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
I. Determine the maximum-tolerated dose and phase II dose of gamma-secretase inhibitor
RO4929097 (RO4929097) when combined with whole-brain radiotherapy (WBRT) or stereotactic
surgery (SRS) in patients with brain metastases secondary to estrogen receptor-negative
breast cancer. (Phase I) II. Determine the safety profile of these regimens in these
patients. (Phase I) III. Determine whether the addition of RO4929097 to WBRT or SRS
significantly increases the percentages of patients who achieve response (complete and/or
partial response) at the 12-week (3-month) time point after cranial radiotherapy. (Phase II)
I. Correlate response and time to progression with molecular, stem cell markers, and
biomarker expression in tumor tissue, archived tumor tissue, and plasma.
II. Compare changes over the first 5 days of therapy with changes over the course of
III. Compare response and time to progression at the first 5 days of therapy with RO4929097
in Notch-positive and -negative tumor tissue expression of molecular and stem cell markers.
IV. Determine the progression-free survival of patients treated with these regimens. (Phase
II) V. Determine the percentage of patients alive and disease-free (in the brain) at 6
months. (Phase II) VI. Determine local control rate (in the brain) at 24- and 48-week time
point in these patients after cranial radiotherapy. (Phase II) VII. Determine distant
failure rate (in the brain) at 24- and 48-week time point in these patients after cranial
radiotherapy. (Phase II) VIII, Determine systemic response rate in patients treated with
these regimens. (Phase II) IX. Determine the percentage of patients alive and without
progression at 6 months. (Phase II) X. Further describe the safety profile of these regimens
in these patients. (Phase II) XI. Compare neurocognitive outcomes in patients treated with
these regimens. (Phase II)
OUTLINE: This is a multicenter, phase I, dose-escalation study of gamma-secretase inhibitor
RO4929097 followed by a phase II study.
PHASE I: Patients with >= 4 brain lesions receive oral gamma-secretase inhibitor RO4929097
(RO4929097) once daily on days 1-3 weekly for up to 10 weeks and undergo whole-brain
radiotherapy (WBRT) once daily, 5 days a week, for 2-4 weeks beginning on day 2. Patients
with =< 3 brain lesions receive oral RO4929097 once daily on days 1-7,15-17, 22-24, 29-31,
and 36-38 and undergo stereotactic radiosurgery (SRS) on day 4. Courses with RO4929097
continue for up to 6 weeks after the completion of radiotherapy in the absence of disease
progression or unacceptable toxicity.
PHASE II: Patients are stratified according to HER2/neu status (positive vs negative), RPA
classification (I vs II), and number of brain metastases (1-3 vs >= 4). Patients are
randomized to 1 of 2 treatment arms.
ARM I: Patients with >= 4 brain lesions undergo WBRT as in phase I and patients with =< 3
brain lesions undergo SRS as in phase I.
ARM II: 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.
Patients may undergo plasma sample collection at baseline and periodically during study for
biomarkers (soluble markers of angiogenesis and circulating endothelial and precursor cells)
studies. Patients may also undergo tumor tissue sample collection periodically for molecular
(Notch activity) and stem cell marker analysis. Archived tumor tissue is also analyzed for
stem cell markers and Notch activity. Patients undergo neurocognitive testing (HVLT-R Free
Recall, Trail Making, Controlled Oral Word Associated, Grooved Pegboard Test [both hands],
HVLT-R: Delayed Recall, and HVLT- R: Delayed Recognition) at baseline and periodically
After completion of study therapy, patients are followed up for 52 weeks.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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)
M.D. Anderson Cancer Center
United States: Food and Drug Administration
|Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|M D Anderson Cancer Center||Houston, Texas 77030|