NCT01088763

Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

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

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 129 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 1 Year – 21 Years
• Healthy volunteers: Not accepted

Summary

This phase I/II clinical trial is studying the side effects and best dose of gamma-secretase inhibitor RO4929097 and to see how well it works in treating young patients with relapsed or refractory solid tumors, CNS tumors, lymphoma, or T-cell leukemia. Gamma-secretase inhibitor RO4929097 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description

PRIMARY OBJECTIVES: 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 (schedule B). 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. SECONDARY OBJECTIVES: 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 imaging. (exploratory) 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. \*NOTE: This trial was intended to be Phase I/II, but the trial never continued to the Phase II portion.

Conditions

• Childhood Atypical Teratoid/Rhabdoid Tumor
• Childhood Central Nervous System Choriocarcinoma
• Childhood Central Nervous System Germinoma
• Childhood Central Nervous System Mixed Germ Cell Tumor
• Childhood Central Nervous System Teratoma
• Childhood Central Nervous System Yolk Sac Tumor
• Childhood Choroid Plexus Tumor
• Childhood Craniopharyngioma
• Childhood Ependymoblastoma
• Childhood Grade I Meningioma
• Childhood Grade II Meningioma
• Childhood Grade III Meningioma
• Childhood Infratentorial Ependymoma
• Childhood Medulloepithelioma
• Childhood Mixed Glioma
• Childhood Oligodendroglioma
• Childhood Supratentorial Ependymoma
• Gonadotroph Adenoma
• Pituitary Basophilic Adenoma
• Pituitary Chromophobe Adenoma
• Pituitary Eosinophilic Adenoma
• Prolactin Secreting Adenoma
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Anaplastic Large Cell Lymphoma
• Recurrent Childhood Brain Stem Glioma
• Recurrent Childhood Central Nervous System Embryonal Tumor
• Recurrent Childhood Cerebellar Astrocytoma
• Recurrent Childhood Cerebral Astrocytoma
• Recurrent Childhood Ependymoma
• Recurrent Childhood Grade III Lymphomatoid Granulomatosis
• Recurrent Childhood Large Cell Lymphoma
• Recurrent Childhood Lymphoblastic Lymphoma
• Recurrent Childhood Medulloblastoma
• Recurrent Childhood Pineoblastoma
• Recurrent Childhood Small Noncleaved Cell Lymphoma
• Recurrent Childhood Spinal Cord Neoplasm
• Recurrent Childhood Subependymal Giant Cell Astrocytoma
• Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
• Recurrent Childhood Visual Pathway and Hypothalamic Glioma
• Recurrent Childhood Visual Pathway Glioma
• Recurrent Pituitary Tumor
• Recurrent/Refractory Childhood Hodgkin Lymphoma
• T-cell Childhood Acute Lymphoblastic Leukemia
• T-cell Large Granular Lymphocyte Leukemia
• TSH Secreting Adenoma
• Unspecified Childhood Solid Tumor, Protocol Specific

Interventions

Type	Name	Description
DRUG	gamma-secretase/Notch signalling pathway inhibitor RO4929097	Given PO
OTHER	diagnostic laboratory biomarker analysis	Correlative studies
OTHER	pharmacological study	Correlative studies
DRUG	dexamethasone	Given IV

Timeline

• Start date: 2010-03-01
• Primary completion: 2011-05-01
• Completion: 2011-05-01
• First posted: 2010-03-17
• Last updated: 2014-11-05

Locations

12 sites across 2 countries: United States, Canada