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Estrogen Receptor NegativePhase 1NCT01071564

RO4929097 and Vismodegib in Treating Patients With Breast Cancer That is Metastatic or Cannot Be Removed By Surgery

A Phase 1 study testing Gamma-Secretase Inhibitor RO4929097, Laboratory Biomarker Analysis and Pharmacogenomic Study in people with Estrogen Receptor Negative and HER2/Neu Negative, 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

This phase I trial studies the side effects and best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with vismodegib in treating patients with breast cancer that is metastatic or cannot be removed by surgery. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Gamma-Secretase Inhibitor RO4929097, Laboratory Biomarker Analysis and Pharmacogenomic Study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
13 participants
Where
3 sitesUnited States
Study dates
Nov 2009to Jun 2014
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

  • Patients must be women with histologically or cytologically confirmed locally advanced breast cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
  • Patients must be human epidermal growth factor receptor 2 (Her-2) non-expressing (if immunohistochemistry [IHC] 0 or 1+; fluorescent in situ [FISH] ratio less than 2; if IHC 2+, FISH ratio must be less than 2.0); once the MTD has been determined, the expansion phase will be limited to patients with estrogen receptor (ER), progesterone receptor (PR), and HER2 negative (i.e. "triple negative") disease; Her-2 will be assessed as above; ER and PR are considered negative if immunoperoxidase staining of tumor cell nuclei is < 5%
  • Patients must have measurable disease per RECIST guidelines or evaluable (non-measurable) disease
  • Patients MUST have tumor accessible and suitable for serial biopsy with 4-6 passes of a 16 or 18 gauge needle
  • Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Prior therapy:
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  • Patients must have failed at least 1 prior systemic therapy for metastatic or locally advanced breast cancer
  • IMPORTANT: Patients with chronic grade 1 or 2 toxicity may be eligible at the discretion of the Principal Investigator (e.g. grade 2 chemo-induced neuropathy); note that patients with ongoing alopecia of any grade will be eligible
  • Chemotherapy: prior chemotherapy is allowed; patients must not have received chemotherapy for 3 weeks prior to the initiation of study treatment and must have full recovery from any acute effects of any prior chemotherapy; patients must not have had nitrosoureas or mitomycin C for 6 weeks prior to the initiation of study treatment
  • Radiation: prior radiation therapy is allowed; patients must not have received minimal radiation therapy (=< 5% of their total marrow volume) within 3 weeks prior to the initiation of study treatment; otherwise, patients must not have received radiation therapy (> 5% of their total marrow volume) within 4 weeks prior to the initiation of study treatment; patients who have received prior radiation to 50% or more of their total marrow volume will be excluded
  • Other therapies: prior experimental (non-Food and Drug Administration [FDA] approved) therapies and immunotherapies are allowed; patients must not have received these therapies for 30 days or five half- lives of the drug prior to the initiation of study treatment and must have full recovery from any acute effects of these therapies; patients who have prior treatment with either a gamma-secretase or hedgehog inhibitor will be excluded from participating in this study
  • Patients must not have received allogeneic stem cell transplant
  • Patients must not have co-morbid condition(s) that, at the opinion of the investigator, prevent safe treatment
  • Patients must not have active infection or fever > 38.5 degree Celsius (C)
  • Patients must not be human immunodeficiency virus (HIV)+, hepatitis B+ or hepatitis C+ (active or previous treatment)
  • All patients must provide archival tissue block or paraffin sample from archival tissue block (approximately 10 sections) for use in pharmacodynamic and pharmacogenomics correlative studies
  • Patients must agree to undergo a total of three serial biopsies for research purposes
  • Patients with brain metastases will be eligible if condition is treated and stable for >= 1 month
  • Patients must have a life expectancy of greater than 12 weeks
  • Hemoglobin >= 9 g/dL
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelets (PLT) >= 100,000/mcL
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN); if liver metastases are present, =< 5 x ULN
  • Alkaline phosphatase =< 2.0 x ULN; if bone or liver metastases are present, =< 5 x ULN
  • Bilirubin =< 1.5 x ULN
  • Creatinine =< 1.5 x ULN OR calculated or measured creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine above institutional normal
  • Women of childbearing potential 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 or GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every cycle 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 study drug; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing study drug, 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 and GDC-0449
  • 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
  • Pre-pubertal females; the parent or guardian of young female patients who have not yet started menstruation should verify that menstruation has not begun; if a young female patient reaches menarche during the study, then she is to be considered as a woman of childbearing potential from that time forward
  • Patient must have the ability to understand and the willingness to sign a written informed consent document
  • Patients must have a corrected QT (QTc) interval of =< 450 msec in males and a QTc =< 470 msec in females as measured by electrocardiogram (ECG) using Bazett's formula

