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Trial registered on ANZCTR


Registration number
ACTRN12613000423718
Ethics application status
Approved
Date submitted
5/04/2013
Date registered
16/04/2013
Date last updated
16/04/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
A phase I study of vinorelbine, cyclophosphamide and Rapamycin for recurrent malignancies in children
Scientific title
A study in children with recurrent malignancies of vinorelbine, cyclophosphamide and rapamycin to assess the feasibility, safety and maximum tolerated dose of this three drug combination in heavily pre-treated and less heavily pre-treated cohorts of patients.
Secondary ID [1] 282258 0
Nil
Universal Trial Number (UTN)
U1111-1141-5343
Trial acronym
RapCV
Linked study record

Health condition
Health condition(s) or problem(s) studied:
recurrent malignancies 288785 0
Condition category
Condition code
Cancer 289144 289144 0 0
Children's - Other
Cancer 289145 289145 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Chemotherapy Days 1-28:
Cyclophosphamide once per day orally according to allocated dose level as per dose levels below.
Rapamycin orally at an initial dosage of 0.8mg/m2/dose twice per day. Dosing will be pharmacologically adjusted on a weekly basis to maintain a trough Rapamycin level between 10 and 15 ng/ml.
Days 1,8,15: vinorelbine intravenously at allocated dose level as per dose levels below.
Repeat cycle every 28 days.

Dose Level 0 = 20 mg/m2/day of cyclophosphamide and 20 mg/m2/week days 1,8,15 of vinorelbine.

Dose Level 1 = 25 mg/m2/day of cyclophosphamide and 20 mg/m2/week days 1,8,15 of vinorelbine.

Dose Level 2 = 25 mg/m2/day of cyclophosphamide and 25 mg/m2/week days 1,8,15 of vinorelbine.

Dose Level -1 (if the first dose level "Dose Level 0" is not tolerated) = 15 mg/m2/day of cyclophosphamide and 10 mg/m2/week days 1,8,15 of vinorelbine.

Each cycle will be considered to be 28 days. Proceed to 2nd and subsequent cycles if platelet counts are acceptable, all toxicities from previous treatment cycles have been resolved and there is no evidence of disease progression. In the absence of tumour progression and/or unacceptable toxicities, the treatment cycles can continue at the treating doctor’s discretion.

Sirolimus levels will be measured by blood tests. A take home medication diary will be used to record any take home tablets.

Participants remain on the same allocated dose level throughout treatment. There is no dose escalation for individual patients.
Intervention code [1] 286881 0
Treatment: Drugs
Comparator / control treatment
This study is a Phase I dose escalation study. Each dose level is uncontrolled.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 289253 0
To determine the safety and tolerability of the combination of vinorelbine, cyclophosphamide, and Rapamycin in children aged less than 22 years old with recurrent or refractory solid tumour/malignant disease who have failed initial and possibly subsequent conventional therapy.

All participants will be closely monitored for adverse drug reactions. Adverse reactions will be recorded and assessed according to CTCAE version 4.
Timepoint [1] 289253 0
Outcome assessed during all treatment cycles for each patient; during treatment phase of study.
Primary outcome [2] 289254 0
To determine the recommended dose combination of vinorelbine, cyclophosphamide, and Rapamycin in children aged less than 22 years old with recurrent or refractory solid tumour/malignant disease who have failed initial and possibly subsequent conventional therapy.
The MTD will be the maximum dose at which fewer than one-third of patients experience DLT during cycle 1 and cycle 2 of therapy.

Adverse events, including those that fulfil the definition of a dose limiting toxicity, will be monitored and reported during all cycles of therapy and up to 30 days following the end of treatment. Only dose limiting toxicities occurring in cycle 1 and cycle 2 will be used to define the maximum tolerated dose.
Timepoint [2] 289254 0
Outcome assessed during first two cycles of treatment for each patient; during treatment phase of study.
Secondary outcome [1] 302111 0
To determine the response of recurrent solid tumour/malignant disease to the combination of vinorelbine, cyclophosphamide, and Rapamycin in children aged less than 22 years old with recurrent or refractory solid tumour/malignant disease who have failed initial and possibly subsequent conventional therapy.
Tumours will be evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1.
Timepoint [1] 302111 0
Outcome assessed after 2nd treatment cycle and every 2 treatment cycles thereafter until patient is off study.
Secondary outcome [2] 302112 0
To determine the progression-free survival for children less than 22 years old that had recurrent or refractory solid tumour/malignant disease and were treated with the combination of vinorelbine, cyclophosphamide, and Rapamycin.
Tumours are evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1.
Timepoint [2] 302112 0
Outcome assessed until the last patient recruited is five years off treatment.

