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Estrogen Receptor NegativePhase 1NCT01238133

Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097, Paclitaxel, and Carboplatin Before Surgery in Treating Patients With Stage II or Stage III Triple-Negative Breast Cancer

A Phase 1 study testing Carboplatin, Gamma-Secretase Inhibitor RO4929097 and Laboratory Biomarker Analysis in people with Estrogen Receptor Negative and HER2/Neu Negative, run by National Cancer Institute (NCI) at 1 site 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

This phase I trial studies the side effects and the best dose of gamma-secretase inhibitor RO4929097 when given together with paclitaxel and carboplatin in patients with stage II or stage III triple-negative breast cancer. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Carboplatin, Gamma-Secretase Inhibitor RO4929097 and Laboratory Biomarker Analysis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
14 participants
Where
1 siteUnited States
Study dates
Dec 2010to Aug 2015
Phase
Phase 1
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 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The patients must have histologically confirmed breast cancer that is human epidermal growth factor receptor 2 (Her-2) negative (immunohistochemistry [IHC] 0-1+ patients are eligible without fluorescence in situ hybridization [FISH]; IHC2+ patients are eligible with negative FISH; if FISH only is done HER2/chromosome enumeration probe [CEP]17 < 2.0); the invasive tumor must be hormone receptor negative defined as both estrogen receptor and progesterone receptor IHC staining present in less than 10% of invasive cancer cells
  • Eligible patients must have clinical stage II-III breast cancer; patients with inflammatory breast cancer are not eligible
  • Patients must have clinically or radiographically measurable primary breast tumor that measures >= 2.0 cm
  • No prior treatment including radiation therapy, chemotherapy or biotherapy for the currently diagnosed breast cancer is allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky > 80%)
  • Hemoglobin >= 9 g/dL
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  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count > 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal
  • Creatinine < 1.5 X institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately
  • Pregnancy testing; women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of RO4929097; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
  • Female patients of childbearing potential are defined as follows:
  • Patients with regular menses
  • Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
  • Women who have had tubal ligation
  • Female patients may be considered to NOT be of childbearing potential for the following reasons:
  • The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy
  • The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months
  • Ability to swallow pills
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • Patients may not be receiving any other investigational agents
  • Patients with inflammatory breast cancer are not eligible
  • Prior history of invasive breast cancer treated with systemic chemotherapy (patients with a history of ductal carcinoma in situ [DCIS] and lobular carcinoma in situ [LCIS] are eligible)
  • Other malignancies unless the patient is considered to be disease-free for 5 or more years prior to study registration; patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal and squamous cell carcinoma of the skin
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or other agents used in the study
  • Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin) are ineligible
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  • Preclinical studies indicate that RO4929097 is a substrate of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
  • Preclinical studies indicate that RO4929097 is a substrate of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and inducer of CYP2C8 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP2C8 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP2C8 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
  • Patients who are serologically positive for hepatitis A, B or C, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
  • Uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia,and hypokalemia; symptomatic congestive heart failure, unstable angina pectoris, and a history of torsades de pointes or other significant cardiac arrhythmias
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with RO4929097
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Cardiovascular: baseline corrected QT interval (QTc) > 450 msec in males or QTc > 470 msec in females
  • A requirement for antiarrhythmics or other medications known to prolong QTc
  • Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study
  • Peripheral neuropathy of grade 2 or higher

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

Other trials in United States

About this study

Official title: A Phase 1 Study of Neoadjuvant Chemotherapy With the Gamma Secretase Inhibitor RO4929097 in Combination With Paclitaxel and Carboplatin in Patients With Clinical Stage II-III Triple Negative Breast Cancer

This phase I trial studies the side effects and the best dose of gamma-secretase inhibitor RO4929097 when given together with paclitaxel and carboplatin in patients with stage II or stage III triple-negative breast cancer. Gamma-secretase inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs use in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving gamma-secretase inhibitor RO4929097 together with paclitaxel and carboplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of RO4929097 (gamma-secretase inhibitor RO4929097) given 3 days on, 4 days off in combination with weekly paclitaxel and every 3 weeks carboplatin that will not cause a 30% or more decrease in paclitaxel area under the plasma-concentration time curve (AUC)0-24hr on day 15 compared to day -1 in patients with clinical stage II-III triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

  1. To measure real-time pharmacokinetics of RO4929097 when administered in combination with weekly paclitaxel and every 3 weeks carboplatin in patients with stage II-III TNBC.

