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Adult Anaplastic OligodendrogliomaPhase 1NCT01269411

RO4929097 in Treating Patients With Recurrent Invasive Gliomas

A Phase 1 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, therapeutic conventional surgery and pharmacological study in people with Adult Anaplastic Oligodendroglioma and Adult Brain Stem Glioma, run by National Cancer Institute (NCI) at 1 site in Canada.

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 trial is studying the side effects and best dose of RO4929097 in treating patients with recurrent invasive gliomas. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
gamma-secretase/Notch signalling pathway inhibitor RO4929097, therapeutic conventional surgery and pharmacological study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
22 participants
Where
1 siteCanada
Study dates
Jul 2011to Feb 2012
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 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have radiographic progression of a histologically confirmed glioblastoma, high-grade astrocytoma, NOS, anaplastic mixed oligo-astrocytoma, or anaplastic oligodendroglioma
  • In patients that present radiographic evidence of progression after concurrent treatment with radiation and low-dose temozolomide, diagnosis of progression should be made after at least 2 cycles of monthly temozolomide in order to rule out pseudoprogression
  • Secondary MGs (evolving from a prior low-grade glioma) can be included as long as they are considered malignant in the latest resection
  • Patients must have at least one enhancing lesion that can be accurately measured as > 1 X 1 cm on a MRI
  • Prior treatment must include radiotherapy (with or without temozolomide)
  • No limit to the number of prior recurrences or surgeries
Show all 49Show fewer
  • For Part B only, surgical resection should be considered a reasonable therapeutic option for a patient that can tolerate surgical resection
  • Patients with multifocal disease can be included as long as resection is considered a reasonable option to manage the nodule that is progressing
  • There must be sufficient tissue available (minimum from a 1 X 1 cm lesion) for a biopsy to be taken during surgery
  • There must be sufficient tissue available for evaluation of p75^NTR status from a prior surgery (using immunohistochemistry on fixed tissue or, in uncommon cases in which frozen tissue is available from a prior surgery, western blot) (part B)
  • ECOG performance status < 2 (Karnofsky > 50%)
  • Life expectancy of greater than 4 weeks
  • Absolute neutrophil count > 1,500/mcL
  • Platelets > 100,000/mcL
  • Hemoglobin > 90 g/L (or > 9 g/dL)
  • Total bilirubin < 2.0 mg/dL
  • BUN < 25 mg/dL
  • AST/ALT < 3 X institutional upper limit of normal
  • Creatinine within institutional normal limits OR creatinine clearance > 60 mL/min
  • No major medical illnesses or psychiatric impairments that, in the investigator's opinion, would prevent administration or completion of protocol therapy
  • Not pregnant or nursing
  • Negative serum pregnancy test
  • Fertile patients must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, during, and for 12 months after completion of study therapy
  • Able to swallow pills
  • Patients with a history of seizures need to have had no generalized seizures in the last month prior to entering the study
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097
  • No malabsorption syndrome or other condition that would interfere with intestinal absorption
  • Patients who are serologically positive for hepatitis A, B, or C, and have a resulting positive serological test, or have a history of liver disease, other forms of hepatitis, or cirrhosis are ineligible
  • No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia (within 7 days prior to study treatment), despite adequate electrolyte supplementation
  • No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia other than chronic, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • Baseline QTc ≤ 450 msec (male) or QTc ≤ 470 msec (female)
  • No history of risk factors for QT interval prolongation, including, but not limited to, family or personal history of long QT syndrome, recurrent syncope without known etiology, or sudden unexpected death
  • No history of torsades de pointes or other significant cardiac arrhythmias or the need for concomitant meds with known potential to prolong QT interval or antiarrhythmics
  • Use of food that may interfere with the metabolism of RO4929097 is prohibited, including grapefruit or grapefruit juice
  • Patients must have recovered from the effects of any prior treatment (systemic chemotherapy/radiotherapy) or surgery (<CTCAE grade 2 toxicities related to prior therapy)
  • Patients who have had chemotherapy, surgery, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study are not eligible
  • Patients may not be receiving any other investigational agents
  • Patients cannot be receiving enzyme-inducing anti-epileptic drugs (EIAEDs)
  • If previously treated with EIAEDs, patients must have been switched to non-EIAEDs 4 weeks prior to starting RO4929097
  • Enzyme-inducing antiepileptic drugs (EIAEDs) include: carbamazepine (Tegretol); oxcarbazepine (Trileptal); phenobarbital (or derivatives); phenytoin (Dilantin)
  • 3.1.10.2 Non enzyme-inducing Antiepileptic Drugs (Non-EIAEDs) include: clobazam (Frisium); clonazepam (Rivotril); gabapentin (Neurontin); levetiracetam (Keppra); lamotrigine (Lamictal); topiramate (Topamax)
  • No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
  • Even though dexamethasone is a moderate inducer of CYP3A4, patients may remain on dexamethasone at the lowest dose possible
  • Stable or decreasing steroid dose within 5 days prior to registration required
  • No medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
  • No other investigational or commercial agents or therapies may be administered with the intent to treat the patient's malignancy
  • No re-irradiation (any technique) is allowed
  • If a patient elects to have a new resection of his/her tumor in the absence of progression of the disease, treatment will be discontinued and no re-challenge will be allowed after this additional surgery

Who cannot join

None listed.

