Clinical Trial of SAHA in Patients With Breast Cancer

Condition(s) targeted: Breast Cancer

Intervention: Vorinostat (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: National University Hospital, Singapore

Official(s) and/or principal investigator(s):
Soo Chin LEE, MBBS,MRCP, Study Chair, Affiliation: National University Hospital, Singapore

Overall contact:
Soo Chin LEE, MBBS, MRCP, Phone: 65-6772-4629, Email: soo_chin_lee@nuh.com.sg

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.

Official title: Phase I/II Clinical Trial of Vorinostat in Patients With Recurrent and/or Metastatic Breast Cancer

Study design: Treatment, Non-Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

EFFICACY MEASUREMENTS:

Disease response/progression will be assessed by using CT scan and RECIST criteria.

The objective response rate, response duration, and progression-free survival, duration of stable disease and time to response for Vorinostat will be determined.

CT scan for measurable disease will be repeated after every 2 treatment cycles.

Beyond 6 treatment cycles of Vorinostat in responding patients, the frequency of CT scan may be increased to every 12 weeks.

SAFETY MEASUREMENTS:

Vital signs, physical examinations, ECOG performance status, Adverse Events, lab safety tests, and electrocardiograms will be obtained or assessed prior to drug administration and at designated intervals throughout the study.

Secondary outcome:

CORRELATIVE STUDIES:

Pharmacokinetic studies will be performed after the first and fifteenth dose of oral Vorinostat.

Germline DNA from peripheral mononuclear cells will be extracted for pharmacogenetic studies for genotyping of drug metabolizing enzymes and cancer genes that may influence disposition and tumor efficacy of Vorinostat.

Histone acetylation studies in peripheral mononuclear cells will be performed at baseline and after 3 weeks of treatment.

Plasma proteomics studies using SELDI-MS with the Ciphergen technology will be collected serially to identify protein markers that are associated with Vorinostat response.

OPTIONAL CORRELATIVE STUDIES:

Tumor histone acetylation studies, genomics and proteomics studies will be optional.

Patients with tumor that is easily assessable for biopsy with minimal risks (eg skin nodules, breast tumor, axillary lymph node) will be recruited to participate in the optional correlative studies.

Tumor tissues will be obtained at baseline, and after 3 weeks of oral Vorinostat.

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Key Inclusion Criteria:

- 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.

Key Exclusion Criteria:

- 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

Soo Chin LEE, MBBS, MRCP, Phone: 65-6772-4629, Email: soo_chin_lee@nuh.com.sg

National University Hospital, Singapore 149547, Singapore; Recruiting
Soo Chin LEE, MBBS,MRCP, Phone: 65-6772-4629, Email: soo_chin_lee@nuh.com.sg
Soo Chin LEE, MBBS,MRCP, Principal Investigator

National Cancer Centre, Singapore 169610, Singapore; Not yet recruiting
Nan Soon WONG, Phone: 65-6436-8388, Email: dmowns@nccs.com.sg
Nan Soon WONG, Principal Investigator

Related 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.

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. Epub 2005 May 16.

Starting date: January 2007
Last updated: February 13, 2008