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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01088763
First received: March 16, 2010
Last updated: June 9, 2014
Last verified: October 2011
  Purpose

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 Intervention 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
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • MTD of RO4929097 administered with dexamethasone determined according to DLTs graded using CTCAE v4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Antitumor activity of RO4929097 with or without dexamethasone assessed by Response Evaluation Criteria for Solid Tumors (RECIST) [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]

Enrollment: 129
Study Start Date: March 2010
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT01088763

Locations
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
Investigators
Principal Investigator: Najat Daw Children's Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01088763     History of Changes
Other Study ID Numbers: NCI-2011-02024, NCI-2011-02024, COG-ADVL0919, CDR0000667505, ADVL0919, ADVL0919, U01CA097452
Study First Received: March 16, 2010
Last Updated: June 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenoma
Adenoma, Basophil
Adenoma, Chromophobe
Adenoma, Acidophil
Astrocytoma
Neoplasms
Choriocarcinoma
Craniopharyngioma
Adamantinoma
Endodermal Sinus Tumor
Ependymoma
Glioma
Hodgkin Disease
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, T-Cell
Lymphoma
Lymphoma, Non-Hodgkin
Lymphomatoid Granulomatosis
Medulloblastoma
Meningioma
Neoplasms, Germ Cell and Embryonal
Oligodendroglioma
Pituitary Neoplasms
Prolactinoma
Spinal Cord Neoplasms
Teratoma
Choroid Plexus Neoplasms
Pinealoma

ClinicalTrials.gov processed this record on August 21, 2014