Trial Information

Hydralazine as Demethylating Agent in Breast Cancer

The objective of this study is to determine the MTD for hydrazaline added to standard
neoadjuvant chemotherapy for operable breast cancer. Four dose levels of hydrazalline are
planned:

Dose Level 1: 150 mg/d 50 mg PO TID Dose Level 2: 200 mg/d 50 mg PO QID Dose Level 3:
225 mg/d 75 mg PO TID

Patients will be treated in cohorts of 3 and no patient may be treated at more that one dose
level. Additional cohorts may not be initiated until toxicity has been fully evaluated in
the current cohort of patients. The MTD is exceeded when a dose level produces a dose
limiting toxicity (DLT) in at least two of the three patients in a cohort. Dose escalation
will proceed by increasing the dose according to the following table.

Number of Events/Number in Cohort Action 0/3 Proceed to
next dose level 1/3 Accrue 3 more patients at the same dose
1/3 + 0/3 Proceed to next dose level 1/3 + 1/3
Stop: Previous dose level is MTD 1/3 + 2/3 Stop: Previous dose
level is MTD 1/3 + 3/3 Stop: Previous dose level is MTD 2/3
Stop: Previous dose level is MTD 3/3
Stop: Previous dose level is MTD

If the MTD has been exceeded by dose escalation and only one cohort with no observed
toxicities was tested at the previous dose level, an additional cohort of 3 patients will be
tested at the previous dose level. Thus, six patients must be treated at the dose declared
the MTD. In the unlikely event that 150 mg/day of hydralazine, the starting dose, produces
two or more DLTs, the daily dose of hydralazine will be reduced by 50mg to100 mg/day. If
two or more toxicities are observed at this reduced dose level, the study will be stopped
and the phase II study will not be performed.

This phase I study will require between 9 to 24 patients. The cohort of six patients
treated at the MTD will be used in the subsequent phase II trial.

Definition of Dose Limiting Toxicities

Because the study drug is not a cytotoxic agent, is being "added" to a toxic chemotherapy
regimen in women likely to be normotensive, and because the drug has been evaluated in the
cardiovascular literature with maximum clinical doses at 300 mg/d, we made the following
decisions that deviate from classic "cytotoxic" agent schemes. The deviations are as
follows:

- Dose escalation beyond the "CLINNICALLY MAXIMAL" dose of 250 mg/d are not planned,
and

- The definition of a DLT will not adhere to the NCI CTC - designed for cytotoxic agents,
but will rather be simply the tolerability of the drug by the patient as documented in
the protocol and reproduced below:

1. Symptomatic hypotension,

2. Blood pressure recording of < 90 mmHg systolic, or <55 mgHg diastolic,

3. Other side effects deemed unacceptable either to the patient or the treating
physician, and

4. Patient request/refusal to continue on study.

Patients having to go off the drug will be considered as DLT events.