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Trial registered on ANZCTR


Registration number
ACTRN12616000228482
Ethics application status
Approved
Date submitted
11/02/2016
Date registered
19/02/2016
Date last updated
30/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to evaluate the safety, tolerability and pharmacokinetics of ACT001 in patients with advanced solid tumors
Scientific title
A phase 1 dose-escalation study to evaluate the safety, tolerability and pharmacokinetics of ACT001 in patients with advanced solid tumors
Secondary ID [1] 288517 0
ACT001-AU-001 (Sponsor protocol code)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid tumors 297590 0
Condition category
Condition code
Cancer 297787 297787 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study drug is ACT001. It will be administered, as oral tablets, in daily doses of 200 mg, 400 mg, 800 mg and 1200 mg. The starting dose will be 200 mg/day (100 mg twice daily). The 30 day initial treatment cycle (Cycle 1) for each patient will consist of a single administration of 100 mg ACT001 in the morning on Day 1 (200 mg, 400 mg or 600 mg for the subsequent cohorts), followed by a 1-day treatment free period (Day 2), and a 28 day period (Days 3 to 30) of repeated drug administration of 200 mg/day ACT001 (100 mg twice daily).
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 next dose level and dose regimen for the next cohort.
If a patient wishes to continue study treatment on completion of Cycle 1, they can continue study treatment in 28-day Cycle 2 (with no treatment free or rest period) and subsequent cycles (same as Cycle 2, all of 28 days' duration), at the discretion of the investigator. Intra-patient dose escalation is allowed once the next higher dose level is confirmed safe.
Patients treatment compliance will be assessed by correlating the missing number of capsule from the empty drug packages returned against the annotation made by the patients in the Patient Diary that will be provided to them.
Intervention code [1] 293880 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] 297315 0
To determine the safety and tolerability of ACT001 given orally to patients with advanced cancer. The safety and tolerability of ACT001 will be evaluated based on descriptive statistics (n, arithmetic mean, standard deviation (SD), median, lower and upper quartiles, minimum and maximum values) and by listings of adverse events occurrence rate, their relationship with the study drug and their classification (as being part or not of the Dose Limiting Toxicity type of events).
As this is a first in human trial possible Adverse Events/Reaction are not known. All the patients will be monitored by performing and assessing the Vital Signs, ECG, Serum Chemistry, Full Blood Examination, Coagulation and Urinalysis at Screening, Day1, Day2, Day 17 and Day 28 of Cycle 1. For the subsequent Cycles, these tests will be performed on Day 1 of each Cycle.
Timepoint [1] 297315 0
At Day1, Day2, Day 17 and Day 28 of Cycle 1. For the subsequent Cycles, these tests will be performed on Day 1 of each Cycle. At any time if adverse events that define the maximum tolerated dose occur.
Primary outcome [2] 297354 0
To determine for ACT001 given orally to patients with advanced cancer the maximum tolerated dose (MTD),defined as any of the following events (graded using NCI CTCAE version 4.0) occurring within 30 days from commencing the first dose of study therapy (i.e. during Cycle 1) and attributed to study drug:
Haematological toxicity:
- Grade 4 neutropenia
- Grade more than or equal to grade 3 febrile neutropenia or neutropenic infection
- Grade 4 thrombocytopenia
- Grade 3 thrombocytopenia with clinically-significant bleeding
Non-haematological toxicity:
- Grade more than or equal to grade 3 nausea, vomiting or diarrhoea despite optimal supportive therapy
- Grade more than or equal to grade 3 hypertension despite appropriate intervention
- Other grade more than or equal to grade 3 non-haematological toxicity, except grade 3 fatigue or transient events (such as allergic reactions or electrolyte disturbances) that are readily controlled with medical therapy and/or are of no clinical concern.
Timepoint [2] 297354 0
At the end of the first 28 Days cycle or at any time if adverse events that define the maximum tolerated dose occur.
Primary outcome [3] 297367 0
To determine the recommended phase 2 dose(s) and schedule for ACT001 given orally to patients with advanced cancer. (This is a primary outcome).
Timepoint [3] 297367 0
By determining the maximum tolerated dose (MTD), defined as any of the following events: Hematological toxicity or Non-hematological toxicity (graded using NCI CTCAE version 4.0) occurring within 30 days from commencing the first dose of study therapy (i.e. during Cycle 1) and attributed to study drug.
Secondary outcome [1] 320695 0
To characterize the pharmacokinetics (PK) of ACT001 and its main metabolite MCL after single and multiple doses.

