Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies
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|ClinicalTrials.gov Identifier: NCT00246103|
Recruitment Status : Completed
First Posted : October 30, 2005
Last Update Posted : February 23, 2017
|Condition or disease||Intervention/treatment||Phase|
|Neoplasms, Advanced||Drug: Valproic acid Drug: Epirubicin Drug: 5-fluorouracil Drug: Cyclophosphamide.||Phase 1|
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).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||82 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies|
|Study Start Date :||March 2004|
|Actual Primary Completion Date :||April 2008|
|Actual Study Completion Date :||April 2008|
Experimental: Dose Escalation and Possible Expansion
Escalating doses of Valproic acid and one dose escalation step of epirubicin. Participants with breast cancer treated at the maximum tolerated dose, will also be treated with 5-fluorouracil and Cyclophosphamide.
Drug: Valproic acid
Beginning Dose, Level 1: 15 mg/kg/day.
Beginning Dose, Level 1: 75 mg/m^2.
Other Name: Ellence
For breast cancer participants treated at MTD of Valproic acid and Epirubicin: 5-fluorouracil 500 mg/m^2.
Other Name: 5-FU
For breast cancer participants treated at MTD of Valproic acid and Epirubicin: cyclophosphamide 500 mg/m^2.
Other Name: CYTOXAN®
- Maximum Tolerated Dose (MTD) [ Time Frame: Up to 2 months ]MTD of Valproic acid in combination with Epirubicin. The maximum tolerated dose (MTD) will be defined as the highest dose level at which less than 2 out of 6 patients (<33%) experience DLT in Cycle 1. A dose limiting toxicity (DLT) will be defined as any one of the specific adverse events (AEs) outlined in the protocol, occurring during Cycle 1 when considered related to therapy that is part of this study.
- Pharmacokinetic Profile [ Time Frame: 6 months ]To determine the pharmacokinetic profile of valproic acid and epirubicin in this combination.
- VPA effects on Histone Acetylation [ Time Frame: 6 months ]To determine VPA effects on histone acetylation in peripheral blood mononuclear cells and VPA effects on histone acetylation and epirubicin induced DNA damage in biopsied tumors.
- MTD for VPA and Epirubicin in Combination with 5-fluorouracil and Cyclophosphamide [ Time Frame: 6 months ]To determine the MTD for VPA and epirubicin in combination with 5-fluorouracil and cyclophosphamide commonly known as a regimen called FEC100.
- Utility of Topo IIα and IIβ as Predictive Factors for Response [ Time Frame: 6 months ]To determine the utility of topo IIα and IIβ as predictive factors for response and their modulation as drug targets in patients with biopsied tumors and to document any responses to this combination.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00246103
|United States, Florida|
|H. Lee Moffitt Cancer Center & Research Institute|
|Tampa, Florida, United States, 33612|
|Principal Investigator:||Pamela Munster, MD||H. Lee Moffitt Cancer Center and Research Institute|
|Principal Investigator:||Adil Daud, MD||H. Lee Moffitt Cancer Center and Research Institute|