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Trial registered on ANZCTR


Registration number
ACTRN12614000552684
Ethics application status
Approved
Date submitted
12/05/2014
Date registered
22/05/2014
Date last updated
22/05/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 study of Temozolomide, Irinotecan, and O6BG (O6-Benzylguanine) for Children with Recurrent or Resistant Neuroblastoma
Scientific title
A Phase 1 study of Temozolomide, Irinotecan, and O6BG (O6-Benzylguanine) for Children with Recurrent or Resistant Neuroblastoma
Secondary ID [1] 284578 0
Nil
Universal Trial Number (UTN)
U1111-1156-7081
Trial acronym
The TIO Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent Neuroblastoma 291867 0
Resistant neuroblastoma 291868 0
Condition category
Condition code
Cancer 292219 292219 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment with O6BG (O6-Benzylguanine) intravenously (120mg/m2/day), Temozolomide* orally and Irinotecan (50 mg/m2/day) intravenously, for 5 days; followed by Peg-GCSF (100 mcg/kg) given subcutaneously on day 6.

O6BG is given at 0-1hr; temozolomide at 1-1.5hr and irinotecan at 1.5-2.5 hr everyday for 5 days.

*Temozolomide will start at dose 0 (55 mg/m2/day) and doses may be escalated or decreased based on the 3+3 Phase 1 study design (see study type/design section below). The other doses of temozolomide that patients may be treated at are: dose 1: 75 mg/m2/day; dose 2: 100 mg/m2/day or dose -1: 40 mg/m2/day.

Cycles last a minimum of 21 days and will continue as per protocol or physician discretion. All medications will be given in clinic except for the day 6 Peg-GCSF which may be given at home as per routine clinical practice.
Intervention code [1] 289355 0
Treatment: Drugs
Comparator / control treatment
This is a dose escalation study - no control or placebo will be used
Control group
Uncontrolled

Outcomes
Primary outcome [1] 292089 0
Determination of the maximum tolerated dose of temozolomide in combination with fixed doses of irinotecan and O6-benzylguanine, using standard toxicity assessments and a 3+3 Phase I design.

Standard toxicity assessments will be assessed using the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) of the National Cancer Institute (NCI).
Timepoint [1] 292089 0
Primary timepoint will be able to be calculated once sufficient numbers of patients have been treated at the doses dependent on the 3 + 3 design.
Secondary outcome [1] 308190 0
Description of the toxicity profile of this combination (including dose limiting toxicities - DLTs) using Common Terminology Criteria for Adverse Events v4.0 (CTCAE) as defined by the National Cancer Institute (NCI).
Timepoint [1] 308190 0
This will be calculated for each patient (using toxicity monitoring) from the first day of chemotherapy and will be reported for each dose assessed in the study until disease progression or death.
Secondary outcome [2] 308191 0
Description of tumour responses and time to tumour progression.

Tumour assessments will be carried out using any of the following tools: MRI/CT/X-ray/MIBG/assessment of bone marrow tumour cells if bone marrow involvement. The same tool must be used for re-assessment throughout the trial.
Timepoint [2] 308191 0
This will be reported and reviewed throughout the study for safety profiling and reporting. The final data will be collated at the end of study. Patients will continue to be followed up, at 3,6 and 9 months post treatment and then annually thereafter for up to 5 years.
Secondary outcome [3] 308192 0
Description of the feasibility of treatment of 12 patients at the MTD. For this study, the regimen will be considered feasible if :
a) > 70% of courses at the MTD can be administered without delays of > 7 days, and b) > 70% of courses at the MTD can be administered without dose reductions.
Timepoint [3] 308192 0
Once the MTD is reached and 12 patients have been treated on the MTD
Secondary outcome [4] 308237 0
Evaluate the impact of methylation of the MGMT gene (in previously resected tumour specimens) on activity of the study regimen.
Timepoint [4] 308237 0
At the conclusion of the study. Samples that may have been stored in the CHW Tumour Bank from an earlier surgery will be requested from the CHW Tumour Bank for all enrolled study participants who have consented to this part of the study. An external laboratory will assess the methylation of the MGMT gene and this information will be assessed alongside treatment response.