For the Single Dose part, based on the individual plasma concentrations and using noncompartmental analysis methods, the following PK parameters for ACT001 and its main metabolites (MCL) will, at a minimum, be determined for the single-dose part:
- Area under the plasma concentration time curve from time zero to the time of the last quantifiable concentration (AUC0-t )
- Area under the plasma concentration time curve from time zero to infinity (AUC0-8)
- Elimination half-life (t1/2 )
- Oral clearance (CL/F)
- Apparent volume of distribution (Vd )
- Maximum observed concentration (Cmax)
- Time to maximum observed concentration (tmax ).

For the Multiple Dose part, based on the individual plasma concentrations and using noncompartmental analysis methods, the following PK parameters for ACT001 and its main metabolites (MCL) will, at a minimum, be determined for the multiple-dose part:
- Maximum concentration at steady state (Cssmax)
- Minimum concentration at steady state (Cssmin)
- Average concentration at steady state (Cav)
- Area under the plasma concentration time curve at steady state from time zero to 24 hours (AUCss0-24)
- tmax, t1/2, fluctuation index (DF), cumulative rate (R).
Timepoint [1] 320695 0
For the Single dose, PK measured on Day 1 before dose and post dose at 0.5, 1, 2, 3, 4, 6, 8, 24 (Day 2) and 48 hours (Day 3 pre-dose administration).
For the Multiple dose, beside the timepoints used for the single dose, PK is collected on Day 17 pre-dose and post dose at 0.5, 1, 2, 3, 4, 6, 8 and 24 hours (Day 18 pre dose) for steady state levels. A further blood PK sample will be obtained pre-dose at Cycle 2 Day 1.
Secondary outcome [2] 320706 0
To explore the relationship between ACT001 PK and clinical endpoints and to make a preliminary evaluation of anti-tumor efficacy after treatment with ACT001.
Timepoint [2] 320706 0
Computed tomographic imaging, Magnetic resonance imaging and Serum tumor markers performed at Screening and Day 28 of Cycle 2 after 8 weeks of treatment.

