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Childhood Atypical Teratoid/Rhabdoid TumorPhase 1NCT01088763

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

A Phase 1 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, diagnostic laboratory biomarker analysis and pharmacological study in people with Childhood Atypical Teratoid/Rhabdoid Tumor and Childhood Central Nervous System Choriocarcinoma, run by National Cancer Institute (NCI) at 12 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 1 year to 21 years
What is being tested?
gamma-secretase/Notch signalling pathway inhibitor RO4929097, diagnostic laboratory biomarker analysis and pharmacological study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
129 participants
Where
12 sitesin 2 countries
Study dates
Mar 2010to May 2011
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
Show all 67Show fewer
  • 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

Who cannot join

None listed.

Trial locations and contacts

12 sites in 2 countries.

12 sites in 2 countries

United States11 sites
  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02115

  • Lurie Children's Hospital-Chicago

    Chicago, Illinois, 60614

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

  • Baylor College of Medicine

    Houston, Texas, 77030

  • Indiana University Medical Center

    Indianapolis, Indiana, 46202

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • Columbia University Medical Center

    New York, New York, 10032

  • Lucile Packard Children's Hospital Stanford University

    Palo Alto, California, 94304

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Stanford University Hospitals and Clinics

    Stanford, California, 94305

Other trials in United States

Canada1 site
  • Hospital for Sick Children

    Toronto, Ontario, M5G 1X8

Other trials in Canada

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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.

  1. To characterize the pharmacokinetics of gamma-secretase inhibitor RO4929097 in children with refractory cancer.

SECONDARY OBJECTIVES:

  1. 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.

Being tested
gamma-secretase/Notch signalling pathway inhibitor RO4929097, diagnostic laboratory biomarker analysis, pharmacological study, dexamethasone
Medical subject headings
Rhabdoid Tumor, Choroid Plexus Neoplasms, Oligodendroglioma, Adenoma, Basophil, Adenoma, Chromophobe, Adenoma, Acidophil, Prolactinoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • gamma-secretase/Notch signalling pathway inhibitor RO4929097Drug

    Also called R4733, RO4929097

    Given PO

  • diagnostic laboratory biomarker analysisOther

    Correlative studies

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • dexamethasoneDrug

    Also called Aeroseb-Dex, Decaderm, Decadron, DM

    Given IV

Study groups in NCT01088763
Study groupRoleWhat they receive
Arm IExperimentalGROUP 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.
Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Other: diagnostic laboratory biomarker analysis; Other: pharmacological study; Drug: dexamethasone

What is being measured

The primary outcome is the main question the study is designed to answer.

  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)

    Measured: 28 days

  2. MTD of RO4929097 administered with dexamethasone determined according to DLTs graded using CTCAE v4.0

    Measured: 28 days

Secondary outcomes (1)
  1. Antitumor activity of RO4929097 with or without dexamethasone assessed by Response Evaluation Criteria for Solid Tumors (RECIST)

    Measured: Up to 30 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Mar 2010 (estimated)
  2. Study startMar 2010
  3. Primary completionMay 2011
  4. Study completionMay 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
129 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01088763
Sponsor's protocol ID
NCI-2011-02024
Other IDs
NCI-2011-02024, COG-ADVL0919, CDR0000667505, ADVL0919, ADVL0919, U01CA097452
Status last verified
Oct 2011
First submitted
16 Mar 2010
Last updated
5 Nov 2014
Results posted
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, diagnostic laboratory biomarker analysis and pharmacological study in people with Childhood Atypical Teratoid/Rhabdoid Tumor and Childhood Central Nervous System Choriocarcinoma, run by National Cancer Institute (NCI) at 12 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 67 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 5 Nov 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early. Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2014.

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