Who cannot join

  • Patients who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for those who received radiation therapy of > 5% of their total marrow volume; 6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from toxicities related to prior therapy are not eligible to participate in this study; patients who have been administered GDC-0449 or RO4929097 as part of a single or limited dosing study, such as a phase 0 study, should not necessarily be excluded from participating in this study solely because of receiving prior GDC-0449 or RO4929097
  • Patients may not have received any other investigational agents within the preceding 30 days or five half- lives of the drug and must have full recovery from any acute effects of these investigational therapies
  • Patients must not have received prior treatment with either a gamma-secretase or hedgehog inhibitor
  • Patients with a requirement for antiarrhythmics or other medications known to prolong QTc
  • Patients must not receive any other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) while on this study except for medications that are prescribed for supportive care but may potentially have an anti-cancer effect (i.e. megestrol acetate, bisphosphonates); these medications must have been started 1 month prior to enrollment on this study
  • Patients with a prior history of seizures
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  • Patients with known active brain metastases will be excluded from this clinical trial; patients with prior treated brain metastases (treated and stable for >= 1 month) are allowed, providing that they were not accompanied by seizures and that a baseline brain magnetic resonance imaging (MRI) scan prior to study entry demonstrates no current evidence of progressive brain metastases
  • Any patient requiring chronic maintenance of white blood cell counts or granulocyte counts through the use of growth factor support (e.g. Neulasta, Neupogen)
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 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 GDC-0449 or RO4929097
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
  • Patients with clinically active liver disease, including active viral or other hepatitis or cirrhosis, are ineligible
  • Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
  • GDC is a cytochrome P450 2C9 (CYP2C9) inhibitor; CYP2C9 is an enzyme that metabolizes warfarin sodium (Coumadin) into an inactive metabolite; patients who are on warfarin anticoagulation are allowed to participate as long as they fit the following 4 criteria:
  • They are therapeutic on a stable warfarin dose
  • Their international normalized ratio (INR) target range is no greater than 3
  • They are monitored with weekly INR testing
  • They have no active bleeding or pathological condition that carries high risk of bleeding.
  • Other anticoagulants, including enoxaparin (Lovenox) and fondaparinux (Arixtra) are also permitted
  • Caution should be exercised when dosing RO4929097 and GDC-0449 concurrently with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP2C8, CYP2C9, CYP2C19, and CYP3A4 should be switched to alternative medications to minimize any potential risk; investigators will make every effort to switch to another agent and assess the eligibility of the patient to participate in this study
  • Baseline QTc > 450 msec in males and QTc > 470 msec in females by ECG using Bazett's formula
  • Patients without accessible tumor or who refuse serial biopsies

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • University of Michigan University Hospital

    Ann Arbor, Michigan, 48109

  • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

    Baltimore, Maryland, 21287

  • Barbara Ann Karmanos Cancer Institute

    Detroit, Michigan, 48201

Other trials in United States

About this study

Official title: A Phase I Study of the Hedgehog Smoothened Antagonist GDC-0449 (NSC # 747691) Plus Pan-Notch Inhibitor RO4929097 (NSC # 749225) Administered in Patients With Advanced Breast Cancer

This phase I trial studies the side effects and best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with vismodegib in treating patients with breast cancer that is metastatic or cannot be removed by surgery. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vismodegib, 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 RO4929097 and vismodegib together may slow the growth of tumor cells and may be a more active treatment for advanced breast cancer.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the safety and tolerability of continuous daily administration of 150 mg/day of GDC0449 (vismodegib) in combination with escalating doses of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) administered on a repeated schedule of days 1-3, 8-10 every 21 days (for a total of 6 days of RO4929097 administration per 21 day cycle) in patients with advanced breast cancer.

II. To determine the dose limiting toxicity (DLT) and identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) for this administration schedule.

SECONDARY OBJECTIVES:

  1. To determine the pharmacokinetics (PK) and pharmacogenetics (PG) of GDC0449 and RO4929097, each alone and in combination.

II. To attempt to evaluate select pharmacodynamic (PD) stem cell differentiation biomarkers in the hedgehog and notch signaling pathways (e.g. GLI family zinc finger [Gli]1/2/3, patched [Ptch] 1/2, hairy and enhancer of split 1, [Drosophila] [Hes1], huntingtin interacting protein 1 [Hip1], hairy/enhancer-of-split related with YRPW motif 1 [Hey1], Notch4, Jagged1, numb homolog [Drosophila] [numb], BMI1 polycomb ring finger oncogene [Bmi-1], cluster of differentiation [CD]44/CD24, aldehyde dehydrogenase [ALDH] proto-oncogene tyrosine-protein kinase [Src] family kinases) and the percentage of breast cancer stem cell (BCSC) in serial breast tumor biopsies before and after GDC0449 or RO4929097 alone and after 1 cycle of treatment with the combination of GDC0449 and RO4929097.