Eligibility
Key inclusion criteria
1. Histologically or cytologically confirmed advanced or metastatic solid tumor, including glioblastoma, with no standard treatment options.
2. Patients with recurrent glioblastoma who satisfy all of the following may be enrolled:
- Progressive tumor despite prior treatment with radiation therapy and temozolomide.
- Measurable disease by Response Assessment in Neuro-Oncology (RANO) criteria using gadolinium-enhanced MRI scanning.
- Either on no glucocorticoids or on a stable dose for 7 days prior to the first dose of study therapy.
- No evidence of intracranial hemorrhage (except for stable grade 1 hemorrhage), not receiving therapeutic anticoagulation or anti-platelet therapy, and have a normal INR and APTT.
- No prior treatment with bevacizumab or other antiangiogenic drugs.
- No radiation in the past 3 months.
3. Male or female and at least 18 years of age.
4. Adequate organ function (ANC more or equal to 1.5 x 10 to the power of 9 /L, platelets more or equal to 75 x 10 to the power of 9 /L, Hb more or equal to 10 g/dl; total bilirubin less or equal to 1.5 times the institutional upper limit of normal (ULN); ALT and AST less or equal to 2.5 times ULN (less or equal to 5.0 times ULN if liver metastasis); plasma creatinine less or equal to 1.5 times ULN;QTc less than 450 ms (male), less than 470 ms (female).
5. A life expectancy of at least 12 weeks.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Female subjects are eligible if they are of:
a) Non-childbearing potential, defined as
- Previous hysterectomy or bilateral oophorectomy.
- Previous bilateral tubal ligation.
- Post-menopausal (total cessation of menses for at least 1 year).
b) Childbearing potential with a negative serum pregnancy test at screening (within 7 days of the first investigational product administration), and uses adequate contraception before study entry and throughout the study until 28 days after the last investigational product administration. Adequate contraception, when used consistently and in accordance with both the product label and the instructions of the physician, are defined as follows:
- Vasectomized partner who is sterile prior to the female patient’s enrolment and is her sole sexual partner.
- An intrauterine device with a documented failure rate of less than 1% per year.
- Double barrier contraception defined as condom with a female diaphragm.
8. Male patients, if sexually active, must agree to use a highly-effective method of contraception (< 1% failure rate per year) with their female partners.
9. Provided written informed consent prior to enrollment.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. The subject has uncontrolled infection.
2. The subject has serious diseases such as unstable angina pectoris, myocardial infarction in the past 6 months, heart failure (New York Heart Association class more than II) or stroke within 6 months prior to the enrollment.
3. A gastrointestinal absorption disorder that would limit the bioavailability of an oral medication or cannot take oral drugs.
4. Uncontrolled brain metastases or spinal cord compression. Patients who were treated with surgical resection or radiation therapy completing at least 4 weeks earlier are eligible if they are neurologically stable, not taking glucocorticoids and have a follow-up MRI scan performed within the previous 4 weeks showing no tumor progression.
5. Pre-existing allergy to ACT001 or related compounds.
6. Treatment with other cancer therapies such as chemotherapy, biological or targeted therapy, immunotherapy or radiation therapy either currently or within 4 weeks of ACT001 dosing (6 weeks for BCNU, CCNU or mitomycin-C). An exception is focal radiation for symptomatic bone metastases, which must not be within 2 weeks of ACT001 dosing.
7. Unresolved toxicity from prior anti-tumour therapy, defined as toxicities (excluding alopecia) that have not resolved to less than grade 2 as scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Exceptions may be allowed for stable toxicities after discussion with the investigator and sponsor.
8. Major surgery within 30 days of commencing first study therapy.
9. Pregnant or breast-feeding females.
10. A history of infection with HIV or hepatitis B or C viruses
11. The subject has participated in other drug clinical trials less than 4 weeks prior to obtaining the informed consent.
12. The subject is, in the opinion of the investigator, unsuitable for any reason.

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
Other design features
The standard 3+3 dose escalation scheme will be used, which involves cohorts of 3-6 patients with dose escalation decisions made using the rules below:
- If 0 out of 3 patents experience DLT, enter 3 patients at the next dose level.
- If at lest 2 or more of the patients experience DLT, dose escalation will be stopped. Three (3) additional patients will be entered at the previous lowest dose level if only 3 patients were treated previously at that dose.
-If 1 out of 3 patients experience DLT, enter at least 3 more patients at this dose level, and reassess the DLT incidence for these 3 supplementary patients: - if 0 patients experience DLT, proceed to the next dose, or, if 1 or more of this supplementary group suffer DLT, then dose escalation will stopped. Three (3) additional patients will be entered at the previous lowest dose level if only 3 patients were treated previously at that dose.
- If maximum 1 out of 6 at highest dose level reached experience DLT, this will be declared the MTD and the recommended dose (RD) for the dose expansion phase. At least 6 patients must be entered at this dose.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
The number of dose levels examined and the emerging ACT001 toxicities will determine the sample size. It is anticipated that approximately 25 subjects will be required to establish the selected dose of ACT001.
All subjects who are exposed to (or started receiving) ACT001 will be included in the safety population. All subjects for whom valid ACT001 PK parameters can be estimated will be included in the PK population on an as-treated basis.
The safety and tolerability of ACT001 will be evaluated based on descriptive statistics (n, arithmetic mean, standard deviation (SD), median, lower and upper quartiles, minimum and maximum values) and by listings of adverse events.
Geometric mean, SD of logarithmically-transformed values, and coefficient of variation (CV) percent will be presented for positively continuous PK parameters. Independent-samples t tests or nonparametric tests are used to determine statistically significant differences between the PK parameters. A linear-regression model is used to determine the dose proportionality. For all the analyses, P less than 0.05 is considered statistically significant.

