Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Urinary Bladder Neoplasms

Hematuria

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Urination Disorders

Hemorrhage

Anticonvulsants

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Valproic Acid

Enzyme Inhibitors

Neurotransmitter Agents

Patients will be administered valproic acid (Depakote ER) for up to 30 days prior to tumor resection

500 mg orally, once daily for up to 30 days

Oleg Shapiro, MD

The goal of this study is to test whether the drug valproic acid can cause changes in bladder tumors that might inhibit their growth.

Bladder cancer is the fourth most common cancer in the United States with over 60,000 new cases each year. It can usually be treated initially by insertion of an endoscope into the bladder and surgically removing the tumor, a procedure known as cystoscopy and trans-urethral resection of bladder tumor (TURBT). For most patients this procedure will successfully remove all of the detectable tumor. Unfortunately over 40% of all patients will develop a cancer recurrence in less than two years and all patients remain at increased risk of recurrence for the remainder of their lives. This risk requires life long monitoring and this is best accomplished with regular cystoscopic examinations. The goal of this study is to test whether the drug valproic acid can cause changes in bladder tumors that might inhibit their growth. Patients with suspected bladder cancer will be invited to participate in the study, if a tumor is observed during cystoscopy it will be sampled for research purposes and then according to standards of care, the patient scheduled for TURBT under general anesthesia. In the interval between discovery of a bladder tumor and resection, usually two to four weeks, the patient will be given valproic acid to take orally. In addition, tumors from patients with known or suspected bladder cancer referred for TURBT or cystectomy will be sampled. The tumor pieces obtained before and after taking valproic acid and from the referral patients not treated with valproic acid will be analyzed to see if the drug has changed what genes are active. We have found that valproic acid causes bladder cancer cells to make more of the protein, thrombospondin-1. This protein inhibits the growth of new blood vessels and so increased thrombospondin-1 in bladder tumors should inhibit their growth by decreasing the blood supply. Valproic acid may change thrombospondin-1 levels through inhibition of histone deacetylases. We will also assay HDAC activity in the tumor specimens. If valproic acid alters thrombospondin-1 levels and HDAC activity in bladder cancer patients further study to see if it can reduce growth will be justified. Valproic acid is a drug approved for the treatment of seizure disorders that is generally well tolerated with few side effects. It may prove useful in reducing bladder cancer recurrence and progression.

Impact of Valproate on Angiogenesis and Histone Deacetylation in Bladder Cancer

Expression of thrombospondin-1 will be assayed using quantitative real-time PCR and western blotting. Comparisons will be intra-patient for paired specimens acquired prior to and after treatment and inter-patient for treated and un-treated patients.

Histone deacetylase activity, angiogenesis, and proliferation markers will be assayed using qPCR and western blotting of tumor biopsy specimens. Comparisons will be intra-patient for paired specimens acquired prior to and after treatment and inter-patient for treated and un-treated patients.

State University of New York - Upstate Medical University

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

Other Dietary Supplements

Antibodies

Antibodies, Monoclonal

Cetuximab

Immunoglobulins

Mitogens

Panitumumab

Benzocaine

Histone Deacetylase Inhibitors

Antineoplastic Agents, Immunological

Tannic Acid

Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks, with sodium valproate oral continuously in a twice daily dose (target daily dose of 20 mg/kg/d at Cycle 1 Day 13, then dose adjusted to maintain serum VPA levels within the target range of 50-100 μg/mL)

Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks

Sodium valproate oral continuously in a twice daily dose (Initial dose of 600mg/d up-titrated to target daily dose of 20 mg/kg/d at Cycle 1 Day 13, then dose adjusted to maintain serum VPA levels within the target range of 50-100 μg/mL); Refer to arm description.

Sodium Valproate

Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description.

Sukanya Sathyamurthie

Louise Christophersen

Amy Williams

Lynda Sok

Alison Richards

Eben-Marie Garzina

Karen Lim

Jade Rice

John Buen

Kirsten Remen

Donna Haberl

Lucy Leonard

The aim of this study is to determine the efficacy of combining the histone deacetylase (HDAC) inhibitor sodium valproate (VPA) with anti-EGFR monoclonal antibody (panitumumab or cetuximab) maintenance in the first-line treatment of patients with RAS wild type metastatic CRC.

The primary objective is to evaluate progression free survival (PFS) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, or panitumumab or cetuximab maintenance alone.

The secondary objectives are (i) to evaluate overall survival (OS) and objective response rates (ORRs; RECIST v 1.1) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, and panitumumab or cetuximab maintenance alone; and (ii) to evaluate the safety (NCI CTCAE v5.0) of first-line maintenance treatment with VPA plus panitumumab or cetuximab, and panitumumab or cetuximab maintenance alone in patients with RAS wild type metastatic CRC.

The tertiary and exploratory objectives are:

* To evaluate Health-Related Quality of Life (EORTC QLQ-C30 and EQ-5D-5L) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, and panitumumab or cetuximab maintenance alone.
* Exploratory analyses including, but not limited to:

  (i) Determining whether changes in levels of histone acetylation in peripheral blood mononuclear cells (PBMCs) are associated with improved efficacy with VPA plus anti-EGFR monoclonal antibody maintenance treatment; and (ii) determining whether potential resistance-conferring mutations in circulating tumour DNA (ctDNA) are associated with efficacy outcomes in patients treated with anti-EGFR monoclonal antibody maintenance.

Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer

A Phase II Randomised Controlled Trial to Determine the Efficacy of Combining the HDAC Inhibitor Sodium Valproate With EGFR Monoclonal Antibody (Panitumumab or Cetuximab) Maintenance in the First-line Treatment of Patients With RAS Wild Type Metastatic Colorectal Cancer (CRC)

Health-Related Quality of Life (HRQoL) will be determined by the global and subscale scores outlined in the EORTC user manual and scoring guidelines. Scores are from 0-100, with higher scores indicating better quality of life.

The EQ-5D-5L will be used to derive utility scores suitable for quality adjusted survival analyses. The scale has five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), each of which are scored at one of five levels ranging from no problems to extreme problems.

Exploratory analysis detecting changes in levels of histone acetylation in PBMCs during treatment

Exploratory analysis detecting the levels of ctDNA during treatment

Progression free survival (PFS) will be defined as the interval from date of registration or randomisation to the date of first evidence of disease progression (measured by RECIST v1.1 criteria) or death whichever occurs first, in each treatment arm.

Overall survival (OS) will be defined as the interval from date of registration or randomisation to date of death from any cause.

ORRs will be calculated as the proportion of participants in each arm who are assessed as having a complete or partial response measured by RECIST v1.1.

Safety of each treatment arm will be assessed by evaluating the number and severity (grade) of adverse events reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Impact of Valproate on Angiogenesis and Histone Deacetylation in Bladder Cancer	NCT01738815	Hematuria Bladder Cancer	Valproic Acid	21 Years -	State University of New York - Upstate Medical University
Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer	NCT05694936	Metastatic Colo...	Sodium Valproat... Panitumumab Cetuximab	18 Years -	Australasian Gastro-Intestinal Trials Group
Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer	NCT05694936	Metastatic Colo...	Sodium Valproat... Panitumumab Cetuximab	18 Years -	Australasian Gastro-Intestinal Trials Group

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