Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000479808
Ethics application status
Approved
Date submitted
12/02/2021
Date registered
22/04/2021
Date last updated
30/08/2024
Date data sharing statement initially provided
22/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
An interventional study to safety, tolerability (how well a substance is tolerated by patients), and Pharmacokinetics (PK, the measure of how the human body processes a substance) of different dosages of Auceliciclib when given to patients with advanced solid tumours as either the only treatment, or in patients with a specific type of cancer, Glioblastoma multiforme (GBM), when given together with a standard of care treatment, Temozolomide (TMZ).
Scientific title
A Phase 1/2, open-label, dose-exploration, combination/ expansion study to evaluate the safety, tolerability and pharmacokinetics of Auceliciclib in advanced solid tumours and in combination with temozolomide in recurrent or newly diagnosed Glioblastoma multiforme (GBM).
Secondary ID [1] 303410 0
Nil known
Universal Trial Number (UTN)
Trial acronym
AugmenTation of Targeted therapy with Auceliciclib, a highly potent and selective CDK4/6 inhibitor- Phase 1a/b trial (ATTACK-1 trial)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 320700 0
Glioblastoma multiforme (GBM) 321293 0
Solid tumors 321296 0
Condition category
Condition code
Cancer 318544 318544 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1/2, open-label, dose-exploration, expansion and/combination study.

The Phase 1 part of the study will assess the safety and tolerability of Auceliciclib and identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for Auceliciclib alone and in combination with Temozolomide (TMZ).

The Dose Escalation Phase (Phase 1a) Auceliciclib monotherapy will involve participants with locally advanced or metastatic cancer (all solid tumours allowed). Each treatment cycle is 28 days, with participants treated with oral Auceliciclib per the planned dose schedule below.

Dose Escalation Phase (Phase 1a) Monotherapy planned doses are:
• Dose level 1: 50 mg once daily on Days 1-21 of each 28-day cycle
• Dose level 2: 100 mg once daily on Days 1-21 of each 28-day cycle
• Dose level 3: 150 mg once daily on Days 1-21 of each 28-day cycle
• Dose level 4: 250 mg once daily on Days 1-21 of each 28-day cycle
• Dose level 5: 350 mg once daily on Days 1-21 of each 28-day cycle
• Dose level 6a: 175mg twice daily on Days 1-28 of each 28 day cycle
• Dose level 6b: 250mg twice daily on Days 1-28 of each 28 day cycle
• Dose level 6c: 500mg twice daily on Days 1-28 of each 28 day cycle

The Auceliciclib and TMZ Combination Therapy Phase (Phase 2a) involves participants with recurrent progressive high grade glioma (e.g GBM). As a potential treatment for GBM, this protocol is exploring two ways of administering TMZ with Auceliciclib across 28-day cycles as follows and per the planned dose schedule below:

1) administering Auceliciclib with standard of care TMZ (Cohorts 4c and 5c).
2) administering Auceliciclib with metronomic TMZ dosing (cohorts 1-6b).

Combination Therapy (Phase 2a) planned doses are:
• Dose level 1b: Auceliciclib 100mg once daily and TMZ 100mg once daily on Days 1-21 of each 28-day cycle
• Dose level 2b: Auceliciclib 150mg once daily and TMZ 100mg once daily on Days 1-21 of each 28-day cycle
• Dose level 3b: Auceliciclib 100mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-21 of each 28-day cycle
• Dose level 4b: Auceliciclib 150mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-21 of each 28-day cycle
• Dose level 5b: Auceliciclib 300mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-28 of each 28-day cycle
• Dose level 6b: Auceliciclib 500mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-28 of each 28-day cycle


An additional 1-6 participants per cohort may be enrolled for compassionate access. Additional participants are optional based on time critical disease and demand by participants requesting to be enrolled onto trial due to lack of available treatment options.

Patients will continue on the study until they are no longer considered to be achieving clinical benefit (i.e. disease progression), they have unacceptable toxicity, they withdraw informed consent, or are withdrawn from the study.

The study timeframe will include a 28-day screening period, 28-day treatment cycles, and a follow-up visit 4-6 weeks from the last dose of study treatment.

