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Trial registered on ANZCTR


Registration number
ACTRN12618001934235
Ethics application status
Approved
Date submitted
5/11/2018
Date registered
28/11/2018
Date last updated
28/11/2018
Date data sharing statement initially provided
28/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to evaluate the safety,tolerability and pharmacokinetics of ACT001 in children with advanced brain and solid tumors
Scientific title
A phase 1 dose-escalation study to evaluate the safety, tolerability and pharmacokinetics of ACT001 in children with advanced brain and solid tumors.
Secondary ID [1] 296432 0
ACT001-AU-002 (Sponsor protocol number)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
advanced brain tumor 310194 0
advanced solid tumors 310195 0
Condition category
Condition code
Cancer 308941 308941 0 0
Children's - Brain
Cancer 308942 308942 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ACT001 self administration will be done twice-daily, in the morning and in the evening, separated by approximately 12 hours and within 30 minutes of completing a meal or snack. Patients will self administer ACT001 orally with a full cup (approximately 240 mL) of noncarbonated room temperature water. Additional water is permitted, if needed, with a maximum of 480 mL.

Alternatively, capsules are able to be opened and dissolved in apple juice with mixing. 100mg ACT001 is well dissolved in 1ml apple juice and is stable at room temperature (25oC) for 24h or at 2-8oC for 10 days.

The study has two parts:
a. Part A
This part of the study will seek to identify the MTD in children with advanced brain or solid tumors. The starting dose will be 80% of the adult RP2D based on body surface area. Evaluation of a cohort of at least three (3) patients completing one cycle of treatment at that dose level is required prior to determining the dose level and dose regimen for the next cohort. If 80% of the adult RP2D is not tolerated, 50% the adult RP2D will be investigated. One cycle has a duration of 28 days. Participants will undergo in one dose level only.

Dose Level % of Adult RP2D Dose/m2
-1 (de-escalation) 50% 117.5 mg/m2 twice a day
1 (starting dose) 80% 118 mg/m2 twice a day
2 100% 235 mg/m2 twice a day
3 125% 295 mg/m2 twice a day

Study duration for participants in the active treatment phase will consist of 2 weeks for completion of screening and up to 24 months of treatment depending on the disease state and tolerability to ACT001 in addition to a safety follow-up visit within 28 days of the last dose. If a patient has a sustained clinical / radiological response by RECIST criteria they may continue ACT001 treatment until they experience an unacceptable adverse event, disease progression or they wish to withdraw consent. Patients will discontinue study drug if there is radiologic evidence of progression unless the investigator determines that the patient is likely to derive benefit from continuing treatment with the study drug.

Continuation of treatment beyond 24 months may be considered, if patients are receiving clinical benefit from the study, at the discretion of the Sponsor. The decision to continue on study should be made by the treating physician and the patient/parent/guardian in consultation with the study chair. If a patient is noted to still have ongoing toxicities at the 30 day safety follow-up visit, they will then be evaluated every 30 days until the toxicity(s) resolves to baseline, stabilizes or is deemed irreversible.

After discontinuation of the active treatment phase, patients will be requested to participate in long term follow-up to assess overall survival. Contact will be made with patient/parent/guardians approximately every 3 months from ending active participation. Long term follow-up will continue for at least 12 months after the last patient is enrolled in the study. Patient/parent/guardians who withdraw full consent will not participate in the long term follow-up.

Part B
The dose expansion phase will involve enrolling an additional 10 patients at the ACT001 Recommended Phase II Dose (RP2D) as defined in Part A. The same Enrolment in Part B will be restricted to children with DIPG, Diffuse Midline H3 K27M glioma post RT, or other high grade glioma after recurrence or progression.

The dosing frequency, duration and mode of administration of ACT001 will follow the same procedures as Part A. Patient Diary will be utilized for both Parts A and B to monitor adherence to intervention.
Intervention code [1] 312766 0
Treatment: Drugs
Comparator / control treatment
Each new cohort will use the previous ones as control group. All patients will receive active study drug. The only change from one cohort to the next one will be the dose.
Control group
Dose comparison

Outcomes
Primary outcome [1] 307908 0
Safety Endpoints
Safety endpoint evaluations will include the following:
•Incidence and severity of AEs;
•Dose-limiting toxicities.

All toxicities or adverse events will be graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4. A dose limiting toxicity (DLT) is a toxicity or adverse event occurring in the first 28 days, which is attributable to the study treatment and meets one of the following criteria:
• Clinically significant Grade 3 or 4, non-haematologic toxicity except:
o nausea and vomiting (NB treatment related grade 3 or 4 nausea or vomiting that persists for greater than 7 days despite medical management will be considered a DLT)
o fever (in the absence of neutropenia)
o asymptomatic hyperglycaemia
o asymptomatic hyperuricaemia of any duration
o biochemical abnormalities of non-clinical significance
o biochemical abnormalities that resolve to grade 2 or better in 7 or less days,
o fatigue
• Clinically significant grade 3 or 4 biochemical abnormalities that persist (at grade 3 or above) for more than 7 days will be considered DLTs.
• Any Grade 2 non-haematological toxicity that persists for greater than or equal to 14 days and is considered sufficiently medically significant or sufficiently intolerable by patients that it requires treatment interruption
• Haematological dose limiting toxicities:
o Grade 4 neutropenia (ANC < 0.5 X 1000000000/L) for 7 or more days that is not due to malignant infiltration
o Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia (Plt < 25 X 1000000000/L) for 7 or more days that is not due to malignant infiltration.

Timepoint [1] 307908 0
All study visits
Secondary outcome [1] 353735 0
Efficacy endpoints
•Disease control rate (DCR): CR+PR+SD
•Objective response rate (OOR): CR + PR

A secondary objective of this study is to make a preliminary evaluation of anti-tumor efficacy after treatment with ACT001. Tumour response will be assessed using RECIST 1.1 criteria (see http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf) or the RANO criteria (see http://jco.ascopubs.org/content/28/11/1963.abstract). Any patient with symptoms suggestive of disease progression should be promptly evaluated with tumour imaging. Assessment of the RECIST 1.1 or RANO criteria response by the treating oncologist and site radiologist will be used to make all study treatment decisions. Tumour response and DLTs will determine the sample size of the study.
No formal sample size calculations were performed.

Timepoint [1] 353735 0
Screening and Cycle 2 Day28/ Day01 of succeeding cycles
Secondary outcome [2] 354461 0
Pharmacokinetic Endpoints

Plasma concentrations of ACT001 will be collected at specified time points from all patients to calculate PK parameters. ACT001 PK parameters to be calculated include:
•Maximum concentration (Cmax);
•Time to maximum concentration (Tmax);
•Area under the concentration-time curve from time 0 to 8 hours (AUC0-8);
•Lag time (tlag);
•Average plasma drug concentration at steady state (Cavg,ss);
•Time to steady state (Tss).
PK parameters for ACT001 will be determined using a non-compartmental analysis method.
Timepoint [2] 354461 0
Cycle 1: Days 1, 2, 4, 7, 14, 21 and 28/1 (of Cycle 2);
Cycle 2: Days 1, 7 14, 21 and 28/1;
Subsequent cycles: Day 1 of each cycle

Eligibility
Key inclusion criteria
1. All patients and/or their parents or legal guardians must give voluntary written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
2. Aged =/> 1year and =/> 21 years old at the time of study enrolment.
3. Karnofsky =/> 50% for patients > 16years of age and Lansky =/> 50% for patients =/> 16 years of age.
a. Neurologic deficits in patients with CNS tumors must have been relatively stable for a minimum of 1 week prior to study enrolment. 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.
b. Patients receiving corticosteroids must be on a stable dose that has not been increased for at least 7 days prior to study enrolment
4. For Part A: Have relapsed or refractory solid or CNS tumors or have a diagnosis of DIPG or Diffuse Midline H3 K27M glioma.
5. For Part B: Patients must have a diagnosis of DIPG or Diffuse Midline H3 K27M glioma following treatment with radiation therapy; OR recurrent or refractory high grade glioma.
6. Have either measurable or evaluable disease for Part B of the study only.
7. 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.
8. Have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
9. Myelosuppresive chemotherapy: Must not have received within 3 weeks of enrolment onto this study (6 weeks if prior nitrosourea).
10. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. PEG-CGSF) or 7 days for short-acting growth factor. 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.
11. Biologic (anti-neoplastic agent): At least 7 days after the last dose of 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.
12. Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody.
13. XRT: =/> 6 weeks since administration of radiation therapy; =/> 24 weeks must have elapsed if prior TBI.
14. MIBG therapy: At least 6 weeks must have elapsed since the completion of radio-labelled MIBG therapy.
15. Stem cell transplant or rescue, including autologous cell transplant: No evidence of active graft vs. host disease and =/> 12 weeks must have elapsed.
16. Haematological function as follows:
• Absolute neutrophil count (ANC) =/> 1.0 x 109/L;
• Platelet count =/> 50 x 109/L (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrolment);
• Lymphocyte count =/> 0.5 x 109/L;
• Haemoglobin =/> 80 g/L (may receive RBC transfusions);
• Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN).

17. Adequate Renal function defined as:
• Creatine clearance or radioisotope GFR =/> 70ml/min/1.73 m2
or
• A serum creatinine based on age/gender as follows:
Age Maximum SerumCreatinine (?mol/L)
Male Female
1 to < 2 years 52 52
2 to < 6 years 70 70
6 to < 10 years 88 88
10 to < 13 years 106 106
13 to < 16 years 132 124
=/> 16 years 150 124
The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC
18. Adequate Liver function defined as:
• Total bilirubin =/< 1.5 x ULN
and
• ALT =/< 5 x ULN (where ULN defined as 45 U/L)
19. Adequate cardiac function defined as:
• Fractional shortening (FS) =/< 28% measured by echocardiography
20. Female patients
• Female patients who are of NON-reproductive potential. (Pre-pubertal females, have undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy)
o The parent or guardian of young female patients who have not yet started menstruation should verify that menstruation has not begun. If a young female patient reaches menarche during the study, then she is to be considered as a woman of childbearing potential from that time forward.

or
• Female patients of childbearing potential must have a negative serum pregnancy test upon study entry and must be willing to use highly effective methods of birth control during the period of therapy and for 6 months following the last study drug administration.
o Highly effective methods of birth control include sexual abstinence, hormonal birth control, or intrauterine device (women), in combination with barrier methods. All study patients must be willing to ensure that corresponding sexual partners practice these same methods of highly effective birth control for the same duration.

21. Male patients
• Male patients that are prepubertal on history and examination
or
• Male patients who are willing to use highly effective methods of birth control during the period of therapy and for 6 months following the last study drug administration.
o Highly effective methods of birth control include sexual abstinence, vasectomy or a condom with spermicide in combination with barrier methods. All study patients must be willing to ensure that corresponding sexual partners practice these same methods of highly effective birth control for the same duration. Highly effective methods of birth control include sexual abstinence, hormonal birth control, or intrauterine device (women), vasectomy or a condom with spermicide (men) in combination with barrier methods. All study patients must be willing to ensure that corresponding sexual partners practice these same methods of highly effective birth control for the same duration.
Minimum age
1 Years
Maximum age
21 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or breast-feeding women.
2. Any active uncontrolled infection.
3. Disease of any major organ system that would compromise their ability to withstand therapy.
4. Pre-existing allergy to ACT001 or related compounds.
5. History of infection with HIV or hepatitis B or C viruses.
6. Concurrent or prior (within 7 days of enrolment) anticoagulant therapy, except low molecular weight heparins or low dose aspirin.
7. Patients currently receiving another investigational drug.
8. Patients currently receiving other antineoplastic agents
9. All herbal supplements, vitamins, and nutritional supplements taken within the last 30 days prior to dosing on Day 1 (and continued use, if appropriate), must be reviewed and approved by the Investigator.
10. Will not be available for protocol-required study visits or procedures, to the best of the patient/parent/guardian’s and investigator’s knowledge.
11. Any kind of disorder that, in the opinion of the investigator, may compromise the ability of the patient/parent/guardian to give written informed consent and/or to comply with all required study procedures.
12. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator would pose a risk to patient safety or interfere with the study evaluation, procedures or completion.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample Size Considerations
No formal sample size calculations were performed.
A maximum of 33 patients will be enrolled for this study. Up to 18 patients will be enrolled in Part A and up to 10 patients in Part B. No fixed gender ratio will be applied to patient selection. Dose expansion in Part B will require enrollment of new patients who are not already enrolled in Part A.

