Estrogen Receptor-positive Breast CancerPhase 1NCT01208441

RO4929097 and Letrozole in Treating Post-Menopausal Women With Hormone Receptor-Positive Stage II or Stage III Breast Cancer

A Phase 1 study testing letrozole, gamma-secretase/Notch signalling pathway inhibitor RO4929097 and therapeutic conventional surgery in people with Estrogen Receptor-positive Breast Cancer and HER2-negative Breast Cancer, run by National Cancer Institute (NCI) at 3 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Who is it for?: Ages 18 years and older, women only
Conditions the study is for: Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer
What is being tested?: letrozole, gamma-secretase/Notch signalling pathway inhibitor RO4929097 and therapeutic conventional surgery
Type of treatment: Pill or oral medicine, Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 28 participants
Where: 3 sitesUnited States
Study dates: Nov 2010to Dec 2011
Phase: Phase 1

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 18 years and older
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

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+)

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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

Who cannot join

None listed.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

University of Alabama at Birmingham
Birmingham, Alabama, 35294
Magee-Womens Hospital of UPMC
Pittsburgh, Pennsylvania, 15213
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, 15232

Other trials in United States

About this study

Official title: 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

This phase I trial is studying the side effects and best dose of RO4929097 when given together with letrozole in treating post-menopausal women with stage II or stage III breast cancer. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving RO4929097 together with letrozole may be an effective treatment for breast cancer.

Read the detailed description

PRIMARY OBJECTIVES:

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:

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.

Conditions: Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer
Being tested: letrozole, gamma-secretase/Notch signalling pathway inhibitor RO4929097, therapeutic conventional surgery, breast biopsy, diagnostic laboratory biomarker analysis
Medical subject headings: Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

letrozoleDrug
Also called CGS 20267, Femara, LTZ
gamma-secretase/Notch signalling pathway inhibitor RO4929097Drug
Also called R4733, RO4929097
therapeutic conventional surgeryProcedure or surgery
breast biopsyProcedure or surgery
Also called biopsy of breast
diagnostic laboratory biomarker analysisOther
pharmacological studyOther
Also called pharmacological studies

Study groups in NCT01208441
Study group	Role	What they receive
Arm I	Experimental	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. Receives: Drug: letrozole; Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Procedure: therapeutic conventional surgery; Procedure: breast biopsy; Other: diagnostic laboratory biomarker analysis; Other: pharmacological study

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: 21 days

Secondary outcomes (20)

Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
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.
Measured: Baseline
Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
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.
Measured: 21 days
Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
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.
Measured: 42 days
Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)
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.
Measured: At time of surgery
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
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.
Measured: Baseline
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
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.
Measured: 21 days
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
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.
Measured: 42 days
Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation
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.
Measured: At time of surgery
Measurement of cell proliferation (Ki-67)
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.
Measured: Baseline
Measurement of cell proliferation (Ki-67)
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.
Measured: 21 days
Measurement of cell proliferation (Ki-67)
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.
Measured: 42 days
Measurement of cell proliferation (Ki-67)
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.
Measured: At time of surgery
Measurement of appoptosis (TUNEL and activated caspase)
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.
Measured: Baseline
Measurement of appoptosis (TUNEL and activated caspase)
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.
Measured: 21 days
Measurement of appoptosis (TUNEL and activated caspase)
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.
Measured: 42 days
Measurement of appoptosis (TUNEL and activated caspase)
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.
Measured: At time of surgery
Measurement of angiogenesis (VEGF and CD31)
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.
Measured: Baseline
Measurement of angiogenesis (VEGF and CD31)
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.
Measured: 21 days
Measurement of angiogenesis (VEGF and CD31)
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.
Measured: 42 days
Measurement of angiogenesis (VEGF and CD31)
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.
Measured: At time of surgery

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Nov 2010Dec 2011

First posted24 Sep 2010 (estimated)
Study startNov 2010
Primary completionDec 2011

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for Estrogen Receptor-positive Breast CancerStudies of the same condition, open and under way.
More trials run by National Cancer Institute (NCI)The 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
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 28 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01208441
Sponsor's protocol ID: NCI-2011-02487
Other IDs: NCI-2011-02487, UPCI-09-080, CDR0000683397, UPCI 09-080, 8554, U01CA099168
Status last verified: Sep 2013
First submitted: 23 Sep 2010
Last updated: 30 Sep 2013
Results posted: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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