- ICH GCP
- 미국 임상 시험 레지스트리
- 임상시험 NCT01208441
RO4929097 and Letrozole in Treating Post-Menopausal Women With Hormone Receptor-Positive Stage II or Stage III Breast Cancer
A Phase Ib Neoadjuvant Study of the Gamma Secretase Inhibitor (RO4929097) in Combination With the Aromatase Inhibitor Letrozole in Post-Menopausal Women With Stage II/III Hormone Receptor-Positive Breast Cancer
연구 개요
상태
상세 설명
PRIMARY OBJECTIVES:
I. To establish the maximum-tolerated dose and the recommended phase II dose of gamma-secretase inhibitor RO4929097 (RO4929097) in combination with letrozole in post-menopausal women with hormone receptor-positive stage II or III breast cancer.
II. To assess the safety of this regimen in these patients.
SECONDARY OBJECTIVES:
I. To evaluate the pharmacokinetics of this regimen, taking into consideration the induction of CYP3A4, in these patients.
II. To characterize the pharmacodynamic effects of letrozole prior to and during administration of RO4929097 with attention to suppression of estradiol and estrone levels.
III. To describe the pharmacodynamic effects of letrozole with or without RO4929097 on the NOTCH pathway, proliferation, angiogenesis, stromal cell infiltration/pathways, and comprehensive genomic analysis in tumor tissue of these patients.
IV. To describe the response, including clinical complete or partial objective response, pathological complete response, and attainment of pathologic stage 0 or I status in these patients.
OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor RO4929097(RO4929097).
Patients receive oral letrozole once daily on days 1-21. Beginning in course 2, patients also receive oral RO4929097 on days 1-3, 8-10, and 15-18. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Beginning 1 week after completion of neoadjuvant therapy, patients undergo surgery or tumor biopsy. Patients continue to receive oral letrozole once daily during surgery and for an additional 4 weeks.
Blood and tumor tissue samples are collected at baseline and periodically during study for pharmacokinetics, pharmacodynamics, and correlative studies.
After completion of study therapy, patients are followed up for 1 month and then every 6 months for 5 years.
연구 유형
등록 (실제)
단계
- 1단계
연락처 및 위치
연구 장소
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Alabama
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Birmingham, Alabama, 미국, 35294
- University of Alabama at Birmingham
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Pennsylvania
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Pittsburgh, Pennsylvania, 미국, 15213
- Magee-Womens Hospital of UPMC
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Pittsburgh, Pennsylvania, 미국, 15232
- University of Pittsburgh Cancer Institute
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion Criteria:
Pathologically confirmed invasive breast cancer
Stage II or III disease (T2-T3, N0-2)
- No N3, T4 disease
Estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)
- H score ≥ 10 or positivity ≥ 10%
- HER2 negative as determined by IHC (1 or 2+) or FISH (< 2.0+)
- Bilateral disease allowed as long as all tumors are ER+ and ≥ 1 is T2-T3
Patient must have disease that is palpable on physical exam and able to be imaged via breast ultrasound
- Defined as ≥ 1 T2 tumor > 2 cm
- Multifocal disease allowed provided that ≥ 1 of the tumors is > 2 cm
- No metastatic disease by CT scans of the chest, abdomen, and pelvis, a PET/CT bone scan, or nuclear medicine bone scan
- No inflammatory breast cancer or presence of breast tumor cells in the dermal lymphatics of the breast
Post-menopausal meeting 1 of the following criteria:
- Bilateral oophorectomy
- Age ≥ 50 years and amenorrheic for > 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression (spontaneous amenorrhea)
- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
- Life expectancy > 3 months
- ANC ≥ 1,000/mm³
- Platelet count ≥ 100,000/mm³
- Hemoglobin ≥ 9 g/dL
- Total bilirubin normal
- AST and ALT ≤ 2.5 times upper limit of normal
- Creatinine normal OR creatinine clearance ≥ 60 mL/min
- Baseline QTcF ≤ 470 msec
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma secretase inhibitor RO4929097 or other agents used in the study
- No malabsorption syndrome or other condition that would interfere with intestinal absorption
- Able to swallow tablets
- Not serologically positive for hepatitis A, B, or C, or have a history of liver disease, other forms of hepatitis, or cirrhosis
- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation
No uncontrolled intercurrent illness including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- History of torsades de pointes or other significant cardiac arrhythmia other than chronic, stable atrial fibrillation
- Psychiatric illness and/or social situations that would limit compliance with study requirements
- Recovered to < grade 2 CTCAE toxicities related to prior therapy
No prior chemotherapy, hormonal therapy, radiotherapy, or biological therapy for breast cancer
- Prior treatment for non-melanoma skin cancer or carcinoma in situ of the cervix allowed
- No prior hormone therapy for ductal carcinoma in situ (DCIS)
- No other concurrent investigational agents
