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

NCT00246103

Last updated date
Study Location
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, 33612, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Advanced Neoplasms
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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 cancer.

- 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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

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Advanced NeoplasmsPhase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies
NCT00246103
  1. Tampa, Florida
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies
Official Title  ICMJE Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies
Brief Summary 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. Epirubicin will be given by infusion on day 3 after the last dose of divalproex. The study will determine the highest dose that these two drugs can be given together and as part of a multidrug regimen with 5-fluorouracil and cyclophosphamide.
Detailed Description

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 ?g/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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms, Advanced
Intervention  ICMJE
  • Drug: Valproic acid
    Beginning Dose, Level 1: 15 mg/kg/day.
    Other Names:
    • Valproic
    • Depakote
    • VPA
  • Drug: Epirubicin
    Beginning Dose, Level 1: 75 mg/m^2.
    Other Name: Ellence
  • Drug: 5-fluorouracil
    For breast cancer participants treated at MTD of Valproic acid and Epirubicin: 5-fluorouracil 500 mg/m^2.
    Other Name: 5-FU
  • Drug: Cyclophosphamide.
    For breast cancer participants treated at MTD of Valproic acid and Epirubicin: cyclophosphamide 500 mg/m^2.
    Other Name: CYTOXAN®
Study Arms  ICMJE 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.
Interventions:
  • Drug: Valproic acid
  • Drug: Epirubicin
  • Drug: 5-fluorouracil
  • Drug: Cyclophosphamide.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 20, 2017)
82
Original Enrollment  ICMJE
 (submitted: October 28, 2005)
65
Actual Study Completion Date  ICMJE April 2008
Actual Primary Completion Date April 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 cancer.
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00246103
Other Study ID Numbers  ICMJE MCC-13693
USFIRB#101881
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party H. Lee Moffitt Cancer Center and Research Institute
Study Sponsor  ICMJE H. Lee Moffitt Cancer Center and Research Institute
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Pfizer
Investigators  ICMJE
Principal Investigator:Pamela Munster, MDH. Lee Moffitt Cancer Center and Research Institute
Principal Investigator:Adil Daud, MDH. Lee Moffitt Cancer Center and Research Institute
PRS Account H. Lee Moffitt Cancer Center and Research Institute
Verification Date January 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP