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Trial registered on ANZCTR


Registration number
ACTRN12621001172897
Ethics application status
Approved
Date submitted
21/07/2021
Date registered
31/08/2021
Date last updated
31/08/2021
Date data sharing statement initially provided
31/08/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to evaluate the safety, tolerability and pharmacokinetics of ACT001 in patients with advanced solid tumors (PART B).
Scientific title
A phase 1 dose-escalation study to evaluate the safety, tolerability and pharmacokinetics of ACT001 in patients with advanced solid tumors (PART B).
Secondary ID [1] 304839 0
ACT001-AU-001 (Sponsor protocol code) - PART B
Universal Trial Number (UTN)
Trial acronym
Linked study record
This study is Part B (sub-study) of study ACTRN12616000228482

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma Multiforme 322928 0
Condition category
Condition code
Cancer 320503 320503 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part B will evaluate the combination treatment of ACT001 with pembrolizumab in patients with recurrent Glioblastoma Multiforme (GBM) only. 3 patients will be treated with ACT001 at a daily oral dose of 400mg in combination with pembrolizumab 200mg administered as an intravenous infusion on Day 1 of each 21-day cycle. Following completion of the first cycle of treatment for the first 3 patients, the SMC will assess the safety and tolerability of the combination treatment of ACT001 and pembrolizumab. If the Safety Monitoring Committee (SMC) assessment deems the combination of ACT001 and pembrolizumab safe and tolerable, 6 additional GBM patients will be enrolled and treated with the same ACT001 and pembrolizumab combination.
Patients will continue treatment with ACT001 and pembrolizumab until tumor progression (assessed by Immunotherapy Response Assessment in Neuro-Oncology [iRANO]) or an adverse event requiring discontinuation from study treatment.
A further 12 GBM patients may be enrolled in Part B of this study if at least 2 of the 9 patients treated with the ACT001+pembrolizumab combination experience a Partial
Response or 6 of 9 patients experience Stable Disease or better.
Alternatively, a decision may also be made to adjust the dose level or to implement patient selection based on biomarker data collected from the first nine patients in Part B.
After progression, patients are assessed for a further 30 days.
Remote patient assessment will continue to monitor overall survival up to 1 year following disease progression.
Each time the IP is dispensed to a patient, received from the depot and / or returned or destroyed, the occurrence will be documented. This documentation indicates the amounts received from the depot, dispensed to the patient, and returned or destroyed, to ensure adherence to the study protocol treatment.
Intervention code [1] 321221 0
Treatment: Drugs
Comparator / control treatment
In Part B there will be no comparator or control treatment with all patients receiving ACT001 and Pembrolizumab.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328331 0
To determine the safety and tolerability of ACT001 in combination with pembrolizumab in patients with recurrent GBM. The safety and tolerability of ACT001 will be evaluated by listings of treatment-emergent adverse events (TEAE's) occurrence rate and their classification (as being part or not of the Dose Limiting Toxicity type of events). Adverse event data will be collected from participant medical records and/or participant self-report to study staff.
Timepoint [1] 328331 0
At the end of Cycle 1 (21 days).
Secondary outcome [1] 398622 0
To characterize the PK of ACT001, and MCL when dosed in combination with pembrolizumab. Based on the individual plasma concentrations and using noncompartmental analysis methods, the following PK parameters for ACT001 and 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 )
Timepoint [1] 398622 0
For Part B, for the first 3 patients enrolled to this aspect of the study only, blood samples for PK analysis from the first 3 patients will be collected pre-dose on Cycle 1 Day 1 and again at 1, 2, 3, 4, 6 and 8 hours following the first single dose of ACT001. A further blood PK sample will be obtained pre-dose on Cycle 2 Day 1.

