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

NCT01238133 | Terminated Phase 1 DMC

• 8 other identifiers: NCI-2011-03813CDR0000687152OSU-OH0072010C0043OSU 100118518P30CA016058U01CA076576
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma

Outcome Measures

Primary Outcomes (2)

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

  Up to 1 year

• 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.

  21 days

Secondary Outcomes (1)

• Pharmacokinetic parameters of gamma-secretase inhibitor RO4929097 and paclitaxel

  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

Study Arms (1)

Treatment (RO4929097, paclitaxel, carboplatin, surgery)

EXPERIMENTAL

Patients 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.

Drug: Carboplatin; Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery

Interventions

Carboplatin DRUG

Given IV

Also known as: Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo

Treatment (RO4929097, paclitaxel, carboplatin, surgery)

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: RO4929097

Treatment (RO4929097, paclitaxel, carboplatin, surgery)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (RO4929097, paclitaxel, carboplatin, surgery)

Paclitaxel DRUG

Given IV

Also known as: Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat

Treatment (RO4929097, paclitaxel, carboplatin, surgery)

Pharmacological Study OTHER

Ancillary studies

Treatment (RO4929097, paclitaxel, carboplatin, surgery)

Therapeutic Conventional Surgery PROCEDURE

Undergo surgery

Treatment (RO4929097, paclitaxel, carboplatin, surgery)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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:

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

Carboplatin; 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Paclitaxel; Taxes

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Economics; Health Care Economics and Organizations

Study Officials

• Ewa Mrozek

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2010
• First Posted: November 10, 2010
• Study Start: December 1, 2010
• Primary Completion: January 1, 2014
• Study Completion: August 1, 2015
• Last Updated: September 4, 2015

Record last verified: 2015-05

Locations

US (1)