Eligibility
Key inclusion criteria
*Age - Patients must be 1- 16 years of age at the time of study entry.
*Diagnosis - Patients must have had a diagnosis of neuroblastoma either by histological verification of neuroblastoma and/or demonstration of tumour cells in the bone marrow with increased urinary catecholamines. Participants are not required to have measurable disease at the time of study entry.
*Disease status - Patients must have neuroblastoma with at least ONE of the following:
-Recurrent/progressive disease at any time. A new biopsy of current tumour sites is not required to document eligibility.
-Resistant disease (i.e. less than a partial response to frontline therapy with minimum of 4 cycles of chemotherapy). No new biopsy is required for eligibility for study for this patient group.
-Persistent disease after at least a partial response to frontline therapy (i.e. patient has had at least a partial response to frontline therapy but still has residual disease by MIBG, CT/MRI, or bone marrow). Patients in this category are REQUIRED to have a biopsy of at least one residual site demonstrating viable neuroblastoma. Tumour by routine bone marrow morphology is sufficient for this patient group to verify persistent disease although bone marrow alone is insufficient for eligibility into the study. If biopsy and/or bone marrow aspirate cell detection demonstrates only ganglioneuroma, then patient is not eligible.
*Location of disease - Patients must have at least ONE of the following sites of disease:

-Tumour on MRI or CT scans or X-ray. For patients with persistent disease, as in point (3) above, a biopsy of site seen on CT/MRI must have demonstrated viable neuroblastoma. If the lesion was radiated, then biopsy must be done > 4 weeks after radiation completed.

-MIBG scan with positive uptake at a minimum of one site. For patients with persistent disease, as in point (3) above, a biopsy of an MIBG positive site must demonstrate viable neuroblastoma. If the lesion was irradiated, then biopsy must be done > 4 weeks after radiation completed.

-Bone marrow with tumour cells seen on routine morphology (not by immunocytology staining only) of one bone marrow sample of a bilateral aspirate and/or biopsy.
*Life Expectancy
Must have a life expectancy of at least 8 weeks.
*Performance level - Performance will be assessed using a Lansky score which must be greater than or equal to 50% for children less than or equal to 16 years of age. Patients who are unable to walk because of paralysis but who are up and in a wheelchair will be considered ambulatory for the purposes of assessing the performance scale.
*Prior Therapy - Patients need to have exhausted standard curative options of therapy.

There is no limit to the number of prior regimens allowed. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
-Myelosuppressive chemotherapy and/or biologics: 2 weeks
-Autologous stem cell transplant, including non-myeloablative therapy with stem cell support: 6 weeks
-Radiotherapy (XRT): No treatment within 2 weeks of study entry. Six week delays are required following large field radiation (TBI, craniospinal, whole abdomen, total lung, >50% marrow space).
-MIBG therapy: 6 weeks
*Organ Function Requirements
1.Adequate Bone Marrow Function Defined as:
-Absolute neutrophil count (ANC) > 1,000/microl
-Platelets > 100,000/microl (transfusion independent, i.e. patients must not have received platelet transfusions within 7 days of enrolment)
-Patients may have bone marrow involvement as long as eligibility criteria met.

*Adequate Renal Function Defined As:
-Serum creatinine <= 1. 5X upper limit of normal
OR
-A normal serum creatinine based on age.

