Breast NeoplasmsPhase 1/2NCT00037609
Safety, Efficacy and Pharmacokinetic Between Capecitabine and Exisulind in Metastatic Breast Cancer Patients
A Phase 1/2 study testing Capecitabine and Exisulind in people with Breast Neoplasms and Metastases, Neoplasm, run by M.D. Anderson Cancer Center at 1 site in United States.
Trial summary
The primary objective of the phase I study is to determine a safe dose for combination therapy with capecitabine and exisulind. A secondary objective is to assess pharmacokinetic interactions between the two drugs and assess the biological activity of exisulind. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Breast Neoplasms, Metastases, Neoplasm
- What is being tested?
- Capecitabine and Exisulind
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 35 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2001to Feb 2003
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Each patient must meet all these criteria in order to be considered for enrollment in the Phase I study:
- Histologically confirmed breast cancer and either clinical, radiological or laboratory evidence of metastatic disease.
- Patients must have received both anthracycline-containing and taxane chemotherapy either as adjuvant treatment or therapy for metastatic breast cancer.
- There is no limit on prior chemotherapy regimens or hormonal therapies received.
- Concomitant bisphosphonate treatment is allowed for patients with bone metastases.
- Patients must have recovered from acute toxic effects of any prior therapy including surgery and radiation.
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- Zubrod performance status < 2. (See Appendix A)
- Adequate bone marrow function: platelets > 100,000/mm3, ANC > 1500 cells/mm3, hemoglobin > 8g/dl.
- Normal renal function: creatinine < 2.0 mg/dl.
- Adequate liver function: Bilirubin < 1.5 mg/dL. Transaminases (SGOT) or LDH, and alkaline phosphatase must be <1.5 x of the upper limit of normal in the absence of bone or liver metastasis, or <2.5 x of the upper limit of normal in the presence of radiologically apparent liver metastasis or bone metastasis, respectively.
- Female patients must be of non-childbearing potential or non-lactating and using adequate contraception. Beta-HCG will be checked in premenopausal patients if clinically indicated.
- Patients with brain metastases whose disease remained stable for more than 6 months after completing therapy to the brain are eligible.
- Written informed consent.
- In addition to the above, patients participating in the Phase II portion of this study:
- Must have bidimensionally measurable or evaluable disease. Lytic lesions seen on plain radiographs will be considered evaluable in conjunction with bone scan abnormalities. Bone scan abnormalities alone, pure blastic bone metastases or irradiated lesions are not considered measurable or evaluable and will not be accepted. Also, pleural or peritoneal effusions will not be considered evaluable disease.
Who cannot join
- A patient must not be enrolled if any of the following criteria applies:
- Known hypersensitivity to sulindac (CLINORIL).
- Known hypersensitivity or contraindications to capecitabine (XELODAR) including prior therapy with capecitabine.
- Clinical or laboratory evidence of significant liver disease.
- Concomitant treatment with cytotoxic agents other than capecitabine or participation in any other investigational study.
- Uncontrolled psychiatric, or social (addictive) disorders that would preclude obtaining informed consent or patient participation in the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Texas M. D. Anderson Cancer Center
Houston, Texas, 77030
About this study
Official title: Phase I-II Study to Evaluate Safety, Efficacy and Pharmacokinetic Interactions Between Capecitabine (XELODA) and Exisulind (APTOSYN) in Patients With Metastatic Breast Cancer
The primary objective of the phase I study is to determine a safe dose for combination therapy with capecitabine and exisulind. A secondary objective is to assess pharmacokinetic interactions between the two drugs and assess the biological activity of exisulind.
The primary objective of the Phase II part of this study is to assess the anti-tumor activity of this combination therapy measured by objective tumor response. Secondary end points also assessed will be toxicity of therapy, duration of response and time to progression.
