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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01238133
First received: November 9, 2010
Last updated: July 28, 2014
Last verified: June 2014

November 9, 2010
July 28, 2014
December 2010
January 2014   (final data collection date for primary outcome measure)
  • MTD of gamma-secretase/Notch signalling pathway inhibitor RO4929097 based on DLT as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 [ Time Frame: 21days ] [ Designated as safety issue: Yes ]
    Analysis will consist of descriptive statistics only. Frequency will be computed for discrete variables with 95% confidence intervals for the proportion.
  • DLT of gamma-secretase/Notch signalling pathway inhibitor RO4929097 as assessed by CTCAE v 4.0 [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • Maximum-tolerated dose of RO4929097 in combination with paclitaxel and carboplatin [ Designated as safety issue: Yes ]
  • Dose-limiting toxicity of RO4929097 in combination with paclitaxel and carboplatin [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01238133 on ClinicalTrials.gov Archive Site
Pharmacokinetics of gamma-secretase/Notch signalling pathway inhibitor RO4929097 and paclitaxel [ Time Frame: 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 ] [ Designated as safety issue: No ]
Only descriptive statistics will be provided.
Pharmacokinetics of RO4929097 and paclitaxel [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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 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 is studying the side effects and the best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 when given together with paclitaxel and carboplatin in patients with stage II or stage III triple-negative breast cancer. Gamma-secretase/Notch signalling pathway 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 or by stopping them from dividing. Giving gamma-secretase/Notch signalling pathway 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.

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of RO4929097 (gamma-secretase/Notch signalling pathway 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 AUC0-24hr on day 15 compared to day-1 in patients with clinical stage II-III triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To measure real-time pharmacokinetics of RO4929097 when administered in combination with paclitaxel and carboplatin in patients with stage II or III TNBC.

II. To measure real-time pharmacokinetics of paclitaxel when administered in combination with RO4929097 and carboplatin in patients with stage II or III TNBC.

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

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

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO4929097 once daily 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.

Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetic studies.

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

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Estrogen Receptor-negative Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Triple-negative Breast Cancer
  • Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
    Given PO
    Other Names:
    • R4733
    • RO4929097
  • Drug: carboplatin
    Given IV
    Other Names:
    • Carboplat
    • CBDCA
    • JM-8
    • Paraplat
    • Paraplatin
  • Drug: paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • TAX
    • Taxol
  • Procedure: therapeutic conventional surgery
    Undergo surgery
  • Other: pharmacological study
    Ancillary studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (RO4929097, paclitaxel, carboplatin, surgery)
Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO4929097 once daily 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.
Interventions:
  • Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
  • Drug: carboplatin
  • Drug: paclitaxel
  • Procedure: therapeutic conventional surgery
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
14
Not Provided
January 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically confirmed breast cancer meeting the following criteria:

    • HER2-negative by any of the following:

      • IHC 0-1+ without fluorescence in situ hybridization (FISH)
      • IHC2+ with negative FISH
      • HER2/CEP17 < 2.0 if only FISH is done
    • Hormone receptor-negative

      • Estrogen receptor-negative (ER-) and progesterone receptor-negative (PR-) by IHC present in < 10% of invasive cancer cells
    • Clinical stage II or III disease
  • Measurable disease

    • Clinically or radiologically measurable primary breast cancer tumor ≥ 2.0 cm
  • No inflammatory breast cancer
  • No history of invasive breast cancer treated with systemic chemotherapy

    • History of ductal carcinoma in situ or lobular carcinoma in situ allowed
  • Menopausal status unknown
  • ECOG performance status (PS) 0-1 (Karnofsky 90-100%)
  • WBC ≥ 3,000/mm³
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin normal
  • AST and ALT < 2.5 times upper limit of normal (ULN)
  • Creatinine < 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
  • Fertile patients must use two forms of contraception (i.e., barrier contraception and one other method of contraception) ≥ 4 weeks prior to, during, and for ≥ 12 months after study treatment
  • Negative pregnancy test
  • Not pregnant or nursing
  • Ability to swallow pills
  • At least 5 years since other malignancy except for curatively treated carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal or squamous cell carcinoma of the skin
  • No history of allergic reactions attributed to compounds of similar chemical or biological 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
  • Not serologically positive for hepatitis A, B, or C
  • No history of liver disease, other forms of hepatitis, or cirrhosis
  • No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia
  • No symptomatic congestive heart failure, unstable angina pectoris, and a history of torsades de pointes or other significant cardiac arrhythmias
  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • Psychiatric illness and/or social situations that would limit compliance with study requirements
  • No baseline QTc > 450 msec in males or QTc > 470 in females
  • No peripheral neuropathy ≥ grade 2
  • No requirement for antiarrhythmics or other medications known to prolong QTc
  • No prior radiotherapy, chemotherapy, or biotherapy for currently diagnosed breast cancer
  • Recovered to < NCI CTCAE grade 2 toxicities related to prior therapy
  • 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 or CYP2C8

    • Switching to alternative medications allowed
  • No concurrent combination antiretroviral therapy for HIV-positive patients
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01238133
NCI-2011-03813, NCI-2011-03813, CDR0000687152, OSU-OH007, OSU 10011, 8518, U01CA076576, P30CA016058
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Ewa Mrozek Ohio State University
National Cancer Institute (NCI)
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP