A PHASE 1/2 STUDY OF RO4929097, AN ORAL SMALL MOLECULE INHIBITOR OF GAMMA-SECRETASE, IN CHILDREN WITH RELAPSED/REFRACTORY SOLID OR CNS TUMORS, LYMPHOMA, OR T-CELL LEUKEMIA
I. To estimate the maximum-tolerated dose (MTD) and recommend a phase II dose of
gamma-secretase inhibitor RO4929097 administered orally to children with relapsed or
refractory solid tumors or lymphoma on two schedules: once daily orally on a 3-day on/4-day
off weekly schedule (schedule A) or once daily for 5 consecutive days weekly schedule
II. To define and describe the toxicities of this drug administered on these schedules to
children with relapsed or refractory solid tumors, lymphoma, or T-cell leukemia.
III. To estimate the MTD and recommended phase II dose of gamma-secretase inhibitor
RO4929097 administered with dexamethasone.
IV. To define and describe the toxicities of gamma-secretase inhibitor RO4929097
administered with dexamethasone.
V. To characterize the pharmacokinetics of gamma-secretase inhibitor RO4929097 in children
with refractory cancer.
I. To preliminarily define the antitumor activity of gamma-secretase inhibitor RO4929097 in
children with solid or CNS tumors and lymphoma within the confines of a phase I study.
II. To obtain initial efficacy data on the antitumor activity of gamma-secretase inhibitor
RO4929097 when combined with dexamethasone in children with relapsed-refractory T-cell
leukemia (T-acute lymphoblastic leukemia [ALL]).
III. To study the effect of gamma-secretase inhibitor RO4929097 on Hes1 (hairy/enhancer of
split) and other components of the Notch signaling pathway in peripheral blood mononuclear
cells and/or T-ALL blasts. (exploratory) IV. To examine archival tumor samples for
expression of JAGGED1, JAGGED2, cleaved NOTCH1, and HES1, and HES5 by IHC and for
amplification of NOTCH1 or NOTCH2 using FISH analysis. (exploratory) V. To preliminarily
assess changes following treatment with gamma-secretase inhibitor RO4929097 using FDG PET
OUTLINE: This is a multicenter, phase I, dose-escalation study of gamma-secretase inhibitor
RO4929097 followed by a phase II study. Patients are enrolled sequentially to group A or B.
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3,
8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 24 courses in the absence
of disease progression or unacceptable toxicity.
GROUP B: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-5,
8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 24 courses in the absence
of disease progression or unacceptable toxicity. Patients may also receive concurrent oral
dexamethasone twice daily on the days of gamma-secretase inhibitor RO4929097 administration.
Once the MTD or recommended phase II dose of RO4929097 plus dexamethasone in children with
solid tumors, including CNS tumors, or lymphoma has been identified, this dose is used for
patients with relapsed-refractory T-ALL (phase 2 portion of the study) to evaluate RO4929097
in combination with dexamethasone using one of the studied schedules. Blood, plasma, bone
marrow, and tumor tissue samples may be collected at baseline and periodically during the
first course for correlative lab and tumor studies, including pharmacokinetics.
After completion of study treatment, patients are followed up for up to 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of RO4929097 determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0)
Children's Oncology Group
United States: Food and Drug Administration
|Baylor College of Medicine||Houston, Texas 77030|
|Washington University School of Medicine||Saint Louis, Missouri 63110|
|Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|St. Jude Children's Research Hospital||Memphis, Tennessee 38105-2794|
|Nationwide Children's Hospital||Columbus, Ohio 43205-2696|
|Indiana University Medical Center||Indianapolis, Indiana 46202|
|Seattle Children's Hospital||Seattle, Washington 98105|
|Childrens Memorial Hospital||Chicago, Illinois 60614|
|Columbia University Medical Center||New York, New York 10032|
|Stanford University Hospitals and Clinics||Stanford, California 94305|
|Lucile Packard Children's Hospital Stanford University||Palo Alto, California 94304|