Demographic Data
For all patients who received at least one dose of investigational product, descriptive statistics (mean, standard deviation, median, minimum, maximum) will be performed for age, gender, body mass index, weight, and height.

Safety/Tolerability Data
All patients who receive at least one dose of the investigational product will be included in the safety and tolerability analysis. Baseline for physical examination, all vital signs, and clinical laboratory assessments will be defined as the last evaluation done before the first administration of investigational product on Day 1.

Pharmacokinetic Data
Plasma concentrations of ACT001 collected at specified time points will be used to calculate pharmacokinetic parameters. Data will be listed for all patients with available ACT001 plasma concentrations. All concentrations below the limit of quantification (LOQ) or missing data will be labeled as such in the concentration data listings. Concentrations designated as LOQ will be treated as 0 in the summary statistics and for the calculation of PK parameters.

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
Recruitment hospital [1] 12292 0
Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 24482 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 301034 0
Commercial sector/Industry
Name [1] 301034 0
Accendatech AU Pty Ltd
Address [1] 301034 0
8/20 Rosella Close, Calamvale, Queensland 4116
Country [1] 301034 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Accendatech AU Pty Ltd
Address
8/20 Rosella Close, Calamvale, Queensland 4116
Country
Australia
Secondary sponsor category [1] 300629 0
Commercial sector/Industry
Name [1] 300629 0
CPR Pharma Services Pty Ltd
Address [1] 300629 0
28 Dalgleish Street, Thebarton, Adelaide 5031 SA
Country [1] 300629 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301788 0
Sydney Children’s Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 301788 0
Corner Hawkesbury Road
and Hainsworth Street
Locked Bag 4001
Westmead NSW 2145
Sydney Australia
DX 8213 Parramatta
Ethics committee country [1] 301788 0
Australia
Date submitted for ethics approval [1] 301788 0
29/01/2018
Approval date [1] 301788 0
18/09/2018
Ethics approval number [1] 301788 0
HREC/18/SCHN/22

Summary
Brief summary
The purpose of this study is to figure out the ideal dosing schedule for a new chemotherapy medication called ACT001.

Who is it for?
You may be eligible for this study if you are aged between 1 and 21 years and have brain cancer or another solid tumour.

Study details
Participants will take capsules of the study medication, either dissolved in apple juice or as tablets, twice per day for 28 days. The amount of medication taken will depend on the results of participants before you.
All participants will provide blood samples and have CT and MRI scans.

It is hoped this research will find better treatment option for children with advanced brain and solid tumours.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88106 0
A/Prof David Ziegler
Address 88106 0
Sydney Children's Hospital
High Street, Randwick 2031, NSW Australia
Country 88106 0
Australia
Phone 88106 0
+61 2 9382 0710
Fax 88106 0
+61 2 9382 1789
Email 88106 0
d.ziegler@unsw.edu.au
Contact person for public queries
Name 88107 0
A/Prof David Ziegler
Address 88107 0
Sydney Children's Hospital
High Street, Randwick 2031, NSW Australia
Country 88107 0
Australia
Phone 88107 0
+61 2 9382 0710
Fax 88107 0
+61 2 9382 1789
Email 88107 0
d.ziegler@unsw.edu.au
Contact person for scientific queries
Name 88108 0
A/Prof David Ziegler
Address 88108 0
Sydney Children's Hospital
High Street, Randwick 2031, NSW Australia
Country 88108 0
Australia
Phone 88108 0
+61 2 9382 0710
Fax 88108 0
+61 2 9382 1789
Email 88108 0
d.ziegler@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results