Read the detailed description
Rationale for this study:
Capecitabine is approved by the Food and Drug Administration (FDA) as 2nd or 3rd line chemotherapy for patients with metastatic breast cancer who previously have failed both anthracycline and taxane chemotherapy. Capecitabine produces objective tumor response of around 20% with a median duration of response of 32 weeks in these patients (1). These results indicate that improvements in the treatment of anthracycline and taxane resistant breast cancer are needed. Exisulind (sulindac sulfone, FGN-1, APTOSYNTM) is a sulfone metabolite of sulindac, a widely used nonsteroidal anti-inflammatory (NSAID) drug. Sulindac sulfone lacks inhibitory activity on the two isoforms of cyclooxygenase, COX 1 and COX 2, and is devoid of gastrointestinal and renal toxicity that is associated with NSAIDs. Exisulind selectively stimulates programmed cell death in a variety of neoplastic cells including colon, prostate, and mammary epithelial cells without affecting normal cells (2,3). Exisulind inhibits the growth of breast cancer cell lines in vitro and also inhibits chemically-induced mammary carcinogenesis in rats (4,5). The drug is also synergistic with a diverse group of cytotoxic compounds including cisplatin, taxanes and retinoids (6). Exisulind exerts its effects by inhibiting a novel phosphodiesterase that belongs to the PDE5 family which specifically degrades cGMP (7). Inhibition of this enzyme results in a rise in intracellular cGMP levels and leads to apoptosis through yet unknown mechanism. Exisulind also inhibits transcription factor NF-kB (8). The NF-kB pathway is activated by cellular stress including exposure to inflammatory cytokines, cytotoxic agents and oxidative stress (9). It is believed that activation of NF-kB protects from cell death, therefore, inhibition of this transcription factor may contribute to the proapoptotic, chemotherapy potentiating effect of exisulind.
Exisulind selectively promotes apoptosis in neoplastic cells whereas chemotherapeutic drugs induce programmed cell death in a non-selective manner. We hypothesize that combination of the 2 drugs will increase response rates by selectively augmenting the cytotoxic activity of chemotherapy. Furthermore, continuous maintenance treatment, between chemotherapy doses, with a minimally toxic drug that selectively induces apoptosis of cancer cells may improve response duration and ultimately may translate into improved survival and better quality of life. Each drug alone has an established maximum tolerated dose in humans. However, the combination of exisulind and capecitabine has not been tested. This phase I-II study is proposed to test safety and efficacy of this combination in patients with metastatic breast cancer.
- Conditions
- Breast Neoplasms, Metastases, Neoplasm
- Being tested
- Capecitabine, Exisulind
- Keywords
- Metastatic breast cancer
- Medical subject headings
- Breast Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CapecitabineDrug
Also called Xeloda
1000 mg/m^2 taken by mouth twice daily.
ExisulindDrug
Also called Aptosyn
125 mg taken by mouth twice daily.
| Study group | Role | What they receive |
|---|---|---|
| Capecitabine + Exisulind | Experimental | Capecitabine 1000 mg/m^2 taken by mouth twice daily. Exisulind 125 mg taken by mouth twice daily. Receives: Drug: Capecitabine; Drug: Exisulind |
What is being measured
The primary outcome is the main question the study is designed to answer.
Response Rate
Measured: Blood tests done every week for first 6 weeks.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2002 (estimated)
- Study startJan 2001
- Primary completionFeb 2003
- Study completionFeb 2003
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast NeoplasmsStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe 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
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- Cell Pathways
- Responsible party
- Sponsor
- Investigators
- Lajos Pusztai, MD, DPHIL, Study chair, UT MD Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00037609
- Sponsor's protocol ID
- ID00-049
- Status last verified
- Oct 2012
- First submitted
- 17 May 2002
- Last updated
- 24 Oct 2012
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Oct 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I-II Study to Evaluate Safety, Efficacy and Pharmacokinetic Interactions Between Capecitabine (XELODA) and Exisulind (APTOSYN) in Patients With Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT00037609
- Acronym / sponsor ID
- ID00-049
- Conditions
- Breast Neoplasms, Metastases, Neoplasm
- Keywords
- Metastatic breast cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants (actual)
- Lead sponsor
- M.D. Anderson Cancer CenterUniversity, hospital or other
- Collaborators
- Cell Pathways
- Study start
- Jan 2001
- Primary completion
- Feb 2003 (actual)
- Study completion
- Feb 2003 (actual)
- First posted
- 20 May 2002 (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.
The primary objective of the phase I study is to determine a safe dose for combination therapy with capecitabine and exisulind. A secondary objective is to assess pharmacokinetic interactions between the two drugs and assess the biological activity of exisulind.
The primary objective of the Phase II part of this study is to assess the anti-tumor activity of this combination therapy measured by objective tumor response. Secondary end points also assessed will be toxicity of therapy, duration of response and time to progression.