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,VIC
Recruitment hospital [1] 5262 0
Epworth Richmond - Richmond
Recruitment hospital [2] 7686 0
Nucleus Network - Melbourne
Recruitment hospital [3] 8798 0
Scientia Clinical Research - Randwick
Recruitment hospital [4] 10807 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 12725 0
3121 - Richmond
Recruitment postcode(s) [2] 15604 0
3004 - Melbourne
Recruitment postcode(s) [3] 16921 0
2031 - Randwick
Recruitment postcode(s) [4] 22547 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 292872 0
Commercial sector/Industry
Name [1] 292872 0
Accendatech AU Pty Ltd
Address [1] 292872 0
8/20 Rosella Close, Calamvale, Queensland, 4116
Country [1] 292872 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] 291616 0
Commercial sector/Industry
Name [1] 291616 0
CPR Pharma Services Pty Ltd
Address [1] 291616 0
28 Dalgleish Street,
Thebarton, Adelaide,5031, SA
Country [1] 291616 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294375 0
Epworth HealthCare Ethics Committee
Ethics committee address [1] 294375 0
Mailbox number 4,
89 Bridge Road,
Richmond, VIC 3121
Ethics committee country [1] 294375 0
Australia
Date submitted for ethics approval [1] 294375 0
11/11/2015
Approval date [1] 294375 0
01/03/2016
Ethics approval number [1] 294375 0
718-15
Ethics committee name [2] 297213 0
Alfred Health Ethics Committee
Ethics committee address [2] 297213 0
55 Commercial Rd,
Melbourne
VIC 3004
Ethics committee country [2] 297213 0
Australia
Date submitted for ethics approval [2] 297213 0
08/12/2016
Approval date [2] 297213 0
13/02/2017
Ethics approval number [2] 297213 0
554/16
Ethics committee name [3] 300259 0
Southern Adelaide Clinical HREC
Ethics committee address [3] 300259 0
Flinders Medical Centre
Ward 6C, Room 6A219
Flinders Drive, Bedford Park SA 5042
Ethics committee country [3] 300259 0
Australia
Date submitted for ethics approval [3] 300259 0
26/05/2017
Approval date [3] 300259 0
05/04/2018
Ethics approval number [3] 300259 0
126.17

Summary
Brief summary
The primary purpose of this study is to evaluate the safety of a new cancer drug, ACT001 which has not yet been tested in humans. The study will also look at the amount of drug in the blood to evaluate the way the body processes the drug and the way the drug acts on the growth of tumours in cancer patients. Who is it for? You may be eligible to participate in this study if you are aged 18 or over, and have been diagnosed with advanced or metastatic solid tumor, including glioblastoma, with no standard treatment options. Study details All participants in this study will receive a specified dose of ACT001 each day for 56 days (two 28 day cycles). The first set of participants will start on the lowest dose level, with the next highest dose only commencing in the next set of participants once the safety of the first dose has been confirmed. Researchers will take a number of blood samples on days 1, 2, 3, 17, 18 and 29 of dosing in each participant to examine the rate that the body processes the drug. Further blood samples, as well as CT and MRI scans will be taken before treatment and at the end of treatment to look for changes in tumour growth. Participants will also be assessed for side effects throughout the study period. It is hoped that the findings of this trial will show whether ACT001 can be safely given to cancer patients, and provide information on the rate of processing of the drug in the body. Using this information, researchers hope to find the best dose to use for further testing of ACT001 in cancer patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63446 0
Dr Jason Lickliter
Address 63446 0
Nucleus Network, The Burnet Tower, Level 5, 89 Commercial Road, Melbourne, VIC 3004
Country 63446 0
Australia
Phone 63446 0
+61 407 527 307
Fax 63446 0
Email 63446 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 63447 0
Dr Jason Lickliter
Address 63447 0
Nucleus Network, The Burnet Tower, Level 5, 89 Commercial Road, Melbourne, VIC 3004
Country 63447 0
Australia
Phone 63447 0
+61 407 527 307
Fax 63447 0
Email 63447 0
J.Lickliter@nucleusnetwork.com.au
Contact person for scientific queries
Name 63448 0
Dr Jason Lickliter
Address 63448 0
Nucleus Network, The Burnet Tower, Level 5, 89 Commercial Road, Melbourne, VIC 3004
Country 63448 0
Australia
Phone 63448 0
+61 407 527 307
Fax 63448 0
Email 63448 0
J.Lickliter@nucleusnetwork.com.au

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