- No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
No concurrent medications that are strong inducers and/or inhibitors or substrates of CYP3A4
- Switching to alternative medications allowed
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No concurrent antiarrhythmics or other medications known to prolong QTc
- No other concurrent anticancer agents or therapies
- No concurrent grapefruit juice
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 해당 없음
- 중재 모델: 단일 그룹 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
---|---|
실험적: Arm I
Patients receive oral letrozole once daily on days 1-21. Beginning in course 2, patients also receive oral RO4929097 on days 1-3, 8-10, and 15-18. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 1 week after completion of neoadjuvant therapy, patients undergo surgery or tumor biopsy. Patients continue to receive oral letrozole once daily during surgery and for an additional 4 weeks. |
다른 이름들:
다른 이름들:
다른 이름들:
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
기간 |
---|---|
MTD defined as the dose level at which no more than 1 of 6 patients experience a DLT, and the dose below that at which at least 2/6 patients have DLT according to NCI CTCAE version 4.0
기간: 21 days
|
21 days
|
2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
---|---|---|
Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
기간: Baseline
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
Baseline
|
Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
기간: 21 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
21 days
|
Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
기간: 42 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
42 days
|
Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
기간: At time of surgery
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
At time of surgery
|
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
기간: Baseline
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
For the analysis of the gene expression data, the overall false discovery rate (FDR), which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation.
|
Baseline
|
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
기간: 21 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
For the analysis of the gene expression data, the overall FDR, which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation.
|
21 days
|
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
기간: 42 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
For the analysis of the gene expression data, the overall FDR, which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation.
|
42 days
|
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
기간: At time of surgery
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
For the analysis of the gene expression data, the overall FDR, which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation.
|
At time of surgery
|
Measurement of cell proliferation (Ki-67)
기간: Baseline
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
Baseline
|
Measurement of cell proliferation (Ki-67)
기간: 21 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
21 days
|
Measurement of cell proliferation (Ki-67)
기간: 42 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
42 days
|
Measurement of cell proliferation (Ki-67)
기간: At time of surgery
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
At time of surgery
|
Measurement of appoptosis (TUNEL and activated caspase)
기간: Baseline
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
Baseline
|
Measurement of appoptosis (TUNEL and activated caspase)
기간: 21 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
21 days
|
Measurement of appoptosis (TUNEL and activated caspase)
기간: 42 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
42 days
|
Measurement of appoptosis (TUNEL and activated caspase)
기간: At time of surgery
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
At time of surgery
|
Measurement of angiogenesis (VEGF and CD31)
기간: Baseline
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
Baseline
|
Measurement of angiogenesis (VEGF and CD31)
기간: 21 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
21 days
|
Measurement of angiogenesis (VEGF and CD31)
기간: 42 days
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
42 days
|
Measurement of angiogenesis (VEGF and CD31)
기간: At time of surgery
|
All measurements are continuous.
Descriptive statistics will be calculated to summarize change of each measurement from the baseline value.
A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value.
|
At time of surgery
|
공동 작업자 및 조사자
수사관
- 수석 연구원: Shannon Puhalla, University of Pittsburgh
연구 기록 날짜
연구 주요 날짜
연구 시작
기본 완료 (실제)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (추정)
연구 기록 업데이트
마지막 업데이트 게시됨 (추정)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- NCI-2011-02487 (레지스트리 식별자: CTRP (Clinical Trial Reporting Program))
- U01CA099168 (미국 NIH 보조금/계약)
- UPCI-09-080
- CDR0000683397
- UPCI 09-080 (기타 식별자: University of Pittsburgh Cancer Institute)
- 8554 (기타 식별자: CTEP)
이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .
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