*Adequate Liver Function Defined As:
-AST and ALT <= 3X upper limit normal
AND
-total bilirubin <= 1.5X upper limit normal for age

*Regulatory Requirements - All patients and/or their parents or legal guardians must sign a written informed consent. All institutional ethics requirements for human studies must be met prior to patient accrual. A patient, parent and youth information sheet and consent form have been prepared for this study.
Minimum age
1 Years
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Pregnancy or Breast-Feeding: Pregnant or lactating females are ineligible as the medications used in this protocol could be harmful to unborn children and infants. Pregnancy tests must be obtained in girls who are post-menarche. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
*Uncontrolled Infection: Patients who have an uncontrolled active infection are excluded from this study.
*Previous Treatment:
1. Patients who have previously received allogeneic stem cell transplant are excluded from this study.
2. Patients treated with temozolomide and/or irinotecan are able to be treated on this study but not those treated with temozolomide, irinotecan and O6BG.
*Other: Patients with diarrhoea at enrolment defined as 3 or more loose stools per day are excluded from this study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is an open-label study - so there are no allocation concealment procedures. Patients will be enrolled by their treating doctor based on eligibility criteria. Interested participants will need to complete a youth information sheet and consent form if they are capable of doing so and their carers will need to complete a parent information sheet and consent form.
All participants and their parents or legal guardians will be required to give their informed consent to be enrolled on this study. If the participants are too young to comprehend the clinical trial information then their parent's/guardian's consent alone will suffice.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is an non-randomised study. All participants will receive the same three drugs. This is a dose escalation study and therefore participants recruited to the study later in the study may receive higher or lower doses of Temozolomide than those patients recruited in the initial cohort.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
3 + 3 Phase 1 Study design
3 patients are treated at dose 0 of Temozolomide.
If 0/3 patients have a severe toxicity reaction (ie a dose limiting toxicity) by the end of the first cycle, the dose escalates to Dose 1.
If 1/3 patients encounter a severe toxicity reaction (ie a dose limiting toxicity) by the end of the first cycle, three more patients are treated at Dose 0; If one or more experience a severe toxicity reaction (ie a dose limiting toxicity) by the end of the first cycle, the MTD has been exceeded. If 2/6 or more experience a Dose Limiting Toxicity the Maximum Tolerated Dose has been exceeded and the dose is potentially de-escalated. If only 1/6 DLTs is observed then the dose can be escalated. If 0 experience a severe toxicity reaction (ie a dose limiting toxicity) by the end of the first cycle, the next 3 patients proceed to Dose 1.
This is repeated as per above.

Translational aspect of the study: The MGMT (methylguanine methyltransferase) protein helps tumour cells protect their DNA from temozolomide damage. Methylation of the MGMT gene reduces the amount of protein produced and thereby affects the action of temozolomide. We are interested in finding out the methylation of this gene.

Methylation of the MGMT gene may be correlated with reduced MGMT protein levels. In this study, we are interested in analysing the MGMT methylation status of the patients' original tumours and whether this correlates with their response to temozolomide. This will be explained in the trial information sheet and be an optional part of the study. Participants and/or their parents/guardians can consent to the study but not to this extra testing.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
The number of patients needed for the study is estimated to be between 15-24, the final number will be determined by the dose limiting toxicities of the 3 drug combination and the 3+3 Phase 1 study design.

Patients who receive the first dose of the study medication will be counted as a study participant. All patients will be evaluable for toxicity from the time of this intervention.

The outcomes of this cancer therapy, in terms of tumour response rates and duration of disease control are of interest, and these data will be collected. Given the heterogeneity of the patients’ diagnoses, and the small number of patients, definitive conclusions regarding chemotherapy efficacy will not be possible. Such analyses will require larger, successor studies, should the approach prove feasible.

Patient Recruitment and Dose Escalation Notes:
This study will use the 3+3 Phase 1 study design. An estimated total of 15-24 patients may be required to complete this study. The projected accrual rate is estimated at 6-10 patients per year; therefore, it is expected that this study will be completed in 2-3 years.

The DSMC will review the doses of temozolomide and safety data after each set of 3 patients have received therapy. After each review, it will be determined if dose escalation is possible for the next set of 3 patients. Upon reaching the MTD, a total of 6-9 more patients, to a total of 12 patients, will be treated at the MTD to evaluate further the MTD for feasibility and toxicity.
The study team will consider stopping the study for futility if half of the patients treated are taken off study due to toxicity at the treatment dose level -1 or the study aims are considered unachievable.