Detailed description
Rationale for this study:
Capecitabine is approved by the Food and Drug Administration (FDA) as 2nd or 3rd line chemotherapy for patients with metastatic breast cancer who previously have failed both anthracycline and taxane chemotherapy. Capecitabine produces objective tumor response of around 20% with a median duration of response of 32 weeks in these patients (1). These results indicate that improvements in the treatment of anthracycline and taxane resistant breast cancer are needed. Exisulind (sulindac sulfone, FGN-1, APTOSYNTM) is a sulfone metabolite of sulindac, a widely used nonsteroidal anti-inflammatory (NSAID) drug. Sulindac sulfone lacks inhibitory activity on the two isoforms of cyclooxygenase, COX 1 and COX 2, and is devoid of gastrointestinal and renal toxicity that is associated with NSAIDs. Exisulind selectively stimulates programmed cell death in a variety of neoplastic cells including colon, prostate, and mammary epithelial cells without affecting normal cells (2,3). Exisulind inhibits the growth of breast cancer cell lines in vitro and also inhibits chemically-induced mammary carcinogenesis in rats (4,5). The drug is also synergistic with a diverse group of cytotoxic compounds including cisplatin, taxanes and retinoids (6). Exisulind exerts its effects by inhibiting a novel phosphodiesterase that belongs to the PDE5 family which specifically degrades cGMP (7). Inhibition of this enzyme results in a rise in intracellular cGMP levels and leads to apoptosis through yet unknown mechanism. Exisulind also inhibits transcription factor NF-kB (8). The NF-kB pathway is activated by cellular stress including exposure to inflammatory cytokines, cytotoxic agents and oxidative stress (9). It is believed that activation of NF-kB protects from cell death, therefore, inhibition of this transcription factor may contribute to the proapoptotic, chemotherapy potentiating effect of exisulind.
Exisulind selectively promotes apoptosis in neoplastic cells whereas chemotherapeutic drugs induce programmed cell death in a non-selective manner. We hypothesize that combination of the 2 drugs will increase response rates by selectively augmenting the cytotoxic activity of chemotherapy. Furthermore, continuous maintenance treatment, between chemotherapy doses, with a minimally toxic drug that selectively induces apoptosis of cancer cells may improve response duration and ultimately may translate into improved survival and better quality of life. Each drug alone has an established maximum tolerated dose in humans. However, the combination of exisulind and capecitabine has not been tested. This phase I-II study is proposed to test safety and efficacy of this combination in patients with metastatic breast cancer.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Capecitabine + Exisulind | Experimental | Drug: Capecitabine, Drug: ExisulindCapecitabine 1000 mg/m^2 taken by mouth twice daily. Exisulind 125 mg taken by mouth twice daily. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (15 listed)
- Each patient must meet all these criteria in order to be considered for enrollment in the Phase I study:
- Histologically confirmed breast cancer and either clinical, radiological or laboratory evidence of metastatic disease.
- Patients must have received both anthracycline-containing and taxane chemotherapy either as adjuvant treatment or therapy for metastatic breast cancer.
- There is no limit on prior chemotherapy regimens or hormonal therapies received.
- Concomitant bisphosphonate treatment is allowed for patients with bone metastases.
Key exclusion criteria (6 listed)
- Known hypersensitivity to sulindac (CLINORIL).
- Known hypersensitivity or contraindications to capecitabine (XELODAR) including prior therapy with capecitabine.
- Clinical or laboratory evidence of significant liver disease.
- Concomitant treatment with cytotoxic agents other than capecitabine or participation in any other investigational study.
- Uncontrolled psychiatric, or social (addictive) disorders that would preclude obtaining informed consent or patient participation in the study.
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 |
|---|---|---|
| CapecitabineAlso: Xeloda1000 mg/m^2 taken by mouth twice daily. | Drug | Capecitabine + Exisulind |
| ExisulindAlso: Aptosyn125 mg taken by mouth twice daily. | Drug | Capecitabine + Exisulind |
Primary outcome
Response Rate
Time frame: Blood tests done every week for first 6 weeks.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Oct 2012.
- UT MD Anderson Cancer Center websiteLink provided by the sponsor.
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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.
Lajos Pusztai, MD, DPHIL study chair
UT MD Anderson Cancer Center
1 site 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 Capecitabine and Exisulind in people with Breast Neoplasms and Metastases, Neoplasm, run by M.D. Anderson Cancer Center at 1 site in United States.
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 15 inclusion and 6 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: finished, as of the sponsor's last update on 24 Oct 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Response Rate (time frame: Blood tests done every week for first 6 weeks.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 24 Oct 2012.