Patients will also be requested to participate in long-term follow-up to assess overall survival. Contact will be made with the patient via telephone approximately every 3 months, commencing 90 days (±2 weeks) after the last dose of study treatment. Long-term follow-up will continue for at least 1 year after the last dose of study treatment.

Auceliciclib will be administered orally in capsule form.
Intervention code [1] 319713 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326503 0
To assess the safety and tolerability of Auceliciclib in patients with advanced solid tumours, who have failed treatment with available therapies known to be active for treatment of their corresponding disease (Dose Exploration Phase).
This will be assessed by looking at the incidence, type, and severity of adverse events; dose limiting toxicities (DLTs); and changes from baseline in vital sign measurements, body weight, physical examination findings, clinical laboratory parameters, electrocardiogram (ECG) parameters.
Timepoint [1] 326503 0
Adverse event information will be recorded from the time of first treatment administration until end of study. DLTs will be recorded from the time of first treatment administration until Day 28 of Cycle 1. Vital signs (blood pressure, pulse rate, respiratory rate, temperature) will be measured using a digital sphygmomanometer, visual measurements and a digital thermometer respectively at Screening, pre-dose on Day 1 Cycle 1 (baseline), 3 and 6 hours post dose on Day 1 Cycle 1, 24 and 48 hours post dose Cycle 1, pre-dose on Days 8 and 15, Day 22 Cycle 1, pre-dose on Days 1, 15 and 22 Cycle 2, pre-dose on Day 1 and 22 Cycle 3 and all subsequent cycles, and End of Study. Body weight will be measured at Screening, pre-dose Day 1 Cycle 1 (baseline), pre-dose on Day 1 Cycle 2 and all subsequent cycles, and End of Study. A full physical examination will be performed at Screening (baseline) and End of Study, with symptom-directed examinations performed pre-dose on Day 1 Cycle 1, Day 2 Cycle 1, pre-dose on Days 3, 8, 15, Day 22 Cycle 1. Clinical laboratory parameters (haematology, chemistry, coagulation, urinalysis) will be tested by collecting blood samples at Screening, pre-dose on Day 1 Cycle 1 (baseline), pre-dose on Days 8 and 15 Cycle 1, Day 22 Cycle 1, Day 15 and 22 Cycle 2, pre-dose Day 22 Cycle 3 and all subsequent cycles, and End of Study. Triplicate ECGs will be taken at Screening and pre-dose on Day 1 Cycle 1 (baseline). Single ECGs will be taken pre-dose on Days 8 and 15 Cycle 1, pre-dose on Day 1 and 15 Cycle 2 and Day 1 of all subsequent cycles and End of Study.
Primary outcome [2] 326505 0
To assess the safety and tolerability of Auceliciclib in combination with TMZ in patients with high grade glioma (e.g. GBM) (Phase 2a), this will be assessed by looking at the incidence, type, and severity of adverse events; dose limiting toxicities (DLTs); and changes from baseline in vital sign measurements, body weight, physical examination findings, clinical laboratory parameters, electrocardiogram (ECG) parameters.
Timepoint [2] 326505 0
Adverse event information will be recorded from the time of first treatment administration until end of study. DLTs will be recorded from the time of first treatment administration until Day 28 of Cycle 1. Vital signs (blood pressure, pulse rate, respiratory rate, temperature) will be measured using a digital sphygmomanometer, visual measurements and a digital thermometer respectively at Screening, pre-dose on Day 1 Cycle 1 (baseline), pre-dose on Day 2, 8, and 22 Cycle 1, pre-dose on Day 1, 15 and 22 Cycle 2, pre-dose on Day 1 and 33 Cycle 3 and all subsequent cycles, and End of Study. Body weight will be measured at Screening, pre-dose Day 1 Cycle 1 (baseline), pre-dose on Day 1 Cycle 2 and all subsequent cycles, and End of Study. A full physical examination will be performed at Screening (baseline) and End of Study, with symptom-directed examinations performed pre-dose on Day 1, 2, 8, 15 and 22 Cycle 1, pre-dose on Day 1, 15 and 22 Cycle 2, pre-dose on Day 1 and 22 Cycle 3 and all subsequent cycles. Clinical laboratory parameters (haematology, chemistry, coagulation, urinalysis) will be tested by collecting blood samples at Screening, pre-dose on Day 1 Cycle 1 (baseline), pre-dose on Day 8, 15 and 22 Cycle 1, pre-dose on Day 1, 15 and 22 Cycle 2 and all subsequent cycles, and End of Study. Triplicate ECGs will be taken at Screening, pre-dose on Day 1 Cycle 1 (baseline), and End of Study. Single ECGs will be taken pre-dose on Day 8 and 15 Cycle 1 and pre-dose on Day 1 and 15 Cycle 2 and Day 1 of all subsequent cycles.
Secondary outcome [1] 391705 0
To determine the MTD and Recommended Phase 2 dose (RP2D) of Auceliciclib in patients with advanced solid tumours and RP2D (Phase 1a) and of Auceliciclib when administered in combination with TMZ in patients with high-grade glioma (Phase 2a). This will be assessed by looking at the incidence of DLTs according to the MTD/R2PD evaluation process. The MTD will be the highest dose level at which less than 1/3 patients experience DLT in the first cycle. A minimum of 6 patients must be enrolled at the MTD level, per dose escalation study design criteria. If the MTD is not reached following completion of dosing, a protocol amendment may be submitted to the Human Research Ethics Committee (HREC) in order to include the evaluation of higher dose levels. The RP2D will be determined by the SRC according to the safety, tolerability and pharmacokinetics of Auceliciclib observed in the dose escalation stage, as well as other available data. The RP2D will not exceed the MTD.
Timepoint [1] 391705 0
DLTs will be recorded from the time of first treatment administration until Day 28 of Cycle 1.
Secondary outcome [2] 391706 0
To evaluate the pharmacokinetics (PK) of Auceliciclib in patients with advanced solid tumours (Phase 1a). Blood samples will be collected and the following PK parameters will be assessed in plasma: • Maximum observed concentration (Cmax) • Time to Cmax (tmax) • Area under the drug concentration-time curve, from time zero to time t (AUC0-t) • Apparent terminal elimination half-life (t1/2)
Timepoint [2] 391706 0
PK samples will be collected from Cycle 1: Day 1 & Day 21; within 10 minutes prior to dosing and at 1, 2, 3, 4, 6, 8, and 10 hours post dose. Days 2, 3, 8, 15, 22 & Day 23; within 10 minutes prior to dosing. Cycle 2: Day 1, 15, & Day 22; within 10 minutes prior to dosing. Cycle 3 onwards: Day 1, & Day 22; within 10 minutes prior to dosing.
Secondary outcome [3] 391707 0
To evaluate the preliminary efficacy of Auceliciclib when administered as a monotherapy in patients with advanced solid tumours (Phase 1a). The preliminary anti-tumour activity of Auceliciclib will be assessed by: • Frequency, quality and durability of response per Response evaluation criteria in solid tumours (RECIST) 1.1 or Response assessment in neuro-oncology (RANO) criteria. Efficacy endpoints will include (but will not be limited to): • Objective response rate (ORR) • Disease control rate (DCR). The ORR is defined as the proportion of patients who achieve a partial response (PR) or complete response (CR) at any time on study. DCR is defined as the proportion of patients with stable disease (SD) greater than or equal to 6 months (24 weeks), PR, or CR.
Timepoint [3] 391707 0
ECOG performance status will be assessed at Screening, Day 1 Cycle 1 (baseline), Day 15 Cycle 1, Day 1, 15 and 22 Cycle 2, Day 1 Cycle 3 and all subsequent cycles, and End of Study. Standard CT/MRI imaging assessments of the chest, abdomen, and pelvis, as well as of other regions where evaluable disease exists will be performed during Screening (baseline), following completion of dosing for Cycle 2 and every 12 weeks (3 cycles) thereafter (e.g. Cycle 5, 8, 11...) until disease progression occurs per RECIST 1.1 or RANO criteria.
Secondary outcome [4] 391709 0
To evaluate the preliminary efficacy of Auceliciclib when administered in combination with TMZ in patients with high-grade glioma (e.g. GBM) (Phase 2a). This is a composite objective evaluating the preliminary efficacy. The following is a description of how the objective will be achieved. The preliminary anti-tumour activity of Auceliciclib will be assessed by: • Changes in Neurologic Assessment in Neuro-Oncology (NANO) scoring assessment • Frequency, quality and durability of response per RECIST 1.1 or RANO criteria. Efficacy endpoints will include (but will not be limited to): • ORR • DCR.
Timepoint [4] 391709 0
ECOG performance status and NANO scale assessment will be assessed at Screening, Day 1 (baseline) and Day 15 Cycle 1, Day 1 Cycle 2 and all subsequent cycles, and End of Study. Standard CT/MRI imaging assessments of the chest, abdomen, pelvis, and brain as well as of other regions where evaluable disease exists will be performed during Screening (baseline), following completion of dosing for Cycle 2 and every 12 weeks (3 cycles) thereafter (e.g. Cycle 5, 8, 11...) until disease progression occurs per RECIST 1.1 or RANO criteria.
Secondary outcome [5] 391710 0
To evaluate the pharmacodynamics (PD) of Auceliciclib in patients with advanced solid tumours. PD parameters include molecular profiling, gene and protein expression.
Timepoint [5] 391710 0
Blood samples for PD will be collected pre-dose on Day 1 & Day 22 of each Cycle and End of Study. If patients consent to tumour biopsy, samples will be collected at any time during the screening window up to Cycle 1 Day 1 (prior to dose administration), and anytime between Cycle 2 Day 1 and Cycle 4 Day 28.
Secondary outcome [6] 391712 0
To evaluate the PD of Auceliciclib when administered in combination with TMZ in patients with high-grade glioma (e.g. GBM) (Phase 2a). PD parameters include molecular profiling, gene and protein expression
Timepoint [6] 391712 0
PD blood samples will be collected from pre-dose at Day 1 & Day 22 of each Cycle from first treatment administration and End of Study (EoS) visit. If consented, additional PD tumor and CSF samples may be collected at any time throughout study, at time of tumor resection or CSF collection.
Secondary outcome [7] 431928 0
To evaluate the pharmacokinetics (PK) of Auceliciclib when administered in combination with TMZ in patients with high-grade glioma (Phase 2a). Blood samples will be collected and the following PK parameters will be assessed in plasma: • Maximum observed concentration (Cmax) • Time to Cmax (tmax) • Area under the drug concentration-time curve, from time zero to time t (AUC0-t) • Apparent terminal elimination half-life (t1/2)
Timepoint [7] 431928 0
PK samples will be collected from Cycle 1: Day 1 & Day 21; within 10 minutes prior to dosing and at 1, 2, 3, 4, 6, 8, and 10 hours post dose. Day 2 & Day 15; within 10 minutes prior to dosing. Cycle 2: Day 1, 15, & Day 22; within 10 minutes prior to dosing. Cycle 3: Day 1, & Day 22; within 10 minutes prior to dosing.

Eligibility
Key inclusion criteria
1. Ability to understand and be willing to sign an informed consent form.
2. Male or female, greater than or equal to 18 years old at the time of screening.
3. Diagnosis of histologically or cytologically confirmed:
a. Locally advanced or metastatic cancer (all solid tumours allowed). Patients must
be considered refractory or intolerant to standard-of-care (SOC) therapies or have
refused SOC therapy (Phase 1a, monotherapy), OR
b. Locally advanced or metastatic cancer that are thought to respond to CDK4/6
inhibition, or non-malignant tumours impacting QOL (e.g. teratoma’s, invasive
neurofibroma’s) that may respond to CDK4/6 inhibition (based on optional
tumour molecular/genetic profile). Patients must be considered refractory or intolerant to SOC therapies or have refused SOC therapy, or have invasive non malignant tumours that cannot be treated with surgery alone (Phase 1b, monotherapy), OR
c. High-grade glioma, such as GBM. Patient must also:
i. Have completed radiation therapy, with concomitant TMZ plus a minimum of 1-3 full cycles of TMZ monotherapy post RTx/CTx as their SOC first-line treatment.
ii. Have recurrent/progressive high-grade glioma >/= 3-6 months post first-line SOC treatment.
4. ECOG performance status of 0 to 2.
5. Able to take oral medications.
6. QT interval corrected using the Fridericia method (QTcF) less than or equal to 450 msec for males and less than or equal to 460 msec for females at screening and on Day 1, prior to dose administration.
7. Evidence of adequate cardiac function.
8. Evidence of adequate hepatic function at screening.
9. Adequate haematology laboratory assessment at screening.
10. Adequate renal function.
11. Adequate coagulation laboratory assessments at screening.
12. Female patients must
a. Be of non-child-bearing potential, or
b. If of child-bearing potential, must agree not to attempt to become pregnant.
13. Male patients must agree not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception
14. Estimated life expectancy of at least 3 months, in the opinion of the Investigator.
15. Willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior treatment with a CDK4/6 inhibitor, unless first approved by medical monitor.
2. Patients with symptomatic primary central nervous system (CNS) tumour, symptomatic CNS metastases, or untreated spinal cord compression that have moderate or severe symptoms.
3. Uncontrolled pleural effusion(s), pericardial effusion or ascites.
4. Evidence of abnormal cardiac function.
5. Cardiac arrhythmia that is considered unstable and requiring medication for stabilisation.
6. Unable to swallow oral medications.
7. Gastrointestinal (GI) conditions that, in the opinion of the Investigator, could affect the absorption of study drug.
8. History of other malignancy within the past 2 years.

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



Intervention assignment
Other
Other design features
Participants will be assigned to different dosages depending on which cohort and/ or dose level they are enrolled into.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Dose Escalation (Phase 1a): Up to 30 patients to be enrolled across 8 monotherapy dose escalation levels (6 patients per cohort). Up to 6 additional patients will be enrolled across three new dose escalation levels ( cohorts 6a, 6b and 6c).

Combination therapy (Phase 2a): Up to 30 patients to be enrolled across 6 treatment arms.

The sample size for this study is based on clinical and practical considerations and not on a formal statistical power calculation.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/06/2021
Actual
16/06/2021
Date of last participant enrolment
Anticipated
31/12/2023
Actual
8/12/2023
Date of last data collection
Anticipated
31/12/2024
Actual
5/01/2024
Sample size
Target
60
Accrual to date
Final
37
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 18683 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 18684 0
Flinders Private Hospital - Bedford Park
Recruitment hospital [3] 20828 0
Sydney Southwest Private Hospital - Liverpool
Recruitment postcode(s) [1] 33121 0
3084 - Heidelberg
Recruitment postcode(s) [2] 33122 0
5042 - Bedford Park
Recruitment postcode(s) [3] 35653 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 307825 0
Commercial sector/Industry
Name [1] 307825 0
Aucentra Therapeutics Pty Ltd.
Country [1] 307825 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Aucentra Therapeutics Pty Ltd.
Address
Level 7, Bradley Building, North Terrace, Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 308534 0
None
Name [1] 308534 0
Address [1] 308534 0
Country [1] 308534 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307830 0
Bellberry Limited Human Research Ethics Committee.
Ethics committee address [1] 307830 0
Ethics committee country [1] 307830 0
Australia
Date submitted for ethics approval [1] 307830 0
09/02/2021
Approval date [1] 307830 0
23/03/2021
Ethics approval number [1] 307830 0
2021-02-112-A-4
Ethics committee name [2] 312264 0
Austin Health Human Research Ethics Committee
Ethics committee address [2] 312264 0
Ethics committee country [2] 312264 0
Australia
Date submitted for ethics approval [2] 312264 0
07/06/2021
Approval date [2] 312264 0
30/08/2021
Ethics approval number [2] 312264 0
HREC/76478/Austin-2021

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108654 0
Dr Ganessan Kichenadasse
Address 108654 0
SOCRU, Suite 201, Level 2 Flinders Private Hospital, 1 Flinders Drive, Bedford Park SA 5042
Country 108654 0
Australia
Phone 108654 0
+61 8 8299 0706
Fax 108654 0
Email 108654 0
[email protected]
Contact person for public queries
Name 108655 0
Jasmine Karanjia
Address 108655 0
Aucentra Therapeutics Pty Ltd, Level 7, Bradley Building, North Terrace, Adelaide, SA 5000
Country 108655 0
Australia
Phone 108655 0
+61 451272401
Fax 108655 0
Email 108655 0
[email protected]
Contact person for scientific queries
Name 108656 0
Paul Wabnitz
Address 108656 0
Level 7, UniSA Cancer Research Institute, Building HB, North Terrace, Adelaide, SA 5000
Country 108656 0
Australia
Phone 108656 0
+61 8 8302 1587
Fax 108656 0
Email 108656 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Subject to internal decision making on how we wish to report the trial results.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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