic breast cancer. This study randomized 469 patients with metastatic disease to
chemotherapy with or without trastuzumab. Results of this study showed survival in patients
who received trastuzumab plus chemotherapy to be almost twice as long as chemotherapy alone
(7.2 vs. 4.5 months, p<0.0001).

We have completed the first single-agent neoadjuvant trastuzumab study in human breast
cancer. The specific aims of this study were to firstly, define the clinical efficacy of
trastuzumab, and secondly, to determine its mechanism of action in human breast cancer
specimens. From September 1999 to June 2003, 27 patients with HER2 overexpressing locally
advanced breast cancer with or without gross metastatic disease, were considered for a phase
II study with neoadjuvant trastuzumab. At presentation, the median tumor size was large at
8x8 cm2 (range 4x4 cm2 to 25x20 cm2). We did not expect measurable evidence of tumor
regression with this short treatment duration. However, regression in the product of
bidimensional tumor measurements with a median decrease of -20.0% (range 0, -60.4%,
p=0.0001) was observed in primary tumors after only 3 weeks of single agent trastuzumab.
Most surprisingly, partial response was observed in 26% (7/27). Minor response was seen in
44% (12/27), and stable disease in 30% (8/27). No tumors increased in size during this
3-week period.

This is the first neoadjuvant trastuzumab monotherapy study in treatment-naive patients with
HER2 overexpressing breast cancers. The clinical efficacy with tumor reductions in some
patients presenting with large initial tumors indicates that the monoclonal antibody can be
safely administered as a single agent without fear of tumor progression. When the study was
first started, the uncertainty of the clinical efficacy of neoadjuvant single agent
trastuzumab limited its duration to 3 weeks. It seems likely that the true response rate
would have been higher if therapy was continued for several months. Based on these data,
longer treatment durations of HER2 targeted therapy, like with GW572016, given as a single
agent should be investigated in clinical trials with careful monitoring of patients to
assess its activity in this setting.

Aim 1: To demonstrate the clinical efficacy of GW572016 when given as neoadjuvant therapy as
a single agent in patients with treatment-naive, locally advanced HER2 overexpressing breast
cancer. We aim to discover the true response rate to inhibiting HER1/2 signal transduction
with GW572016 in breast cancer patients.

Aim 2: To determine if GW572016 inhibits HER1 and HER2 signaling in situ.The mechanism of
therapeutic action of GW572016 is not fully understood.


Inclusion Criteria:



1. All patients must be female.

2. Signed informed consent.

3. Locally advanced breast cancers or primary breast cancers with concomitant gross
metastatic disease are eligible. Locally advanced cancers must be of clinical and/or
radiologic size >/- 5 cm, and/or are deemed surgically inoperable, with Stage IIIb,
IIIc, or IV disease.

4. HER2 overexpressing tumors defined as HercepTest score of 3+, or >/- 10% cells
moderately or strongly HER2 positive by other methods, or semi-quantitative score of
>/- 5 (in Dr. Allred's laboratory) or gene amplified.

5. Negative serum pregnancy test (BHCG) within 7 days of starting study, if of
child-bearing potential.

6. Kidney and liver function tests - all within 1.5 times the institution's upper limit
of normal.

7. Performance status (WHO scale) less than 2 and life expectancy greater than 6 months.

8. Age greater than 18 years.

9. No brain or leptomeningeal disease.

10. No previous or current malignancies at other sites within the last 5 years, with
exception of adequately treated core-biopsied in situ carcinoma of the cervix uteri
and basal or squamous cell carcinoma of the skin.

Exclusion Criteria:

1. Pregnancy or unwillingness to use a reliable contraceptive method in women of
child-bearing potential.

2. Severe underlying chronic illness or disease.

3. Cardiomyopathy or baseline LVEF <50%.

4. Other investigational drugs while on study.

5. Severe or uncontrolled hypertension, history of congestive heart failure or severe
coronary arterial disease.

6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with ulcerative colitis are also
excluded.

7. Taking any GW572016-prohibited medication (see GW572016 Prohibited Medications List
in protocol) within 7 days of first dose of study medications.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical Response

Outcome Description:

Clinical efficacy was assessed by bidimensional tumor measurements of the primary cancer at baseline, and at the end of week 6. Clinical complete response (cCR) was defined as complete disappearance of the primary tumor. Clinical partial response (cPR) was defined as a decrease by at least 50% of the sum of the products of the largest perpendicular diameters. An increase of more than 25% was defined as clinical progressive disease (cPD). Any response that does not meet the definition of cCR, cPR, or cPD was defined as stable disease (cSD).

Outcome Time Frame:

at the end of week 6.

Safety Issue:

No

Principal Investigator

Mothaffar Rimawi, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor Breast Center

Authority:

United States: Food and Drug Administration

Study ID:

H 15430

NCT ID:

NCT00206427

Start Date:

August 2004

Completion Date:

February 2012

Related Keywords:

  • Breast Cancer
  • Advanced
  • Breast
  • Cancer
  • Neoadjuvant
  • HER2
  • Breast Neoplasms

Name

Location

USC Norris Comprehensive Cancer CenterLos Angeles, California  90089
University of New MexicoAlbuquerque, New Mexico  87131
Baylor Breast CenterHouston, Texas  77030