Eligibility
Key inclusion criteria
1. Patients must be < 22 years of age at the time of study entry.
2. Patients must have had histologic verification of the solid tumour/malignancy either at the time of original diagnosis or at relapse (excluding brain stem and optic pathway tumours). Participants are not required to have measurable disease at the time of study entry. The following histologies are eligible: All brain tumours, Rhabdomyosarcoma, Soft tissue sarcomas, Osteogenic sarcoma, Ewing sarcoma, Neuroblastoma, Wilms’ tumour.
3. Patient’s disease must be relapsed or refractory following initial therapy.
4. Patient’s disease must be one for which there is no curative therapy.
5. Performance: Karnofsky greater than or equal 50% for patients 16 years of age and over and Lansky greater than or equal 50 for patients less than 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 performance score.
6. Life expectancy must be greater than or equal 8 weeks
7. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea). Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. XRT: greater than or equal 2 wks for local palliative XRT (small port); greater than or equal 6 months must have elapsed if prior craniospinal XRT or if greater than or equal 50% of the pelvis has been radiated; greater than or equal 6 wks must have elapsed if other substantial BM radiation. Patients with recurrent brain tumours should be greater than or equal 8 weeks from completion of standard fraction radiation unless there is biopsy proof of the presence of recurrent tumour. Patients who underwent radiosurgery within 9 months must have documentation of progressive disease either by biopsy, PET scan or MR spectroscopy.
8. Concomitant medications: Growth factor(s) must not have received within 1 week of entry onto this study. Systemic corticosteroid therapy is permissible only in patients with CNS tumours for treatment of increased intracranial pressure or symptomatic tumour oedema. Patients with CNS tumours who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to study entry.
9. Organ Function Requirements: Adequate Bone Marrow Function Defined as: Peripheral absolute neutrophil count (ANC) > 1000/microL, Platelet count > 100,000/microL (transfusion independent, i.e. patients must not have received platelet transfusions within 7 days of enrolment), Haemoglobin > 80.0 g/L (may receive RBC transfusions). Adequate Renal Function Defined As: Creatinine clearance or radioisotope GFR greater than or equal 70ml/min/1.73 m2 and a normal serum creatinine based on age. Adequate Liver Function Defined As: Total bilirubin < 1.5 x upper limit of normal (ULN) for age, and ALT < 2.5 x upper limit of normal (ULN) for age and albumin greater than or equal 20 g/L.
10. 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.
Minimum age
0 Years
Maximum age
21 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. 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.
2. Patients who have an uncontrolled infection are excluded from this study.
3. Patients who have previously received Rapamycin, Everolimus, Tacrolimus or Temsirolimus 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)
At study entry, all participants will be stratified according to their treatment history. Stratum 1 participants are those that are heavily pre-treated(have received chemotherapy within six months of study entry; have received prior nitrosourea or have received prior craniospinal radiation). Stratum 2 patients are those that are less heavily pre-treated (i.e. do not meet the afore-mentioned criteria for heavily treated. The treatment plan for both strata is identical, although outcome measures will be analysed separately for the two strata.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable, no randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The Rolling Six phase 1 trial design will be used for the conduct of this study. Two to six patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of patients enrolled at the current dose level, (2) the number of patients who have experienced DLT at the current dose level, and (3) the number of patients entered but with tolerability data pending at the current dose level. Accrual is suspended when a cohort of six has enrolled or when the study endpoints have been met.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
The maximim tolerated dose will be the maximum dose at which fewer than one-third of patients experience a dose limiting toxicity (DLT) during Cycles 1-2 of therapy. In the event that two DLTs observed in 6 evaluable patients within a dose level are considered different classes of Adverse Effects (e.g. hepatotoxicity and myelosuppression), expansion of the cohort to 12 patients will be considered if all of the following conditions are met: One of the DLTs does not appear to be dose-related, the Adverse Effects are readily reversible.
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting toxicities, the dose escalation can proceed.

All patients will be evaluable for toxicity from the time of their first treatment. Any patient who experiences DLT at any time during protocol therapy is considered evaluable for Adverse Events. Patients without DLT who receive at least 85% of the prescribed dose per protocol guidelines during Cycles 1 and 2 are also considered evaluable for Adverse Events. Patients who are not evaluable for Adverse Events during Cycle 1 and 2 will be replaced.
The Rolling Six phase 1 trial design will be used for the conduct of this study. Two to six patients can be concurrently enrolled onto a dose level, dependent upon (1) the
number of patients enrolled at the current dose level, (2) the number of patients who have experienced DLT at the current dose level, and (3) the number of patients entered but with tolerability data pending at the current dose level. Accrual is suspended when a cohort of six has enrolled or when the study endpoints have been met.