II. To measure real-time pharmacokinetics of paclitaxel when administered in combination with RO4929097 (3 days on, 4 days off) and every 3 weeks carboplatin in patients with stage II-III TNBC.

III. To evaluate the rate of pathologic and clinical complete response to the treatment with combination of RO492097, paclitaxel, and carboplatin in patients with clinical stage II-III TNBC.

OUTLINE: This is a dose-escalation study of gamma secretase inhibitor RO4929097 (RO4929097).

Patients receive gamma-secretase inhibitor RO4929097 orally (PO) once daily (QD) on days 1-3, 8-10, and 15-17, paclitaxel intravenously (IV) over 60 minutes on days 1, 8, and 15 (day -1 of course one), and carboplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Within 4 weeks after completion of neoadjuvant therapy, patients undergo definitive breast surgery.

After completion of study treatment, patients are followed up for 1 year.

Being tested
Carboplatin, Gamma-Secretase Inhibitor RO4929097, Laboratory Biomarker Analysis, Paclitaxel, Pharmacological Study
Medical subject headings
Breast Neoplasms, Triple Negative Breast Neoplasms

What participants receive

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

  • CarboplatinDrug

    Also called Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino

    Given IV

  • Gamma-Secretase Inhibitor RO4929097Drug

    Also called RO4929097

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • PaclitaxelDrug

    Also called Anzatax, Asotax, Bristaxol, Praxel

    Given IV

  • Pharmacological StudyOther

    Ancillary studies

  • Therapeutic Conventional SurgeryProcedure or surgery

    Undergo surgery

Study groups in NCT01238133
Study groupRoleWhat they receive
Treatment (RO4929097, paclitaxel, carboplatin, surgery)ExperimentalPatients receive gamma-secretase inhibitor RO4929097 PO QD on days 1-3, 8-10, and 15-17, paclitaxel IV over 60 minutes on days 1, 8, and 15 (day -1 of course one), and carboplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Within 4 weeks after completion of neoadjuvant therapy, patients undergo definitive breast surgery.
Receives: Drug: Carboplatin; Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery

What is being measured

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

  1. Incidence of adverse events of gamma-secretase inhibitor RO4929097 as assessed by CTCAE v 4.0

    Measured: Up to 1 year

  2. MTD of gamma-secretase inhibitor RO4929097 based on DLT as assessed by CTCAE version (v) 4.0

    Analysis will consist of descriptive statistics only. Frequency will be computed for discrete variables with 95% confidence intervals for the proportion.

    Measured: 21 days

Secondary outcomes (1)

  1. Pharmacokinetic parameters of gamma-secretase inhibitor RO4929097 and paclitaxel

    AUC0-24hrs, clearance, maximum concentration, and maximum time (for gamma-secretase inhibitor RO4929097 only) when each drug is administered alone versus when they are co-administered will be compared. Only descriptive statistics will be provided.

    Measured: At baseline, at 30, 55, 70 and 90 minutes, and 2, 3, 4, 6, 8 and 24 hours of days 1, 8, 15, and 17 of course 1

Timeline

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

  1. First posted10 Nov 2010 (estimated)
  2. Study startDec 2010
  3. Primary completionJan 2014
  4. Study completionAug 2015

Resources

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
14 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01238133
Sponsor's protocol ID
NCI-2011-03813
Other IDs
NCI-2011-03813, CDR0000687152, OSU-OH007, 2010C0043, OSU 10011, 8518, P30CA016058, U01CA076576
Status last verified
May 2015
First submitted
9 Nov 2010
Last updated
4 Sep 2015
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Carboplatin, Gamma-Secretase Inhibitor RO4929097 and Laboratory Biomarker Analysis in people with Estrogen Receptor Negative and HER2/Neu Negative, run by National Cancer Institute (NCI) 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 23 inclusion and 18 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: stopped early, as of the sponsor's last update on 4 Sep 2015. 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 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.

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 was stopped early. Results are not available in the source record.

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?

Incidence of adverse events of gamma-secretase inhibitor RO4929097 as assessed by CTCAE v 4.0 (time frame: Up to 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01238133.

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 4 Sep 2015.

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