III. To determine tumor response in patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST).

IV. To perform molecular profiling of the tumor cell and BCSC populations before and after GDC0449 or RO4929097 alone and after 1 cycle of treatment with the combination of GDC0449 and RO4929097 at the MTD.

OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway inhibitor RO4929097.

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) on day 1 or days -2, -1, and 1 of course 1 and days 1-3 and 8-10 of course 2 and all subsequent courses. Patients also receive vismodegib PO once daily (QD) beginning day 8 of course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Being tested
Gamma-Secretase Inhibitor RO4929097, Laboratory Biomarker Analysis, Pharmacogenomic Study, Pharmacological Study, Vismodegib
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.

  • Gamma-Secretase Inhibitor RO4929097Drug

    Also called RO4929097

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacogenomic StudyOther

    Also called PHARMACOGENOMIC

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

  • VismodegibDrug

    Also called Erivedge, GDC-0449, Hedgehog Antagonist GDC-0449

    Given PO

Study groups in NCT01071564
Study groupRoleWhat they receive
Treatment (RO4929097 and vismodegib)ExperimentalPatients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO on day 1 or days -2, -1, and 1 of course 1 and days 1-3 and 8-10 of course 2 and all subsequent courses. Patients also receive vismodegib PO QD beginning day 8 of course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Other: Pharmacological Study; Drug: Vismodegib

What is being measured

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

  1. MTD and/or RP2D of gamma-secretase/Notch signalling pathway inhibitor RO4929097, determined according to incidence of DLT, graded using the NCI CTCAE

    Measured: 6 weeks

  2. Occurrence of adverse events and the associated National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade

    Measured: Up to 30 days after completion of study treatment

  3. Occurrence of DLTs and the associated NCI CTCAE grade

    Measured: 6 weeks

Secondary outcomes (5)

  1. Change in gene expression levels

    Will be summarized with descriptive statistics appropriate to such distributions.

    Measured: Baseline to up to 30 days

  2. Change in percentage of select BCSC biomarkers in the Hh and Notch signaling pathways

    Will be summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 90% confidence interval for the mean).

    Measured: Baseline to 2 weeks of intervention

  3. Max concentration (Cmax), time to Cmax (tmax), terminal half-life (t1/2), area under curve 0-infinity (AUC0-inf), AUC 0-next dose (AUCtlast), accumulation index (AI), Cmax steady state (Css, max), and min concentration steady state (Css, min)

    Single and multiple-dose PK parameters summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 90% confidence interval for the mean).

    Measured: Course 1 days 1-3 or days -2, -1, and 1; course 1 days 17 and 21; and course 2 days 1, 7, 10, and 11

  4. Measurement of tumor response using RECIST criteria before and after treatment

    Will be described by point estimates and exact 90% confidence intervals for proportions using Wilson's method.

    Measured: Up to 30 days after completion of study treatment

  5. Pharmacogenetics (PG) parameters, including, but not limited to, metabolizing enzymes (e.g., CYP3A5, 2C9, and UGT1A1) and transporters (e.g., ABCG2 and ABCB1)

    Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 90% confidence interval for the mean).

    Measured: Baseline

Timeline

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

  1. First posted19 Feb 2010 (estimated)
  2. Study startNov 2009
  3. Primary completionJun 2014
  4. Study completionJun 2014

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
13 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01071564
Sponsor's protocol ID
NCI-2012-02064
Other IDs
NCI-2012-02064, CDR0000662081, 2009-099, 8420, P30CA022453, U01CA062487, U01CA070095
Status last verified
Apr 2014
First submitted
18 Feb 2010
Last updated
15 Apr 2015
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Gamma-Secretase Inhibitor RO4929097, Laboratory Biomarker Analysis and Pharmacogenomic Study in people with Estrogen Receptor Negative and HER2/Neu Negative, run by National Cancer Institute (NCI) at 3 sites 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 38 inclusion and 23 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 15 Apr 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites 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?

MTD and/or RP2D of gamma-secretase/Notch signalling pathway inhibitor RO4929097, determined according to incidence of DLT, graded using the NCI CTCAE (time frame: 6 weeks). The study lists 3 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 NCT01071564.

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 15 Apr 2015.

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