Eligibility
Key inclusion criteria
1. Histologically or cytologically confirmed advanced or metastatic 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 that is equivalent to = 12.5 mg of prednisone daily
- 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 radiation in the past 3 months
3. Male or female and at least 18 years of age.
4. Adequate organ function (ANC greater than or equal to 1.5 × 109 /L, lymphocytes greater than or equal to 0.5 × 109 /L,
platelets greater than or equal to 75 × 109 /L, Hb greater than or equal to 10 g/dl; total bilirubin less than or equal to 1.5 × institutional upper
limit of normal (ULN); ALT and AST less than or equal to 2.5 × ULN (less than or equal to 5.0 × ULN if liver metastasis); plasma creatinine less than or equal to 1.5 × ULN; QTc < 450 ms (male), < 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 greater than or equal to 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
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- The patient has an uncontrolled infection.
- The patient has serious diseases or stroke within 6 months prior to enrolment.
- The patient has a gastrointestinal absorption disorder or cannot take oral drugs.
- Uncontrolled brain metastases or spinal cord compression. Patients who were treated with surgical resection or radiation therapy at least 4 weeks earlier are eligible if they are neurologically stable, not taking glucocorticoids and have had an MRI scan performed within the previous 4 weeks showing no tumour progression. (GBM patients taking a steroid dose equivalent to 12.5mg of prednisone are eligible)
- Pre-existing allergy to ACT001 or pembrolizumab or related compounds.
- 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). Pembrolizumab is exempt from this exclusion in Part B
- Unresolved toxicity from prior anti-tumour therapy.
- Patients with active autoimmune diseases or history of autoimmune diseases except for patients with vitiligo or alopecia, or those with hypothyroidism following autoimmune thyroiditis on a stable replacement dose of thyroid hormone are not excluded.
- Patients who have received chronic glucocorticoid treatment at levels above the equivalent of prednisone at > 12.5 mg/day or dexamethasone at > 2 mg/day, or other immunosuppressive medication within 14 days prior to the first dose of the study drug.
- Major surgery within 30 days of commencing first study therapy.
- Patients who have received organ transplantation
- Pregnant or breast-feeding females.
- A history of infection with HIV or hepatitis B or C viruses
- The subject has participated in other drug clinical trials within 4 weeks prior to informed consent.
- 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
3 patients will be treated with ACT001 and pembrolizumab. Following completion of the first cycle of treatment for the first 3 patients, the SMC will assess the safety and tolerability of the combination treatment of ACT001 and pembrolizumab. If the SMC assessment deems the combination of ACT001 and pembrolizumab safe and tolerable, 6 additional GBM patients will be enrolled and treated with the same ACT001 and pembrolizumab combination. A further 12 GBM patients may be enrolled if at least 2 of the 9 patients treated with the ACT001 and pembrolizumab experience a Partial Response or 6 of 9 patients experience Stable Disease or better.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
It is anticipated that initially 3 patients will be dosed with the ACT001 and pembrolizumab combination with a further 6 patients expanding to 18 patients if a therapeutic benefit is determined
Data will be listed and summarized according to the sponsor’s reporting standards, where applicable.
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 and by listings of adverse events.
Independent-samples t tests or nonparametric tests are used to determine statistically signicant differences between the PK parameters. A linear-regression model is used to determine the dose proportionality. For all the analyses, P < 0.05 is considered statistically signicant.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
15/04/2021
Date of last participant enrolment
Anticipated
29/04/2022
Actual
Date of last data collection
Anticipated
13/07/2023
Actual
Sample size
Target
21
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 20039 0
Epworth Richmond - Richmond
Recruitment hospital [2] 20040 0
Flinders Private Hospital - Bedford Park
Recruitment hospital [3] 20041 0
Scientia Clinical Research - Randwick
Recruitment postcode(s) [1] 34749 0
2031 - Randwick
Recruitment postcode(s) [2] 34747 0
3121 - Richmond
Recruitment postcode(s) [3] 34748 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 309212 0
Commercial sector/Industry
Name [1] 309212 0
Accendatech AU Pty Ltd
Country [1] 309212 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Accendatech AU Pty Ltd
Address
Suite 2903, 201 Elizabeth St., Sydney, New South Wales, 2000 Australia
Country
Australia
Secondary sponsor category [1] 310174 0
Commercial sector/Industry
Name [1] 310174 0
Avance Clinical Pty Ltd
Address [1] 310174 0
Level 1, 2 Ann Nelson Drive, Thebarton, South Australia, 5031
Country [1] 310174 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309063 0
Alfred Health Ethics Committee
Ethics committee address [1] 309063 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 309063 0
Australia
Date submitted for ethics approval [1] 309063 0
26/08/2020
Approval date [1] 309063 0
30/10/2020
Ethics approval number [1] 309063 0
HREC/16/Alfred/189 (Local reference: 554/16)
Ethics committee name [2] 309064 0
Southern Adelaide Clinical HREC
Ethics committee address [2] 309064 0
Flinders Medical Centre Ward 6C, Room 6A219 Flinders Drive, Bedford Park SA 5042
Ethics committee country [2] 309064 0
Australia
Date submitted for ethics approval [2] 309064 0
26/05/2017
Approval date [2] 309064 0
05/04/2018
Ethics approval number [2] 309064 0
SAC HREC amendment approval - 126.17

Summary
Brief summary
The primary purpose of this study is to evaluate the safety of a new cancer drug, ACT001. Part B will evaluate the combination treatment of ACT001 with pembrolizumab in patients with recurrent GBM (Glioblastoma Multiforme brain cancer) only.

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 glioblastoma. Those who participated in Part A of the study (ACTRN12616000228482) may be eligible to also participate in this study, subject to principal investigator approval.

Study details:
Participants will receive oral ACT001 twice every day for 21 days, together with intravenous (IV) infusion of pembrolizumab on the first day. After 21 days, once the safety of this treatment is determined, all participants will be given the treatment in recurrent 21-day cycles until tumour progression or adverse event. Researchers will take a number of blood samples from the initial 3 participants in Day 1 of the first and second 21-day cycle, to examine the rate that the body processes the drug. MRI scans and assessments of treatment response will be taken before treatment and then every 9 weeks 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 the combination treatment of ACT001 with pembrolizumab can be safely given to cancer patients, and provide information on the rate of processing of ACT001 by the body when pembrolizumab is also given. Using this information, researchers hope to find if the combination of ACT001 and pembrolizumab is safe and effective.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112842 0
Dr Jason Lickliter
Address 112842 0
Nucleus Network, The Burnet Tower, Level 5, 89 Commercial Road, Melbourne, VIC 3004
Country 112842 0
Australia
Phone 112842 0
+61 407 527 307
Fax 112842 0
Email 112842 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 112843 0
Jason Lickliter
Address 112843 0
Nucleus Network, The Burnet Tower, Level 5, 89 Commercial Road, Melbourne, VIC 3004
Country 112843 0
Australia
Phone 112843 0
+61 407 527 307
Fax 112843 0
Email 112843 0
J.Lickliter@nucleusnetwork.com.au
Contact person for scientific queries
Name 112844 0
Jason Lickliter
Address 112844 0
Nucleus Network, The Burnet Tower, Level 5, 89 Commercial Road, Melbourne, VIC 3004
Country 112844 0
Australia
Phone 112844 0
+61 407 527 307
Fax 112844 0
Email 112844 0
J.Lickliter@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Commercial information


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIHypocretenolides: collective total syntheses and activities toward metastatic colon cancer2024https://doi.org/10.1039/d4sc01469c
N.B. These documents automatically identified may not have been verified by the study sponsor.