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

NCT01071564 | Terminated Phase 1 DMC

• 7 other identifiers: NCI-2012-02064CDR00006620812009-0998420P30CA022453U01CA062487U01CA070095
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 3

Brief 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. 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.

Conditions

Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Outcome Measures

Primary Outcomes (3)

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

  6 weeks

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

  Up to 30 days after completion of study treatment

• Occurrence of DLTs and the associated NCI CTCAE grade

  6 weeks

Secondary Outcomes (5)

• Change in gene expression levels

  Baseline to up to 30 days

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

  Baseline to 2 weeks of intervention

• 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)

  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

• Measurement of tumor response using RECIST criteria before and after treatment

  Up to 30 days after completion of study treatment

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

  Baseline

Study Arms (1)

Treatment (RO4929097 and vismodegib)

EXPERIMENTAL

Patients 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.

Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Other: Pharmacological Study; Drug: Vismodegib

Interventions

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: RO4929097

Treatment (RO4929097 and vismodegib)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (RO4929097 and vismodegib)

Pharmacogenomic Study OTHER

Correlative studies

Also known as: PHARMACOGENOMIC

Treatment (RO4929097 and vismodegib)

Pharmacological Study OTHER

Correlative studies

Treatment (RO4929097 and vismodegib)

Vismodegib DRUG

Given PO

Also known as: Erivedge, GDC-0449, Hedgehog Antagonist GDC-0449

Treatment (RO4929097 and vismodegib)

Eligibility Criteria

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

You may qualify if:

• 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:
• 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)

You may not qualify if:

• 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
• 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:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

Location

University of Michigan University Hospital

Ann Arbor, Michigan, 48109, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Pharmacogenomic Testing; HhAntag691

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Genetic Testing; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Patricia LoRusso

  Barbara Ann Karmanos Cancer Institute

  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: February 18, 2010
• First Posted: February 19, 2010
• Study Start: November 1, 2009
• Primary Completion: June 1, 2014
• Study Completion: June 1, 2014
• Last Updated: April 15, 2015

Record last verified: 2014-04

Locations

US (3)