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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01088763
Recruitment Status : Terminated
First Posted : March 17, 2010
Last Update Posted : November 5, 2014
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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.

Condition or disease Intervention/treatment Phase
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 Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097 Other: diagnostic laboratory biomarker analysis Other: pharmacological study Drug: dexamethasone Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 129 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : March 2010
Actual Primary Completion Date : May 2011
Actual Study Completion Date : May 2011

Arm Intervention/treatment
Experimental: Arm I

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.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given PO
Other Names:
  • R4733
  • RO4929097

Other: diagnostic laboratory biomarker analysis
Correlative studies

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Drug: dexamethasone
Given IV
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM

Primary Outcome Measures :
  1. 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) [ Time Frame: 28 days ]
  2. MTD of RO4929097 administered with dexamethasone determined according to DLTs graded using CTCAE v4.0 [ Time Frame: 28 days ]

Secondary Outcome Measures :
  1. Antitumor activity of RO4929097 with or without dexamethasone assessed by Response Evaluation Criteria for Solid Tumors (RECIST) [ Time Frame: Up to 30 days ]

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed malignancy (at diagnosis or relapse)

    • Biopsy not required for intrinsic brain stem tumors or optic pathway gliomas
  • No B-cell precursor acute lymphoblastic lymphoma (ALL) or acute myeloid leukemia
  • No T-cell leukemia with CNS3 disease
  • Measurable or evaluable disease
  • Current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
  • Neurologic deficits in patients with CNS tumors must have been relatively stable for 1 week
  • No active CNS leukemia
  • Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) or Lansky PS 50-100% (for patients ≤ 16 years of age)

    • Patients who are unable to walk because of paralysis,but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the PS
  • Patients with solid tumors without bone marrow involvement must meet the following criteria:

    • Peripheral ANC ≥ 1,000/mm^3
    • Platelet count ≥ 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions within the past 7 days)
    • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)
  • Patients with known bone marrow metastatic disease must meet the above criteria and must not be known to be refractory to red cell or platelet transfusion
  • Patients with leukemia must meet the following criteria:

    • Platelet count ≥ 20,000/mm^3 (may receive platelet transfusions)
    • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)
    • Must not be known to be refractory to RBC or platelet transfusions
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age/gender as follows:

    • ≤ 0.6 mg/dL (patients 1 to < 2 years)
    • ≤ 0.8 mg/dL (patients 2 to < 6 years)
    • ≤ 1 mg/dL (patients 6 to < 10 years)
    • ≤ 1.2 mg/dL (patients 10 to < 13 years)
    • ≤ 1.4 mg/dL (female patients ≥ 13 years)
    • ≤ 1.5 mg/dL (male patients 13 to < 16 years)
    • ≤ 1.7 mg/dL (male patients ≥ 16 years)
  • Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal (ULN) for age
  • ALT ≤ 110 U/L (for the purpose of this study, the ULN for ALT is 45 U/L)
  • Serum albumin ≥ 2 g/dL
  • No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia defined as < lower limit of normal despite adequate electrolyte supplementation
  • Baseline QTc < 450 msec
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective double-method contraception (i.e., one highly effective method and one additional effective method) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study treatment
  • Female patients may not donate ova during or after study treatment
  • Able to comply with the safety monitoring requirements of the study, in the opinion of the investigator
  • Able to swallow tablets and capsules
  • No known malabsorption syndrome or other condition that would interfere with intestinal absorption
  • No known serological positivity for hepatitis A, B, or C, no known history of liver disease, and no other forms of hepatitis or cirrhosis
  • No known HIV positivity
  • No uncontrolled infection
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or dexamethasone
  • Patients may not donate blood during or for ≥ 12 months after completion of study treatment
  • No hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia that is uncontrolled despite adequate electrolyte supplementation
  • No prior gamma-secretase inhibitor RO4929097
  • Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
  • More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) (for patients with solid tumors, CNS tumors, or lymphomas)
  • Patients with T-cell leukemia must meet the following criteria:

    • Patients who relapsed on standard ALL maintenance chemotherapy must not have received maintenance chemotherapy within the past 3 days
    • Patients who relapsed when they were not receiving standard ALL maintenance therapy are eligible provided it has been ≥ 14 days since the completion of cytotoxic chemotherapy with the exception of hydroxyurea
    • Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours before the start of study treatment
  • At least 6 months since prior total-body irradiation (TBI), craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis
  • At least 6 weeks since other prior substantial bone marrow radiotherapy
  • At least 2 weeks since prior local palliative radiotherapy (small port)
  • At least 3 months since prior stem cell transplantation or rescue without TBI and no evidence of active graft-vs-host disease
  • At least 7 days since the completion of therapy with a biologic agent

    • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur (the duration of this interval must be discussed with the study chair)
  • At least 7 days or 3 half-lives, whichever is longer, since prior treatment with a monoclonal antibody
  • More than 7 days since prior growth factors that support platelet or white cell number or function
  • At least 7 days since prior corticosteroids
  • No other concurrent investigational drugs
  • No other concurrent anticancer agents including chemotherapy (except for hydroxyurea), radiotherapy, immunotherapy, or biologic therapy

    • Patients with T-ALL who benefit from treatment with gamma-secretase inhibitor RO4929097 in combination with dexamethasone may receive intrathecal methotrexate
  • No concurrent warfarin sodium (Coumadin®)
  • No concurrent medications that are strong inducers and/or inhibitors of CYP3A4
  • No concurrent medications or food that may interfere with the metabolism or gamma-secretase inhibitor RO4929097, including ketoconazole and fresh-squeezed grapefruit juice

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01088763

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United States, California
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States, 94304
Stanford University Hospitals and Clinics
Stanford, California, United States, 94305
United States, Illinois
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States, 60614
United States, Indiana
Indiana University Medical Center
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Najat Daw Children's Oncology Group
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT01088763    
Other Study ID Numbers: NCI-2011-02024
NCI-2011-02024 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL0919 ( Other Identifier: Children's Oncology Group )
ADVL0919 ( Other Identifier: CTEP )
U01CA097452 ( U.S. NIH Grant/Contract )
First Posted: March 17, 2010    Key Record Dates
Last Update Posted: November 5, 2014
Last Verified: October 2011
Additional relevant MeSH terms:
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Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, T-Cell
Lymphoma, Large-Cell, Anaplastic
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Lymphomatoid Granulomatosis
Endodermal Sinus Tumor
Rhabdoid Tumor
Pituitary Neoplasms
Leukemia, Large Granular Lymphocytic
Choroid Plexus Neoplasms
Spinal Cord Neoplasms