Use of Hydralazine and Valproic Acid in Advanced Solid Tumor Malignancies

Study Overview
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Brief Summary
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Primary Objective: The primary endpoint to this study will be to document the toxicities, and reversibility of toxicities, of this regimen of hydralazine and valproic acid in patients with advanced, unresectable, previously treated lung cancers, for whom no acceptable standard therapy is available. A primary endpoint will be to determine any potential dose limiting toxicities, and the Maximal Tolerated Dose of this regimen. Secondary Objectives: The secondary endpoint of this study will be to determine any potential anti-tumor effects, as determined by the objective tumor response (complete and partial responses), clinical benefit (complete and partial responses, and clinical benefit), the time to tumor response, the time to tumor progression, and the overall survival.

Detailed Description
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This study will be an open-label, non-randomized, dose-escalation phase I trial which will enroll in sequential cohorts.

Official Title
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A Phase 1 Protocol of Hydralazine and Valproic Acid in Advanced Solid Tumor Malignancies

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: Hydralazine and Valproic Acid: Cohort -1
* Drug: Hydralazine and Valproic Acid: Cohort 0
* Drug: Hydralazine and Valproic Acid: Cohort 1
* Drug: Hydralazine and Valproic Acid: Cohort 2
* Drug: Hydralazine and Valproic Acid: Cohort 3
* Drug: Hydralazine and Valproic Acid: Cohort 4
* Drug: Hydralazine and Valproic Acid: Cohort 5


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients with lung cancer who have disease which has been previously treated and/or for which there is no acceptable standard treatment regimen available, and cannot be treated definitively with either surgery or radiotherapy. All will be appropriate candidates for treatment, and are not candidates for treatment with protocols of higher priority. All patients should have an ECOG/Zubrod/SWOG performance status of less than 2 at the time of the initiation of therapy Adequate end-organ function No severe comorbid disease Ability to provide informed consent. Signed Informed Consent ECOG/Zubrod/SWOG Performance Status less than 2 Life expectancy greater than 8 weeks Male or female' age greater than 18 years Patients of childbearing potential must be using an effective means of contraception. Histologic diagnosis of lung cancer that is advanced and cannot be treated adequately by radiotherapy or surgery; or metastatic disease, and for which there is no standard chemotherapeutic option remaining or available All participants must have either previously received or refused standard chemotherapy Baseline laboratory values (bone marrow, renal, hepatic): Adequate bone marrow function: Absolute neutrophil count greater than 1000/µL Platelet count greater than 100'000/µL Renal function: a. Serum creatinine less than 2.0 mg % Hepatic function: Bilirubin less than 1.5x normal Serum calcium less than 12 mg/dl Exclusion Criteria Pregnant or lactating females Myocardial infarction or ischemia within the 6 months before Cycle 0' Day 0 Uncontrolled' clinically significant dysrhythmia Prior radiotherapy to an indicator lesion unless there is objective evidence of tumor growth in that lesion Prior autoimmune disease Uncontrolled metastatic disease of the central nervous system Radiotherapy within the 2 weeks before Cycle 1' Day -14 Surgery within the 2 weeks before Cycle 1' Day -14 Any co morbid condition that' in the view of the attending physician' renders the patient at high risk from treatment complications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydralazine and Valproic Acid<br>Starting dose of Hydralazine is 25 mg orally daily, days 1-28. (See Intervention for Dose Escalation Schema) Valproic acid 250 mg orally three times per day for days -14 through -8, then 500 mg orally three times per day daily for days -7 through 28, with the dose titrated to keep the serum level between 0.4 and 0.7 mM. | Drug: Hydralazine and Valproic Acid: Cohort -1<br>* Initially, 3 patients will be enrolled into each cohort, beginning with the hydralazine 25 mg PO daily, with the valproic acid dosing beginning two weeks earlier to achieve a steady state level of valproic acid in the blood. In this cohort, Hydralazine is administered at 10 mg/day.<br>* Other names: Apresoline (Hydralazine);Drug: Hydralazine and Valproic Acid: Cohort 0<br>* Initially, 3 patients will be enrolled into each cohort, beginning with the hydralazine 25 mg PO daily, with the valproic acid dosing beginning two weeks earlier to achieve a steady state level of valproic acid in the blood. Hydralazine is administered at 25 mg/day in this cohort.<br>* Other names: Apresoline (Hydralazine);Drug: Hydralazine and Valproic Acid: Cohort 1<br>* Initially, 3 patients will be enrolled into each cohort, beginning with the hydralazine 25 mg PO daily, with the valproic acid dosing beginning two weeks earlier to achieve a steady state level of valproic acid in the blood. Hydralazine is administered at 50 mg/day in this cohort.<br>* Other names: Apresoline (Hydralazine);Drug: Hydralazine and Valproic Acid: Cohort 2<br>* Initially, 3 patients will be enrolled into each cohort, beginning with the hydralazine 25 mg PO daily, with the valproic acid dosing beginning two weeks earlier to achieve a steady state level of valproic acid in the blood. Hydralazine is administered at 100 mg/day in this cohort as 25 mg four times per day.<br>* Other names: Apresoline (Hydralazine);Drug: Hydralazine and Valproic Acid: Cohort 3<br>* Initially, 3 patients will be enrolled into each cohort, beginning with the hydralazine 25 mg PO daily, with the valproic acid dosing beginning two weeks earlier to achieve a steady state level of valproic acid in the blood. Hydralazine is administered at 200 mg/day in this cohort as 50 mg four times per day.<br>* Other names: Apresoline (Hydralazine);Drug: Hydralazine and Valproic Acid: Cohort 4<br>* Initially, 3 patients will be enrolled into each cohort, beginning with the hydralazine 25 mg PO daily, with the valproic acid dosing beginning two weeks earlier to achieve a steady state level of valproic acid in the blood. Hydralazine is administered at 300 mg/day in this cohort as 75 mg four times per day.<br>* Other names: Depakote (Valproic Acid);Drug: Hydralazine and Valproic Acid: Cohort 5<br>* Initially, 3 patients will be enrolled into each cohort, beginning with the hydralazine 25 mg PO daily, with the valproic acid dosing beginning two weeks earlier to achieve a steady state level of valproic acid in the blood. Hydralazine is administered at 400 mg/day in this cohort as 100 mg four times per day.<br>* Other names: Depakote (Valproic Acid);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A primary endpoint will be to determine any potential dose limiting toxicities, & the Maximal Tolerated Dose of hydralazine & valproic acid regimen. |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine any potential anti-tumor effects, as determined by the objective tumor response, clinical benefit, the time to tumor response, the time to tumor progression, and the overall survival. |  | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Cancer, Advanced Lung Cancer, Unresectable Lung cancer, Previously treated lung cancer