Breast CancerPhase 1/2NCT00416130
Clinical Trial of SAHA in Patients With Breast Cancer
A Phase 1/2 study testing Vorinostat in people with Breast Cancer, run by National University Hospital, Singapore at 2 sites in Singapore.
Trial summary
Purpose: evaluate the safety of Vorinostat. evaluate the effectiveness of Vorinostat in treating breast cancer evaluate how the study subject's body reacts to Vorinostat, how these reactions relate to the subject's genes, and whether protein changes in the subject blood may be used to predict how the subject's cancer… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Vorinostat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 49 participants
- Where
- 2 sitesSingapore
- Study dates
- Jan 2007to Jan 2015
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Cytologically or histologically confirmed adenocarcinoma of the breast that is recurrent and/or metastatic
- Must have measurable disease as defined by RECIST criteria
- No more than 2 prior chemotherapy for recurrent and/or metastatic disease excluding neoadjuvant or adjuvant chemotherapy
- Previously received anthracycline- and taxane-containing chemotherapy for treatment of breast cancer in the neoadjuvant, adjuvant, or metastatic setting
- Must be able to swallow capsules
- Adequate bone marrow reserve and liver function
- Women in reproductive age group must agree to practice effective contraception during the entire study period unless documentation of infertility exists.
Who cannot join
- Prior treatment with any HDAC inhibitor. Patients who have received such agents for other indications, e.g. epilepsy, may enroll in the trial after a 30 day washout period.
- Known CNS involvement by tumor
- Concurrent use of oral retinoids or any vitamin A, other than a single multivitamin tablet daily
- Acute infection requiring intravenous antibiotics or antifungal agents,known HIV infection, active hepatitis B and/or hepatitis C infection
- Uncontrolled intercurrent illness
- Cancer other than breast cancer with the exception of basal cell carcinoma or disease that has been in remission for ≥5 years
- Pregnant or lactating women
Trial locations and contacts
2 sites in 1 country.
Singapore2 sites
National University Hospital
Singapore, 149547
National Cancer Centre
Singapore, 169610
About this study
Official title: Phase I/II Clinical Trial of Vorinostat in Patients With Recurrent and/or Metastatic Breast Cancer
Purpose:
- evaluate the safety of Vorinostat.
- evaluate the effectiveness of Vorinostat in treating breast cancer
- evaluate how the study subject's body reacts to Vorinostat, how these reactions relate to the subject's genes, and whether protein changes in the subject blood may be used to predict how the subject's cancer will respond to Vorinostat
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.
Read the detailed description
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.
- Conditions
- Breast Cancer
- Being tested
- Vorinostat
- Keywords
- Phase I/II Clinical Trial, Vorinostat, SAHA, Recurrent Breast Cancer, Metastatic Breast Cancer
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VorinostatDrug
Also called MK-0683
MK-0683 capsules, 100 mg, 400mg once a day, continuously (at dose level 0 - Phase 1 part of the study)
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Vorinostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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.
Measured: 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.
Measured: (Visit 1) and every 12 weekly while on treatment.
Secondary outcomes (5)
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
Measured: Cycle 1 Day 1 (Week 1) and Cycle 1 Day 15 (Week 3)
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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: at baseline, and 3 weeks after initiation of Vorinostat treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Dec 2006 (estimated)
- Study startJan 2007
- Primary completionJan 2015 (estimated)
- Study completionJan 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 49 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Principal investigator, Haematology-Oncology, National University Hospital, Singapore
- Investigators
- Soo Chin LEE, MBBS,MRCP, Study chair, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00416130
- Sponsor's protocol ID
- BR05/24/06
- Other IDs
- DSRB Reference Code: B/06/275, HSA No: CTC0600314
- Status last verified
- Dec 2013
- First submitted
- 26 Dec 2006
- Last updated
- 10 Dec 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 11731433Kelly 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.
PubMed 15897550
Study at a glance
From the registry record, last updated by the sponsor on 10 Dec 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Clinical Trial of Vorinostat in Patients With Recurrent and/or Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT00416130
- Acronym / sponsor ID
- BR05/24/06
- Conditions
- Breast Cancer
- Keywords
- Phase I/II Clinical Trial, Vorinostat, SAHA, Recurrent Breast Cancer, Metastatic Breast Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 49 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- Jan 2007
- Primary completion
- Jan 2015 (estimated)
- Study completion
- Jan 2015 (estimated)
- First posted
- 27 Dec 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Purpose:
- evaluate the safety of Vorinostat.
- evaluate the effectiveness of Vorinostat in treating breast cancer
- evaluate how the study subject's body reacts to Vorinostat, how these reactions relate to the subject's genes, and whether protein changes in the subject blood may be used to predict how the subject's cancer will respond to Vorinostat
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Vorinostat | Experimental | Drug: VorinostatA 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Cytologically or histologically confirmed adenocarcinoma of the breast that is recurrent and/or metastatic
- Must have measurable disease as defined by RECIST criteria
- No more than 2 prior chemotherapy for recurrent and/or metastatic disease excluding neoadjuvant or adjuvant chemotherapy
- Previously received anthracycline- and taxane-containing chemotherapy for treatment of breast cancer in the neoadjuvant, adjuvant, or metastatic setting
- Must be able to swallow capsules
Key exclusion criteria (7 listed)
- Prior treatment with any HDAC inhibitor. Patients who have received such agents for other indications, e.g. epilepsy, may enroll in the trial after a 30 day washout period.
- Known CNS involvement by tumor
- Concurrent use of oral retinoids or any vitamin A, other than a single multivitamin tablet daily
- Acute infection requiring intravenous antibiotics or antifungal agents,known HIV infection, active hepatitis B and/or hepatitis C infection
- Uncontrolled intercurrent illness
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VorinostatAlso: MK-0683MK-0683 capsules, 100 mg, 400mg once a day, continuously (at dose level 0 - Phase 1 part of the study) | Drug | Vorinostat |
Primary outcome
Clinical laboratory tests
Time frame: Screening (Visit 1) and weekly during Cycle 1
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
Vital signs
Time frame: Screening (Visit 1) and at subsequent visits
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.
Electrocardiograms
Time frame: (Visit 1) and every 12 weekly while on treatment.
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.
5 secondary outcomes
Vorinostat concentration in serum samples
Time frame: Cycle 1 Day 1 (Week 1) and Cycle 1 Day 15 (Week 3)
Level of histone H3 acetylation
Time frame: Baseline and 3 weeks after initiation of Vorinostat treatment
Known functional single nucleotide polymorphisms
Time frame: prior to start of treatment
Baseline plasma protein profiles and changes in response to chemotherapy
Time frame: 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)
Time frame: at baseline, and 3 weeks after initiation of Vorinostat treatment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Dec 2013.
- Background: PubMed 11731433Munster 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.
- Background: PubMed 15897550Kelly 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Soo Chin LEE, MBBS,MRCP study chair
National University Hospital, Singapore
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Vorinostat in people with Breast Cancer, run by National University Hospital, Singapore at 2 sites in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Dec 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical laboratory tests (time frame: Screening (Visit 1) and weekly during Cycle 1). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00416130, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2013.