AG014699 in Treating Patients With Locally Advanced or Metastatic Breast Cancer or Advanced Ovarian Cancer - Full Text View

Sponsor:	Cancer Research UK
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00664781

Purpose

RATIONALE: AG014699 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying the side effects and best dose of AG014699 and to see how well it works in treating patients with locally advanced or metastatic breast cancer or advanced ovarian cancer.

Condition	Intervention	Phase
brca1 Mutation Carrier brca2 Mutation Carrier Breast Cancer Ovarian Cancer	Drug: PARP-1 inhibitor AG014699 Genetic: protein expression analysis Genetic: western blotting Other: immunohistochemistry staining method Other: liquid chromatography Other: mass spectrometry Other: pharmacological study	Phase II

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	A Cancer Research UK Phase II Proof of Principle Trial of the Activity of the Intravenous PARP-1 Inhibitor, AG-014699, in Known Carriers of a BRCA 1 or BRCA 2 Mutation With Locally Advanced or Metastatic Breast or Advanced Ovarian Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer Ovarian Cancer

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Assessment of antitumor activity according to RECIST using tumor size measured clinically or radiologically with CT scan, MRI, plain x-ray, or other imaging techniques [ Designated as safety issue: No ]
Safety profile [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Time to progression and overall survival [ Designated as safety issue: No ]
Plasma levels measured by Liquid Chromatography/Mass Spectrometry/Mass Spectrometry [ Designated as safety issue: No ]
Poly(ADP-ribose) polymerase (PARP) activity measured ex vivo using validated assays [ Designated as safety issue: No ]
PARP expression using quantitative Western blotting immuno-assays [ Designated as safety issue: No ]
Pharmacogenomics including CYP2D6 and CYP3A5 enzymes, drug transport proteins, as well as polymorphisms in the genes coding for the PARP enzymes themselves [ Designated as safety issue: No ]
BRCA mutation status, PARP activity, and PARP expression in tumor biopsy samples (when possible) [ Designated as safety issue: No ]
DNA repair enzyme status using immunohistochemical techniques in paraffin sections from original diagnostic biopsies/operative procedures (where available) [ Designated as safety issue: No ]
DNA double strand break repair pathway function in cells obtained from ascitic or pleural fluid (where available) for primary cell culture and analysis for DNA repair [ Designated as safety issue: No ]

Estimated Enrollment:	56
Study Start Date:	December 2007
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

To determine the response rate to PARP-1 inhibitor AG014699 in patients with locally advanced or metastatic breast or advanced ovarian cancer shown to express the BRCA 1 or 2 mutations.
To evaluate the toxicity of this drug in these patients.

Secondary

To evaluate the time to progression and overall survival in patients treated with this drug.
To study pharmacokinetics of this drug in these patients.
To evaluate the Poly(ADP-ribose) polymerase (PARP) activity in peripheral blood lymphocytes from BRCA 1 and 2 heterozygotic patients.

OUTLINE: This is a dose-escalation study followed by an open label multicenter study. Patients are stratified according to tumor type (breast vs ovarian) and mutation status ( BRCA 1 vs BRCA 2).

Patients receive PARP-1 inhibitor AG014699 IV (at one of several possible dosages) over 30 minutes once daily on days 1-5. Treatment repeats every 21 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve stable or responding disease may receive additional courses of treatment at the discretion of the chief investigator or Drug Development Office (DDO).

Patients undergo blood sample collection periodically for pharmacokinetic and pharmacodynamic studies. Samples are analyzed for tumor marker (CA 125 and/or CA 15.3) measurements, AG-014699 plasma levels via liquid chromatography/mass spectrometry/mass spectrometry, PARP activity, and PARP protein expression via western blotting immunoassays. Paraffin embedded sections from original diagnostic biopsy are also collected and analyzed for PARP protein expression via immunohistochemical technique. Pleural and ascitic fluid may be collected and analyzed for DNA DS break repair proficiency via immunohistochemical technique. Some patients also undergo biopsy of tumors and samples are analyzed for BRCA 2 mutation as well as PARP activity via validated PARP immunoblotting assay.