Trial locations and contacts

1 site in 1 country.

Canada1 site

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

Official title: Phase I Pharmacodynamic and "High Content" Study of the Gamma-Secretase Inhibitor RO4929097 in Patients With Recurrent Malignant Gliomas (MGs) Targeting p75NTR to Inhibit Brain Tumor Initiating Cells (BTICs) and Recurrent Invasive Gliomas

This phase I trial is studying the side effects and best dose of RO4929097 in treating patients with recurrent invasive gliomas. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Read the detailed description

PRIMARY OBJECTIVES:

  1. Determine, in patients with recurrent MGs (many of whom receive dexamethasone, a moderate CYP3A4 inducer), the safety and maximum-tolerated dose of RO4909297 administered at 2 dose levels.

II. Determine the pharmacokinetics, intratumoral drug concentration, target modulation, and evidence of any treatment effect in the malignant glioma tumor tissue by R04929097 administered at the dose found in Part A.

SECONDARY OBJECTIVES:

  1. Determine the pharmacokinetic (PK) profile of RO4909297 in patients with recurrent MGs (many of whom receive dexamethasone, a moderate CYP3A4 inducer).

II. Determine the progression-free survival of patients with recurrent malignant glioma following treatment with R04929097.

III. Determine if the RPTD dose of RO4929097 significantly inhibits p75^NTR cleavage and processing.

IV. Determine the effects of RO4929097 on the establishment and growth of BTIC cultures in neurosphere growth conditions, effects on proliferation, ability to self-renewal, and ability to differentiate along lineage-specific pathways.

  1. Determine the ability of RO4929097 to inhibit Notch signaling, by assessing downstream target activation, in glioma tissue of patients with recurrent MG.

VI. Determine the association between a number of serum, tumor, and BTIC markers and response to R04929097.

OUTLINE: This is a multicenter, dose-escalation (part A) study followed by an open-label (part B) study.

PART A: Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PART B: Patients receive oral RO4929097 once daily on days 1-7 and undergo surgery on day 8. Beginning 28 days later, patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Post resection tumor specimens are collected for correlative studies, including pharmacokinetic and biomarker assays.

After completion of study therapy, patients are followed up at 30 days and then every 3 month for up to 6-12 months.

Being tested
gamma-secretase/Notch signalling pathway inhibitor RO4929097, therapeutic conventional surgery, pharmacological study, laboratory biomarker analysis
Medical subject headings
Oligodendroglioma, Glioblastoma, Gliosarcoma, Glioma, Brain Neoplasms

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 orally

  • therapeutic conventional surgeryProcedure or surgery

    Undergo surgery

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • laboratory biomarker analysisOther

    Correlative

Study groups in NCT01269411
Study groupRoleWhat they receive
Treatment (RO4929097 and surgery)ExperimentalPART A: Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. PART B: Patients receive oral RO4929097 once daily on days 1-7 and undergo surgery on day 8. Beginning 28 days later, patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Procedure: therapeutic conventional surgery; Other: pharmacological study; Other: laboratory biomarker analysis

What is being measured

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

  1. Maximum-tolerated dose (MTD) defined as the dose level in which less than or equal to 1 out of 6 patients experience dose limiting toxicity (DLT) assessed using NCI CTCAE version 4.0

    Measured: 21 days

  2. Pharmacokinetic (PK) profile of RO4909297

    Measured: Pre-dose, 1, 2, 4, 8, and 24 hours

Secondary outcomes (4)

  1. Progression-free survival following treatment with R04929097

    The Kaplan-Meier method will be used.

    Measured: From registration to time of progression or death, whichever occurs first, assessed up to 12 months

  2. Inhibition of p75NTR cleavage and processing

    Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients. The Wilcoxon signed-rank and rank sum tests will be used.

    Measured: Up to 12 months

  3. Establishment and growth of BTIC cultures in neurosphere growth conditions, effects on proliferation, ability to self-renewal, and ability to differentiate along lineage-specific pathways

    Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients. The Wilcoxon signed-rank and rank sum tests will be used.

    Measured: Up to 12 months

  4. Inhibition of Notch signaling, by assessing downstream target activation

    Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients. The Wilcoxon signed-rank and rank sum tests will be used.

    Measured: Up to 12 months

Timeline

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

  1. First posted4 Jan 2011 (estimated)
  2. Study startJul 2011
  3. Primary completionFeb 2012

Why it stopped: Administratively complete.

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
22 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01269411
Sponsor's protocol ID
NCI-2011-02565
Other IDs
PHL-075, N01CM00032, CDR0000691784
Status last verified
Feb 2013
First submitted
31 Dec 2010
Last updated
7 Feb 2013
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, therapeutic conventional surgery and pharmacological study in people with Adult Anaplastic Oligodendroglioma and Adult Brain Stem Glioma, run by National Cancer Institute (NCI) at 1 site in Canada.

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 49 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 7 Feb 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in 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 (reason given: Administratively complete.). 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) defined as the dose level in which less than or equal to 1 out of 6 patients experience dose limiting toxicity (DLT) assessed using NCI CTCAE version 4.0 (time frame: 21 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?

On the ClinicalTrials.gov record for NCT01269411.

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 7 Feb 2013.

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