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Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies

Phase 1
18 Years
Not Enrolling
Neoplams, Advanced

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Trial Information

Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies

This is a Phase I dose escalation trial with escalating doses of Valproic acid and one dose
escalation step of epirubicin. VPA will be escalated starting at a dose that is recommended
for use as an anti-convulsant or to treat migraine headaches. Recommended concentrations for
seizure control is 15-60 mg/kg. Pharmacokinetic studies from healthy volunteers and patients
suggested a linear increase in plasma concentrations. A daily dosing of 16 mg/kg divalproex
(delayed-release VPA) resulted in a peak VPA plasma concentration of 127 μg/ml (~0.9 mM) 27.
The recommended Phase II dose of VPA was 60 mg/kg/d when given by a one-hour intravenous
infusion twice daily for 5 days every three weeks.

Synergistic activity between VPA and epirubicin has been observed at 0.5 mM of VPA in our
preclinical laboratory studies. Patients will receive an intravenous loading dose of VPA
followed by divalproex in two daily doses for 5 doses. The loading dose of VPA will avoid a
delay in peak plasma concentrations and excessive nausea. Epirubicin will be given by
infusion on day 3 after the last dose of divalproex.

Once the MTD for this two drug regimen has been determined, the maximum tolerated dose will
be determined as part of the FEC regimen (5-fluorouracil, epirubicin and cyclophosphamide).

Inclusion Criteria:

- Patients must have cytologically/histologically documented solid tumor malignancies

- Age > 18 years old

- Patients must have ECOG performance status 0-2

- Patients must be able to give informed consent and able to follow guidelines given in
the study

- The patient has no major impairment of hematological function, as defined by the
following laboratory parameters: WBC >3.0x109/L; ANC > 1.5 x 109/L; Hgb >9.0g/dL; PLT
>100x109/L (untransfused). Red blood cell transfusions and repeat evaluations for
study entry are allowed

- All patients of reproductive potential must use an effective method of contraception
during the study and six months following termination of treatment. (Not applicable
to patients with bilateral oophorectomy and/or hysterectomy or to female patients who
are older than 50 years and have not had a menstrual cycle in more than one year.

- Patients must have measurable or evaluable disease by staging studies performed
within 4 weeks of enrollment (evaluable disease refers to ovarian cancer with an
elevated CA-125 or prostate cancer with elevated PSA only)

- Once MTD for VPA and epirubicin is reached, the trial will be limited to patients
with breast cancer

- At the MTD for VPA and FEC MTD for the trial will be expanded to 15 patients with
advanced (inflammatory, Stage >IIIB or regional stage IV) or metastatic breast

- Patients must have biopsiable disease and be willing to undergo pre and post-VPA
biopsies in cycle 1; Patients must have measurable disease, Patients from the last
cohort may be included if they were biopsied

Exclusion Criteria:

- Patients may not have had cumulative anthracycline exposure greater than doxorubicin
300 mg/m2 or epirubicin 600 mg/m2.

- Patients must not have evidence of significant active infection (e.g., pneumonia,
cellulitis, wound abscess, etc.) at time of study entry.

- Patients must have adequate renal and normal hepatic function (creatinine < 1.5 x
upper limit of normal (ULN), bilirubin and SGOT (AST), SGPT (ALT) within 1.5 x the
upper institutional normal limits) obtained within 4 weeks prior to registration.

- Pregnant and breast feeding women are excluded from the study because effects on the
fetus are unknown and there may be a risk of increased fetal wastage.

- Women of childbearing age must have a negative pregnancy test and be willing
to use a highly effective method of contraception. Men who are sexually active must
also be willing to use an accepted and effective method of contraception.

- Patients taking anti-arrhythmic medication or with a history of cardiac failure or
with ejection fraction £ 50 % are excluded. Patients with a history of long QT
syndrome are excluded from study. Patients with a history of ventricular tachycardia
or fibrillation are also excluded. Patients must have normal sinus rhythm and normal
PR and QT intervals on EKG.

- Patients with uncontrolled CNS metastasis or a history of seizures are excluded.
Patients with stable CNS metastasis (either surgically resected, treated with gamma
knife or stable for 3 months following WBRT are eligible)

- Patients with stable brain metastases will need an MRI within 4 weeks prior to start
of therapy

Type of Study:


Study Design:

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

Outcome Measure:


Principal Investigator

Pamela Munster, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

March 2004

Completion Date:

April 2008

Related Keywords:

  • Neoplams, Advanced
  • Valproic Acid
  • Epirubicin
  • Solid Tumor
  • Malignancies
  • Neoplasms



H. Lee Moffitt Cancer Center & Research InstituteTampa, Florida  33612