Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| DSRB Reference Code: B/06/275 | Other Identifier | NHG Domain Specific Review Board | |
| HSA No: CTC0600314 | Other Identifier | Health Science Authority (Singapore) |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Purpose:
We hypothesize that Vorinostat, as a novel class of anti-cancer agents, may induce response in patients with recurrent or metastatic breast cancer who have been previously treated with anthracyclines and taxanes. In addition, we hypothesize that serum Vorinostat levels may correlate with clinical response and toxicities, and that Vorinostat may induce unique protein changes in the plasma in responding patients, and that these proteins may in turn be used as predictive biomarkers for treatment response.
Breast cancer is sensitive to a range of chemotherapeutics agents, but despite initial sensitivity, resistance typically emerges, resulting in disease relapse or progression. Exploration of novel classes of agents in the treatment of breast cancer is therefore in urgent need. Vorinostat or SAHA, a potent inhibitor of histone deacetylase (HDAC) activity, represents a novel class of anti-cancer agents in early stages of development. Vorinostat is active in inducing differentiation, cell growth arrest, and/or apoptosis in a wide variety of transformed cells in culture, and has shown activity against breast cancer in cell lines and animal models. Exploratory pharmacokinetic analysis has demonstrated that oral Vorinostat has excellent bioavailability. Oral Vorinostat has been administered to more than 300 patients enrolled in completed or ongoing clinical studies. The maximum tolerated dose (MTD) is 400 mg q.d. or 200 mg b.i.d. continuously, or 300 mg b.i.d. x 3 consecutive days per week. Dose-limiting toxicities (DLT) are non-hematologic (anorexia, dehydration, diarrhea and fatigue), that resolve quickly once drug administration is interrupted. This study will evaluate the safety and efficacy of Vorinostat in breast cancer patients who have failed anthracyclines and taxanes, and if proven active, will add an important new class of agents to the treatment armamentarium of breast cancer. The study will be divided into 2 phases: phase I to determine the MTD in our population, starting with 400mg q.d. continuously, with progressive dose decrements in the event of DLT; and phase 2 to determine efficacy of Vorinostat at MTD in 12-37 evaluable patients. Correlative studies (pharmacokinetics, pharmacogenetics, plasma proteomics, tumor histone acetylation, genomics and proteomics) will be carried out to identify markers that will predict treatment response and/or toxicity to Vorinostat, to achieve the future goal of tailored therapy.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vorinostat | Experimental | A phase I portion that will determine the safety of 400mg Vorinostat once a day, continuously in the Asian population. A pre-determined dose reduction schema will be followed in the event of significant dose-limiting toxicities at this dose. Phase II will recruit additional patients at the determined dose with the goal of evaluating drug efficacy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Vorinostat | Drug | MK-0683 capsules, 100 mg, 400mg once a day, continuously (at dose level 0 - Phase 1 part of the study) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Clinical laboratory tests | Laboratory tests will include the following: full blood count, albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, creatinine, glucose, LDH, potassium, total protein, AST, ALT, sodium and uric acid | Screening (Visit 1) and weekly during Cycle 1 |
| Vital signs | Vital signs will include pulse, blood pressure, temperature, and respiration rate. Any treatment-emergent clinically significant vital sign abnormalities should be reported and followed as an adverse event. | Screening (Visit 1) and at subsequent visits |
| Electrocardiograms | ECG results will be reviewed by the investigator, and any treatment-emergent clinically significant ECG abnormality should be reported and followed as an adverse event. | (Visit 1) and every 12 weekly while on treatment. |
| Measure | Description | Time Frame |
|---|---|---|
| Vorinostat concentration in serum samples | Vorinostat and its two metabolites SAHA-glucuronide and n-phenyl succinamic acid in human serum samples will be isolated by high throughput liquid chromatograph (HTLC) on-line extraction system.AUC, terminal elimination rate constant,total serum clearance (CL), volume of distribution (Vz) and bioavailability after oral administration will be calculated | Cycle 1 Day 1 (Week 1) and Cycle 1 Day 15 (Week 3) |
Not provided
Key Inclusion Criteria:
Key Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Soo Chin LEE, MBBS,MRCP | National University Hospital, Singapore | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National University Hospital | Singapore | 149547 | Singapore | |||
| National Cancer Centre |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11731433 | Background | Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res. 2001 Dec 1;61(23):8492-7. | |
| 15897550 | Background | Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, Richon VM. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005 Jun 10;23(17):3923-31. doi: 10.1200/JCO.2005.14.167. Epub 2005 May 16. |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000077337 | Vorinostat |
| ID | Term |
|---|---|
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Level of histone H3 acetylation | 10ml whole blood will be collected in heparinized tubes at baseline and 3 weeks after initiation of Vorinostat treatment, and centrifuged to obtain peripheral mononuclear cells. Histones will be isolated and acetylated histone H3 evaluated by Western blot analysis and enzyme linked immunosorbent assay (ELISA). | Baseline and 3 weeks after initiation of Vorinostat treatment |
| Known functional single nucleotide polymorphisms | Known functional single nucleotide polymorphisms (SNPs) of genes encoding for proteins that are relevant to the pharmacokinetic disposition and pharmacodynamics of Vorinostat will be characterized. More comprehensive genotyping using high-throughput sequencing techniques will be carried out in 'outliers' who have extreme pharmacokinetic parameters, or who experience exceptional toxicity or tumor response, to identify novel functional SNPs. | prior to start of treatment |
| Baseline plasma protein profiles and changes in response to chemotherapy | Plasma proteomics studies using SELDI-MS with the Ciphergen technology will be collected serially to identify protein markers that are associated with Vorinostat response. | baseline, on day 1 of each subsequent treatment cycle for the first 6 cycles, followed by 3 monthly until documented disease progression. |
| Tumor histone acetylation studies, genomics and proteomics studies (optional) | Tumor samples will be snap frozen in liquid nitrogen for subsequent RNA and protein extraction for tumor histone acetylation studies, gene expression studies and proteomic studies in an attempt to identify biomarkers that correlate with Vorinostat biological effects and clinical response. | at baseline, and 3 weeks after initiation of Vorinostat treatment |
| Singapore |
| 169610 |
| Singapore |
| D017437 |
| Skin and Connective Tissue Diseases |
| D000588 |
| Amines |
| D006877 | Hydroxamic Acids |
| D006898 | Hydroxylamines |
| D006880 | Hydroxy Acids |
| D002264 | Carboxylic Acids |