Dose level assignment is based on the number of participants currently enrolled in the cohort, the number of DLTs observed, and the number of participants at risk for
developing a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, when three participants are enrolled onto a dose cohort, if toxicity data is available for all three when the fourth participant entered and there are no DLTs, the dose is escalated and the fourth participant is enrolled to the subsequent dose level. If data is not yet available for one or more of the first three participants and no DLT has been observed, or if one DLT has been observed, the new participant is entered at the same dose level. Lastly, if two or more DLTs have been observed, the dose level is de-escalated. This process is repeated for participants five and six. In place of suspending accrual after every three participants, accrual is only suspended when a cohort of six is filled. When participants are inevaluable for toxicity, they are replaced with the next available participant if escalation or de-escalation rules have not been fulfilled at the time the next available participant is enrolled onto the study.
Overall, a minimum of 12 (6 in each stratum) and a maximum of 48 (24 in each stratum) patients will be enrolled on this study.

Recruitment
Recruitment status
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,WA
Recruitment hospital [1] 839 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [2] 840 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [3] 841 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 6659 0
2145 - Westmead
Recruitment postcode(s) [2] 6660 0
2310 - Hunter Region
Recruitment postcode(s) [3] 6661 0
6840 - Perth

Funding & Sponsors
Funding source category [1] 287024 0
Self funded/Unfunded
Name [1] 287024 0
Address [1] 287024 0
Country [1] 287024 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australian New Zealand Childrens Haematology Oncology Group
Address
PO Box 5418
Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 285806 0
None
Name [1] 285806 0
Address [1] 285806 0
Country [1] 285806 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289062 0
Sydney Childrens Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 289062 0
The Childrens Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Ethics committee country [1] 289062 0
Australia
Date submitted for ethics approval [1] 289062 0
Approval date [1] 289062 0
24/03/2010
Ethics approval number [1] 289062 0
09/CHW/156
Ethics committee name [2] 289063 0
Princess Margaret Hospital for Children Ethics Committee
Ethics committee address [2] 289063 0
Princess Margaret Hospital
Roberts Rd
Subiaco
Western Australia 6008
Ethics committee country [2] 289063 0
Australia
Date submitted for ethics approval [2] 289063 0
Approval date [2] 289063 0
07/03/2013
Ethics approval number [2] 289063 0
2013008EP

Summary
Brief summary
This study will evaluate the safety and tolerability of combining the 3 drugs, vinorelbine, cyclophosphamide, and Rapamycin, in children with recurrent/refractory malignant disease. Who is it for? You (or your child) may be eligible to join this study if you/they are aged less than 22 years of age and have been diagnosed with any of the following solid tumours/malignancies: all brain tumours, Rhabdomyosarcoma, Soft tissue sarcomas, Osteogenic sarcoma, Ewing sarcoma, Neuroblastoma, Wilms’ tumour. The disease must have either relapsed or not responded to initial therapy. Trial details All participants in this trial will undergo treatment with a combination of the three drugs vinorelbine, cyclophosphamide, and rapamycin. Cyclophosphamide is administered one per day orally, rapamycin is administered twice per day orally, and vinorelbine will be administered on days 1, 8 and 15 of each 28 day cycle intravenously (i.e. into the vein). This cycle will be repeated every 28 days. If the initial dose level is tolerated by patients, then it will be increased for the next patient group in order to determine the optimum dose combination for both heavily pre-treated and less heavily pre-treated participants. In addition to evaluating the toxicity of this drug regimen and determining a dosage range, the potential efficacy of the regimen will be assessed. All participants will be regularly monitored and assessed for a period of up to 5 years in order to evaluate the safety and tolerability of this treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39046 0
Dr Geoff McCowage
Address 39046 0
Oncology Department
The Childrens Hospital at Westmead
Locked Bag 4001
Westmead
NSW 2145
Country 39046 0
Australia
Phone 39046 0
+61298452141
Fax 39046 0
Email 39046 0
geoff.mccowage@health.nsw.gov.au
Contact person for public queries
Name 39047 0
Dr Geoff McCowage
Address 39047 0
Oncology Department
The Childrens Hospital at Westmead
Locked Bag 4001
Westmead
NSW 2145
Country 39047 0
Australia
Phone 39047 0
+61298452141
Fax 39047 0
Email 39047 0
geoff.mccowage@health.nsw.gov.au
Contact person for scientific queries
Name 39048 0
Dr Geoff McCowage
Address 39048 0
Oncology Department
The Childrens Hospital at Westmead
Locked Bag 4001
Westmead
NSW 2145
Country 39048 0
Australia
Phone 39048 0
+61298452141
Fax 39048 0
Email 39048 0
geoff.mccowage@health.nsw.gov.au

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