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A Phase II Open Label Trial of PF-00299804 Monotherapy in Patients With HER-2 Positive Advance Gastric Cancer After Failure of At Least One Prior Chemotherapy Regimen

Phase 2
18 Years
Not Enrolling
Advanced Gastric Cancer, HER2

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Trial Information

A Phase II Open Label Trial of PF-00299804 Monotherapy in Patients With HER-2 Positive Advance Gastric Cancer After Failure of At Least One Prior Chemotherapy Regimen

The role of HER-2 during carcinogenesis and its prognostic role in breast cancer has been
already well established. Furthermore the value of HER-2 as a reasonable therapeutic target
in breast cancer has translated into the good clinical therapeutic result using HER-2
targeting agent, such as trastuzumab and lapatinib.

In case of gastric cancer, the incidence of HER-2 positivity (2+, 3+ on IHC and/or FISH (+))
is reported as similar as that of breast cancer, that is 22% of all cases. A recent ToGA
Trial, phase III trial comparing trastuzumab combined with chemotherapy
(fluoropyrimidine+cisplatin) versus chemotherapy alone in chemotherapy-naïve HER-2 (+)
gastric cancer shows the significant benefit of using trastuzumab in terms of overall
survival and progression-free survival. It provides the clinical evidence of HER-2 as a
reasonable and potential therapeutic target in gastric cancer.

Nowadays, lapatinib, HER-1 and HER-2 dual inhibitor, is also testing under the clinical
trial in gastric cancer.

PF-00299804 is an orally available, potent, and highly selective irreversible small molecule
inhibitor of the Human Epidermal Growth Factor Receptor (HER) family of tyrosine
kinases:HER-1 (EGFR), HER-2 and HER-4 (HER-3 does not possess kinase activity). PF-00299804
inhibits the tyrosine kinase activity of the HER family through binding at the ATP binding
site, which results in covalent modification of a cystine in the ATP binding pocket. The
unique irreversible and highly selective properties of PF-00299804 for the HER kinase family
results in sustained suppression of receptor tyrosine kinase activity. The long-lasting
inhibition of receptor phosphorylation reduces concern over potentially short plasma
half-lives. Furthermore, the low nanomolar potency and irreversible binding of the intended
targets reduce the need for high peak plasma levels, which in turn could minimize
target-nonspecific toxicities.

In preclinical study, PF-00299804 is highly active in HER-2 amplified gastric cancer cell
lines.(SNU preclinical data)

Overall, the standard of care for advanced gastric cancer has been of modest benefit with
plateau in response rates using various combination chemotherapies. Therefore, development
of treatment options for these advanced gastric cancer patients, especially HER-2 (+)
gastric cancer patients, remains a target of active research.

So, the investigators plan this phase II trial of PF-00299804 monotherapy in patients with
HER-2 positive advance gastric cancer after failure of at least one chemotherapy regimen.

Inclusion Criteria:

- Age > 18 years

- A patient who is able to walk and should have ECOG performance status of 0-2.

- Histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction
with inoperable locally advanced or recurrent and/or metastatic disease, not amenable
to curative therapy.

- HER2 positive tumour (primary tumour or metastasis defined as 1) 3+ on IHC and/or 2)
FISH (+)

- Failure to at least one chemotherapy regimen

* trastuzumab or lapatinib-pretreated patient is eligible

- Measurable or non-measurable-evaluable disease according to the Response Evaluation
Criteria in Solid Tumors (RECIST)

- Adequate bone marrow function, including:

- Adequate renal function, including:

- Adequate liver function, including:

- Adequate Cardiac Function, including:

1. 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically
significant changes that do not require medical intervention;

2. QTc interval 470 msec and without history of Torsades de Pointes or other
symptomatic QTc abnormality;

3. LVEF (by MUGA or echocardiogram) of ≥50%.

- Brain metastasis allowed if any necessary treatment has been completed and the
patient is radiologically and neurologically stable off corticosteroids at least 2
weeks prior to enrollment

- A patient with the willingness to comply with the study protocol during the study
period and capable of complying with it.

- A patient who signed the informed consent prior to the participation of the study and
who understands that he/she has a right to withdrawal from participation in the study
at any time without any disadvantages.

Exclusion Criteria:

- Patients with known active brain metastases or any leptomeningeal metastases;

a. Patients with previously diagnosed brain metastases for which treatment (radiation
or surgery) is recommended in judgment of investigator are eligible if they have
completed their CNS treatment and have recovered from the acute effects of radiation
therapy or surgery prior to the start of study medication, have discontinued
corticosteroid treatment for these metastases for at least 2 weeks and are
neurologically stable.

- Radiotherapy (other than palliative radiotherapy to lesions that will not be followed
for tumor assessment on this study, ie, non-target lesions), biological or
investigational agents within 2 weeks of baseline disease assessments

- Any surgery (not including minor procedures) within 4 weeks of baseline disease
assessments; or not fully recovered from any side effects of previous procedures;

- Any clinically significant gastrointestinal abnormalities, which may impair intake,
transit or absorption of the study drug, such as the inability to take oral
medication in tablet form;

- Current enrollment in another therapeutic clinical trial;

- Any psychiatric or cognitive disorder that would limit the understanding or rendering
of informed consent and/or compromise compliance with the requirements of this

- Patients with known interstitial lung disease;

- Uncontrolled or significant cardiovascular disease

- Prior malignancy: Patients will not be eligible if they have evidence of other
malignancy (other than non-melanoma skin cancer or in situ cervical cancer, or
localized and presumed cured prostate cancer with PSA < ULN) within the last 5 years.

- Organ allogenic transplantation requiring immunosuppressive therapy.

- A patient who developed uncontrolled serious infection or other uncontrolled serious
concomitant diseases.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

progression-free survival at 4-months (PFS4mo)

Outcome Description:

PFS is defined as the interval from the date of enrollment to the date of disease progression or death due to any cause, whichever occurs first. PFS4m is defined as the proportion of patients alive and progression-free at 4 months relative to all enrolled patients.

Outcome Time Frame:

10 months

Safety Issue:


Principal Investigator

Yung-Jue Bang, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Seoul National University Hospital


Republic of Korea: Food and Drug Administration

Study ID:




Start Date:

July 2010

Completion Date:

June 2012

Related Keywords:

  • Advanced Gastric Cancer
  • HER2
  • advanced gastric cancer
  • HER2
  • PF00299804
  • Stomach Neoplasms