Use of Hydralazine and Valproic Acid in Advanced Solid Tumor Malignancies

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

1. 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.

2. 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.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: 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

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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.
2. All will be appropriate candidates for treatment, and are not candidates for treatment with protocols of higher priority.
3. All patients should have an ECOG/Zubrod/SWOG performance status of less than 2 at the time of the initiation of therapy
4. Adequate end-organ function
5. No severe comorbid disease
6. Ability to provide informed consent.
7. Signed Informed Consent
8. ECOG/Zubrod/SWOG Performance Status less than 2
9. Life expectancy greater than 8 weeks
10. Male or female' age greater than 18 years
11. Patients of childbearing potential must be using an effective means of contraception.
12. 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
13. All participants must have either previously received or refused standard chemotherapy
14. Baseline laboratory values (bone marrow, renal, hepatic):

Adequate bone marrow function:

1. Absolute neutrophil count greater than 1000/µL
2. Platelet count greater than 100'000/µL

Renal function:

a. Serum creatinine less than 2.0 mg %

Hepatic function:

1. Bilirubin less than 1.5x normal
2. Serum calcium less than 12 mg/dl

Exclusion Criteria

1. Pregnant or lactating females
2. Myocardial infarction or ischemia within the 6 months before Cycle 0' Day 0
3. Uncontrolled' clinically significant dysrhythmia
4. Prior radiotherapy to an indicator lesion unless there is objective evidence of tumor growth in that lesion
5. Prior autoimmune disease
6. Uncontrolled metastatic disease of the central nervous system
7. Radiotherapy within the 2 weeks before Cycle 1' Day -14
8. Surgery within the 2 weeks before Cycle 1' Day -14
9. Any co morbid condition that' in the view of the attending physician' renders the patient at high risk from treatment complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hydralazine and Valproic Acid; 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; 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.; Other Names: Depakote (Valproic Acid); Apresoline (Hydralazine); Drug: Hydralazine and Valproic Acid: Cohort 0; 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.; Other Names: Depakote (Valproic Acid); Apresoline (Hydralazine); Drug: Hydralazine and Valproic Acid: Cohort 1; 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.; Other Names: Depakote (Valproic Acid); Apresoline (Hydralazine); Drug: Hydralazine and Valproic Acid: Cohort 2; 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.; Other Names: Depakote (Valproic Acid); Apresoline (Hydralazine); Drug: Hydralazine and Valproic Acid: Cohort 3; 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.; Other Names: Depakote (Valproic Acid); Apresoline (Hydralazine); Drug: Hydralazine and Valproic Acid: Cohort 4; 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.; Other Names: Depakote (Valproic Acid); Apresoline (Hydralazine); Drug: Hydralazine and Valproic Acid: Cohort 5; 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.; Other Names: Depakote (Valproic Acid); Apresoline (Hydralazine)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: New Mexico Cancer Care Alliance
• Investigators: Principal Investigator: Monte Shaheen, M.D., University of New Mexico Cancer Center

Publications and helpful links

Helpful Links

• University of New Mexico Cancer Center
• New Mexico Cancer Care Alliance

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: March 26, 2009
• First Submitted That Met QC Criteria: October 14, 2009
• First Posted (Estimate): October 16, 2009

Study Record Updates

• Last Update Posted (Estimate): January 18, 2016
• Last Update Submitted That Met QC Criteria: January 15, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Lung Cancer; Advanced Lung Cancer; Unresectable Lung cancer; Previously treated lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid; Hydralazine
• Other Study ID Numbers: INST 0712C; NCI-2011-02651 (Registry Identifier: NCI CTRP)