After completion of study treatment, patients are followed for 28 days.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed locally advanced or metastatic breast cancer or advanced ovarian cancer
Must meet 1 of the following criteria:
- Proven a carrier of a known mutation of BRCA 1 or BRCA 2
- Considered highly likely a carrier of BRCA 1 or 2 mutation (score of ≥ 20 per Manchester criteria)
No more than 3 prior chemotherapy regimens for patients with breast or ovarian cancer within the past 5 years
- More than 2 months since prior carboplatin- or cisplatin-containing chemotherapy for ovarian cancer
Measurable disease, as defined by RECIST criteria and measured by X-ray, CT scan, or MRI
- Patients with bone disease must have other measurable disease for evaluation
- Previously irradiated lesions cannot be used for measurable disease
No known brain metastases
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

WHO performance status 0-1
Life expectancy ≥ 12 weeks
Menopausal status not specified
Hemoglobin ≥ 9.0 g/dL
Absolute neutrophils ≥ 1,500/mm ^3
Platelets ≥ 100,000/mm ^3
Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
ALT and/or AST ≤ 2.5 times ULN (≤ 5 times ULN if due to tumor)
Glomerular filtration rate (GFR) ≥ 50 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use two highly effective forms of contraception (i.e., oral, injected, or implanted hormonal contraception, intrauterine device, barrier method of condom plus spermicide, or are surgically sterile) 4 weeks prior to (females), during, and for 6 months after (males and females) completion of study therapy
Able to cooperate with treatment and follow-up
No non-malignant systemic disease, including active uncontrolled infection
No other concurrent malignancy, except adequately treated cone-biopsied carcinoma in situ of the uterine cervix, basal cell or squamous cell carcinoma of the skin, or breast and ovarian carcinoma
- Cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years, and are deemed at low risk for recurrence are eligible
No active or unstable cardiac disease or history of myocardial infarction within the past 6 months
- Patients with cardiovascular signs or symptoms should have a MUGA scan or echocardiogram, and those with a left ventricular ejection fraction (LVEF) below the institutional limit of normal should be excluded
No other condition which, in the investigator's opinion, would not make the patient a good candidate for this study

PRIOR CONCURRENT THERAPY:

At least 4 weeks since prior radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy, biological agents, or investigational agents (6 weeks for nitrosoureas and mitomycin C)
At least 4 weeks since prior major thoracic and/or abdominal surgery and recovered
Concurrent radiotherapy for the control of bone pain or skin lesions allowed, but not within 5 days of the last dose of study drug
Concurrent bisphosphonates allowed provided the dose is stable and treatment was started at least 2 weeks prior to recruitment
No prior PARP inhibitors
No unresolved toxicities from prior treatments except for alopecia or certain grade 1 toxicities, which in the opinion of the Investigator and Drug Development Office (DDO), should not exclude the patient
No concurrent anticancer therapy or investigational drugs
No concurrent tetracycline antibiotic therapy for prolonged periods (short courses [5-7 days] for treatment of infection are allowed)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00664781

Locations

United Kingdom, England
Cancer Research UK and University College London Cancer Trials Centre	Recruiting
London, England, United Kingdom, W1T 4TJ
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk
Christie Hospital	Recruiting
Manchester, England, United Kingdom, M20 4BX
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk
Derriford Hospital	Recruiting
Plymouth, England, United Kingdom, PL6 8DH
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk
Leeds Cancer Centre at St. James's University Hospital	Recruiting
Leeds, England, United Kingdom, LS9 7TF
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk
Northern Centre for Cancer Treatment at Newcastle General Hospital	Recruiting
Newcastle-Upon-Tyne, England, United Kingdom, NE4 6BE
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk
Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	Recruiting
Birmingham, England, United Kingdom, B15 2TT
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk
Southampton General Hospital	Recruiting
Southampton, England, United Kingdom, SO16 6YD
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk
United Kingdom, Scotland
Beatson West of Scotland Cancer Centre	Recruiting
Glasgow, Scotland, United Kingdom, G12 0YN
Contact: Contact Person 44-191-256-3599 ruth.plummer@newcastle.ac.uk

Sponsors and Collaborators

Cancer Research UK

Investigators

Principal Investigator:

Ruth Plummer

Northern Centre for Cancer Treatment at Newcastle General Hospital

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Study ID Numbers:	CDR0000593558, CRUK-PH2/052, CRUK-PARP/BRCA, EU-20842, EUDRACT-2006-002348-27
Study First Received:	April 22, 2008
Last Updated:	August 1, 2009
ClinicalTrials.gov Identifier:	NCT00664781 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
recurrent breast cancer
stage III ovarian epithelial cancer
stage IV ovarian epithelial cancer

recurrent ovarian germ cell tumor
stage III ovarian germ cell tumor
stage IV ovarian germ cell tumor
ovarian stromal cancer
ovarian sarcoma
BRCA1 mutation carrier
BRCA2 mutation carrier

Additional relevant MeSH terms:

Ovarian Neoplasms
Skin Diseases
Gonadal Disorders
Genital Neoplasms, Female
Breast Neoplasms
Endocrine System Diseases
Urogenital Neoplasms

Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Neoplasms
Neoplasms by Site
Breast Diseases
Endocrine Gland Neoplasms

ClinicalTrials.gov processed this record on November 30, 2009