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RO4929097 And Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01217411
First received: October 7, 2010
Last updated: July 1, 2013
Last verified: July 2013
  Purpose

This randomized phase I/II trial is studying the side effects and the best dose of RO4929097 when given together with whole-brain radiation therapy or stereotactic radiosurgery and to see how well it works compared to whole-brain radiation therapy or stereotactic radiosurgery alone in treating patients with brain metastases from breast cancer or other cancers (such as lung cancer or melanoma). RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy, such as whole-brain radiation therapy, uses high energy x-rays to kill tumor cells. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. Giving RO4929097 together with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.


Condition Intervention Phase
Estrogen Receptor-negative Breast Cancer
Extensive Stage Small Cell Lung Cancer
HER2-negative Breast Cancer
HER2-positive Breast Cancer
Male Breast Cancer
Recurrent Breast Cancer
Recurrent Melanoma
Recurrent Non-small Cell Lung Cancer
Recurrent Small Cell Lung Cancer
Stage IV Breast Cancer
Stage IV Melanoma
Stage IV Non-small Cell Lung Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Radiation: stereotactic radiosurgery
Radiation: whole-brain radiation therapy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Two Phase I Studies in Patients With Brain Metastases From Any Primary Histology, Followed by a Randomized Phase 2 Study of RO4929097 Combined With CNS Radiotherapy in Patients With Brain Metastases From Breast Cancer Whose Tumors Are Estrogen Receptor Negative

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum-tolerated dose (MTD) of RO4929097 in combination with WBRT, determined according to incidence of DLT graded using the NCI CTCAE version 4.0 (phase I) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
  • MTD of RO4929097 in combination with SRS, determined according to incidence of DLT graded using the NCI CTCAE version 4.0 (phase I) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
  • Response rate (complete or partial response) (phase II) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    We will report proportions, their 95% confidence intervals, differences in proportions and 95% confidence intervals for the difference in proportions. Confidence intervals will be constructed using two-sided 95% and will be based on the normal approximation.


Enrollment: 132
Study Start Date: October 2010
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (WBRT or SRS)
Patients with >= 4 brain lesions undergo WBRT as in phase I and patients with =< 3 brain lesions undergo SRS as in phase I.
Radiation: stereotactic radiosurgery
Undergo radiosurgery
Radiation: whole-brain radiation therapy
Undergo radiotherapy
Other Names:
  • WBRT
  • whole-brain radiotherapy
Experimental: Arm II (WBRT or SRS and RO4929097)
Patients with >= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =< 3 brain lesions receive RO4929097 and undergo SRS as in phase I.
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given orally
Other Names:
  • R4733
  • RO4929097
Radiation: stereotactic radiosurgery
Undergo radiosurgery
Radiation: whole-brain radiation therapy
Undergo radiotherapy
Other Names:
  • WBRT
  • whole-brain radiotherapy

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must meet 1 of the following criteria:

    • Histologically or cytologically confirmed breast or other cancer, such as lung cancer, melanoma, etc., with newly diagnosed metastatic disease to the brain (phase I)

      • Patients who have available systemic therapeutic options with a demonstrated survival benefit will not be eligible
    • Histologically or cytologically confirmed breast cancer with newly diagnosed metastatic disease to the brain

      • Estrogen receptor-negative disease (phase II)
  • Patients with newly diagnosed brain metastases who have received therapeutic regimens with well-characterized, delayed toxicity (e.g., hematologic toxicity observed following carmustine or mitomycin C) will not receive experimental therapy until the patient has adequately recovered from all drug-related toxicities
  • Measurable disease in the brain, defined as >= 1 lesion that can be accurately measured in >= 2 dimensions (longest diameter and its longest perpendicular diameter to be recorded)
  • Tumor HER2/neu status positive or negative
  • No leptomeningeal metastases
  • Menopausal status not specified
  • Karnofsky performance status (PS) 70-100%

    • Recursive Partitioning Analysis (RPA) class I or II
    • A small feasibility cohort of 10 RPA class III (Karnofsky PS < 70%) allowed, however they will not be included in the efficacy analysis
  • WBC >= 3,000/mm^3
  • ANC >= 1,000/mm^3
  • Platelet count >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Total bilirubin normal
  • AST (SGOT) =< 2.5 times upper limit of normal (ULN)
  • ALT (SGPT) =< 2.5 times ULN
  • Creatinine normal OR creatinine clearance >= 60 mL/min
  • Fertile patients must use 2 forms of effective contraception (i.e., barrier contraception and one other method of contraception) for the duration of study and for >= 12 months after treatment
  • Negative pregnancy test
  • Not pregnant or nursing
  • Able to swallow pills
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097
  • No malabsorption syndrome or other condition that would interfere with intestinal absorption
  • Not known to be serologically positive for hepatitis A, B, or C, or have a history of liver disease, other forms of hepatitis, or cirrhosis
  • No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation
  • No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia
  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure (NYHA class III or IV)
    • Unstable angina pectoris
    • A history of torsades de pointes or other significant cardiac arrhythmias
    • Stable atrial fibrillation
    • Psychiatric illness and/or social situations that would limit compliance with study requirements
  • Baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
  • No requirement for antiarrhythmics or other medications known to prolong QTc
  • The use of oral or intravenous corticosteroids is allowed as needed for symptomatic management of cerebral edema

    • Typical doses of dexamethasone include 4 mg, up to four times daily, administered either orally or intravenously
  • Any type or number of prior therapies allowed

    • No prior therapy with Notch inhibitors
    • No prior cranial radiation
    • Therapy-naive patients allowed
  • At least 14 days since any prior experimental therapy, chemotherapy, or radiotherapy and recovered to < grade 2 toxicities
  • No other concurrent investigational agents
  • No concurrent combination antiretroviral therapy in HIV-positive patients
  • No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
  • No concurrent medications that are generally accepted by the QTdrugs.org Advisory Board to carry a risk for Torsades de Pointes, including antiemetics
  • No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
  • No concurrent medications or food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including ketoconazole and grapefruit juice
  • No other concurrent anticancer agents or therapies
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01217411

Locations
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: Morris Groves M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01217411     History of Changes
Other Study ID Numbers: NCI-2011-02533, 2009-0582, MDA-2009-0582, CDR0000686136, 8543, U01CA069852, U01CA076576, N01CM00039, U01CA062461
Study First Received: October 7, 2010
Last Updated: July 1, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Melanoma
Small Cell Lung Carcinoma
Breast Diseases
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Skin Diseases
Thoracic Neoplasms

ClinicalTrials.gov processed this record on November 27, 2014