Ignite Creation Date:
2024-05-05 @ 11:26 AM
Last Modification Date:
2024-10-26 @ 9:07 AM
Study NCT ID:
NCT00037609
Status:
COMPLETED
Last Update Posted:
2012-10-24
First Post:
2002-05-17
Brief Title:
Safety Efficacy and Pharmacokinetic Between Capecitabine and Exisulind in Metastatic Breast Cancer Patients
Sponsor:
MD Anderson Cancer Center
Organization:
MD Anderson Cancer Center
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2012-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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
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 23 Exisulind inhibits the growth of breast cancer cell lines in vitro and also inhibits chemically-induced mammary carcinogenesis in rats 45 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
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 23 Exisulind inhibits the growth of breast cancer cell lines in vitro and also inhibits chemically-induced mammary carcinogenesis in rats 45 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None