A statistician will assess the study results.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 2451 0
The Children's Hospital at Westmead - Westmead

Funding & Sponsors
Funding source category [1] 289217 0
Charities/Societies/Foundations
Name [1] 289217 0
The Kids Cancer Project will provide funding for the manufacture of the O6BG drug.
Address [1] 289217 0
The Kids' Cancer Project
PO Box 6400
Alexandria, NSW 2015

Country [1] 289217 0
Australia
Primary sponsor type
Hospital
Name
The Sydney Children's Hospitals Network
Address
Locked Bag 4001
Westmead NSW 2145
Country
Australia
Secondary sponsor category [1] 287939 0
None
Name [1] 287939 0
Address [1] 287939 0
Country [1] 287939 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290985 0
The Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 290985 0
Locked Bag 4001
Westmead
2145 NSW
Ethics committee country [1] 290985 0
Australia
Date submitted for ethics approval [1] 290985 0
06/02/2014
Approval date [1] 290985 0
14/05/2014
Ethics approval number [1] 290985 0
HREC/14/SCHN/53

Summary
Brief summary
This study aims to evaluate whether treatment with Temozolomide, Irinotecan, and O6BG (O6-Benzylguanine) is tolerable, feasible, and effective for children with recurrent or resistant neuroblastoma (within the confines of a Phase 1 study).

Who is it for?
You or your child may be eligible to join this study if you/they are aged between 1-16 years and have had a diagnosis of neuroblastoma and it has recurred or is resistant to treatment. Patients need to have exhausted standard curative options of therapy, and must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

Study details
All participants in this study will undergo chemotherapy treatment with the drugs Temozolomide and Irinotecan, in conjunction with a new investigative agent known as O6BG (O6-Benzylguanine), followed by Peg-GCSF treatment. This is a dose escalation study design, which means that earlier patients will start on lower doses and this will determine the dose that later patients receive.

The O6BG (120 mg/m2/day) is given first by intravenous infusion over one hour, followed by oral temozolomide (dependent on dose escalation stage of the study - 40/55/75 or 100 mg/m2/day) and after half an hour, the irinotecan (50 mg/m2/day) is given intravenously for one hour. This treatment is repeated for four more days (i.e. over a total of 5 days). On day 6, the patient is given Peg-GCSF (100 mcg/Kg). Each treatment cycle lasts a minimum of 21 days.

Treatment will continue every 21 days until the doctor believes there is no more benefit for the patient. Participants will be regularly monitored to evaluate toxicity (weekly), feasibility of treatment and disease response (every 2 months) until the end of treatment and then every 3 months after treatment until the one year anniversary of the patient starting treatment; at which point patients will be monitored annually therafter up to 5 years.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 48274 0
Dr Geoff McCowage
Address 48274 0
The Children's Hospital at Westmead
Oncology Department
Locked Bag 4001
Westmead 2145 NSW
Country 48274 0
Australia
Phone 48274 0
+612 9845 2141
Fax 48274 0
+612 9845 2171
Email 48274 0
geoff.mccowage@health.nsw.gov.au
Contact person for public queries
Name 48275 0
Dr Kimberley Lilischkis
Address 48275 0
The Children's Hospital at Westmead
Oncology Department
Locked Bag 4001
Westmead 2145 NSW
Country 48275 0
Australia
Phone 48275 0
+612 9845 2138
Fax 48275 0
+612 9845 2171
Email 48275 0
kimberley.lilischkis@health.nsw.gov.au
Contact person for scientific queries
Name 48276 0
Dr Geoff McCowage
Address 48276 0
The Children's Hospital at Westmead
Oncology Department
Locked Bag 4001
Westmead 2145 NSW
Country 48276 0
Australia
Phone 48276 0
+612 9845 2141
Fax 48276 0
+612 9845 2171
Email 48276 0
geoff.mccowage@health.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
No Results