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A Phase I Study of Herceptin/Flavopiridol in HER-2 Positive Metastatic Breast Cancer

Phase 1
18 Years
Not Enrolling
HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Thank you

Trial Information

A Phase I Study of Herceptin/Flavopiridol in HER-2 Positive Metastatic Breast Cancer


I. To evaluate the safety and tolerability of flavopiridol in combination with Herceptin in
HER-2 positive metastatic breast cancer.


I. To determine the dose of flavopiridol necessary to achieve a target plasma level of
300-500 nM of flavopiridol in combination with a fixed dose of Herceptin.

II. To assess the feasibility of measuring cyclin D1 in circulating tumor cells and tissue
biopsies before and after therapy as a surrogate marker of flavopiridol activity.

III. To monitor target activity of flavopiridol and Herceptin in plasma, circulating tumor
cells and tissue biopsies from breast cancer patients.

OUTLINE: This is a multicenter, dose-escalation study of flavopiridol.

Patients receive trastuzumab (Herceptin) IV over 30-90 minutes on days 1, 8, and 15 followed
by flavopiridol IV continuously over 24 hours on days 1 and 8. Courses repeat every 21 days
in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated
dose is determined (MTD). The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional
cohort of 10 patients receives flavopiridol at the MTD and trastuzumab on the once weekly
schedule to assess the true toxicity rate. A second cohort of 10 patients receives
flavopiridol at the MTD and trastuzumab once every 21 days to assess the tolerability of
this schedule.

PROJECTED ACCRUAL: A total of 30-50 patients will be accrued for this study.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed invasive breast cancer,
with stage IV disease; patients without pathologic or cytologic confirmation of
metastatic disease should have unequivocal evidence of metastasis by physical exam or
radiologic study

- Either the primary tumor or the metastasis must overexpress HER2; acceptable methods
of measurement of HER2 expression include immunohistochemistry (IHC) and fluorescence
in situ hybridization (FISH); tumors tested by IHC must be 3+ positive for HER2
overexpression using the DAKO Herceptest or the CB-11 antibody (recently FDA approved
for HER-2 testing); tumors tested by FISH must be positive by either the Vysis
Pathyvision method or the Ventana INFORM method; patients may have measurable or
evaluable disease

- Patients may have received 0-3 prior chemotherapeutic regimens for metastatic breast

- Patients may have received up to two prior Herceptin-containing regimens in the
metastatic setting

- Patients may have received prior radiation therapy in either the metastatic or early
stage settings; radiation therapy must be completed at least 7 days prior to study

- Patients may have received hormonal therapy (therapies) in the adjuvant or metastatic
setting; patients must discontinue hormonal therapy prior to study participation

- Life expectancy of greater than 6 months

- ECOG performance status < 2 (Karnofsky > 60%)

- Absolute neutrophil count >= 1,500/mm^3

- Platelets >= 100,000/mm^3

- Total bilirubin =< 1.5 mg/dl

- AST(SGOT)/ALT(SGPT) =< 3 X upper limit normal

- Creatinine =< 2.0 mg/dl

- LVEF >= 50%

- EKG no acute changes

- Patients may not receive concurrent hormonal therapy, chemotherapy, or radiation
treatments while on study; patients requiring radiation therapy during protocol-based
treatment will be taken off study with the exception of whole brain radiation or
stereotactic radiosurgery for brain metastases; protocol-based therapy will be held
during the therapy and for 1 week after treatment but may be resumed; patients may
not receive other experimental treatments while on study; patient receiving
bisphosphonates may continue to receive treatment while on study; patients may
initiate bisphosphonate therapy while on study provided that there has been no
evidence of progressive disease and that the bone sites do not constitute the only
sites of evaluable disease; if patients are on Lupron prior to the start of this
trial, than they must continue on Lupron throughout the course of this study

- Patients must be neither pregnant nor expect becoming pregnant or conceiving a child
while on study; women of child-bearing potential and men must agree to use adequate
contraception prior to study entry and for the duration of study participation;
should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had more than three chemotherapy regimens in the metastatic
setting, more than two Herceptin-containing regimens in the metastatic setting,
radiation therapy within 1 week prior to study entry, or those who have not recovered
from reversible adverse events due to prior treatments for cancer, are ineligible

- Patients with active brain metastases or leptomengingeal carcinomatosis are excluded
from this clinical trial; patients with a history of treated CNS metastases are
eligible if they do not have active symptoms from their CNS disease

- Patients with a history of grade 3 or 4 allergic reactions attributed to compounds of
similar chemical or biologic composition to the agents used in the study are
ineligible; patients who experienced grade 1 or 2 hypersensitivity reactions to prior
Herceptin are eligible IF these reactions did not prevent further administration

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements are ineligible

- Pregnant women are excluded from this study

- Patients with a contraindication to taking coumadin or other warfarin products are

Type of Study:


Study Design:

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

Outcome Measure:

MTD defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT) assessed using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2.0

Outcome Time Frame:

3 weeks

Safety Issue:


Principal Investigator

Lyndsay Harris

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

April 2002

Completion Date:

Related Keywords:

  • HER2-positive Breast Cancer
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male



Dana-Farber Cancer Institute Boston, Massachusetts  02115