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

This study has been terminated.
(Slow accrual coupled with discontinuation of study drug.)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01217411
First received: October 7, 2010
Last updated: January 22, 2015
Last verified: October 2011
  Purpose

This randomized phase I/II trial studies the side effects and the best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor 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 breast cancer or other cancers (such as lung cancer or melanoma) that have spread to the brain. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Whole-brain radiation therapy uses high energy x-rays deliver radiation to the entire brain to treat tumors that can and cannot be seen. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. It is not yet known whether 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
Tumors Metastatic to Brain
Unspecified Adult Solid Tumor, Protocol Specific
Drug: Gamma-secretase/Notch signalling pathway inhibitor RO4929097
Radiation: Whole-brain radiation therapy (WBRT)
Radiation: Stereotactic radiosurgery (SRS)
Procedure: Cognitive assessment
Other: Laboratory biomarker analysis
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 Whole-brain Radiotherapy (WBRT) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
    Maximum-tolerated dose (MTD) of RO4929097 in combination with WBRT, determined according to incidence of dose limiting toxicity (DLT) graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)

  • MTD of RO4929097 in Combination With Stereotactic Surgery (SRS) [ 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)

  • Response Rate (Complete or Partial Response) (Phase II) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Only participants with measurable disease present at baseline, received at least 6 weeks of therapy, and had disease re-evaluated considered evaluable for response. Complete Response (CR): Disappearance all lesions; Partial Response (PR): =/>50% decrease in sum bidimensional products all lesions reference baseline sum of bidimensional products of all lesions; Progressive Disease (PD): >25% increase in sum bidimensional products of lesions, or progression of any treated lesion not target lesion, or appearance of 1 or > new lesions at least 6 mm in unidimensional size. Stable Disease (SD): Neither sufficient shrinkage for PR nor increase for PD, reference smallest sum of bidimensional products of all lesions.


Enrollment: 5
Study Start Date: October 2010
Study Completion Date: November 2011
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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: Whole-brain radiation therapy (WBRT)
Undergo WBRT
Other Names:
  • WBRT
  • whole-brain radiotherapy
Radiation: Stereotactic radiosurgery (SRS)
Undergo SRS
Procedure: Cognitive assessment
Ancillary studies
Other: Laboratory biomarker analysis
Correlative studies
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 PO
Other Names:
  • R4733
  • RO4929097
Radiation: Whole-brain radiation therapy (WBRT)
Undergo WBRT
Other Names:
  • WBRT
  • whole-brain radiotherapy
Radiation: Stereotactic radiosurgery (SRS)
Undergo SRS
Procedure: Cognitive assessment
Ancillary studies
Other: Laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Patients who have histologically or cytologically confirmed breast cancer or other cancers (such as lung cancer, melanoma, etc) with newly diagnosed metastatic disease to the brain will be eligible for the Phase 1 study only, however, those patients who have available systemic therapeutic options with a demonstrated survival benefit will not be eligible; for Phase 2, patients must have histologically or cytologically confirmed estrogen receptor negative breast cancer with newly diagnosed metastatic disease to the brain
  • Patients must have measurable disease in the brain, defined as at least one lesion that can be accurately measured in at least two dimensions (longest diameter and its longest perpendicular diameter to be recorded)
  • There is no limit on type or number of prior therapies, except that prior therapy with notch inhibitors is not allowed, and patients should not have received prior cranial radiation; therapy naïve patients are eligible; at least 14 days (2 weeks) must have elapsed from any prior experimental therapy, chemotherapy or radiotherapy; toxicities from prior chemotherapy or radiotherapy should have resolved to < grade 2; patients with newly diagnosed brain metastases who have received therapeutic regimens with well-characterized, delayed toxicity (e.g. hematologic toxicity observed following carmustine [BCNU] or mitomycin C) will not receive experimental therapy until the patient has adequately recovered from all drug related toxicities
  • Karnofsky performance status (KPS) >= 70%; Recursive Partitioning Analysis (RPA) class I or II; a small feasibility cohort of 10 RPA class III (KPS < 70%) patients may be enrolled, however these patients, if enrolled will not be included in the efficacy analysis
  • Hemoglobin >= 9g/dL
  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x institutional upper limit of normal
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limits of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Tumor HER2/neu status may be positive or negative
  • Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) 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; prior to dispensing RO4929097, the investigator must confirm and document the patient's agreement to the use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
  • Ability to understand and the willingness to sign a written informed consent document
  • A tumor site (outside the central nervous system) for needle biopsy for research purposes is preferable
  • Ability to swallow pills

Exclusion Criteria:

  • At least 14 days (2 weeks) must have elapsed from any prior experimental therapy, chemotherapy or radiotherapy; toxicities from prior chemotherapy or radiotherapy should have resolved to < grade 2
  • Patients may not be receiving any other investigational agents
  • Patients with leptomeningeal metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097
  • Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
  • Patients taking medications that are generally accepted by the QTdrugs.org Advisory Board to carry a risk of torsades de pointes, including antiemetics, are ineligible
  • Preclinical studies indicate that RO4929097 is a substrate of CYP450 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
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
  • Patients who are known to be serologically positive for hepatitis A, B or C, or have a history of liver disease, other forms of 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
  • Uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia; uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, a history of torsades de pointes or other significant cardiac arrhythmias, stable atrial fibrillation, 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
  • Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
  • Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study
  • A requirement for antiarrhythmics or other medications known to prolong QTc
  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, NCI-2011-02533, MDA-2009-0582, CDR0000686136, 2009-0582, 8543, U01CA069852, U01CA062461, N01CM00039, U01CA076576, P30CA016672
Study First Received: October 7, 2010
Results First Received: January 22, 2015
Last Updated: January 22, 2015
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 May 21, 2015