Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000640101
Ethics application status
Approved
Date submitted
12/04/2019
Date registered
30/04/2019
Date last updated
23/08/2024
Date data sharing statement initially provided
30/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2, open label study of orally administered PAX-1 monotherapy in patients with recurrent glioblastoma.
Scientific title

A Phase 2, open label study of orally administered PAX-1 monotherapy in patients with recurrent glioblastoma.
Secondary ID [1] 297965 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma 312371 0
Condition category
Condition code
Cancer 310928 310928 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The changes to the trial were made after patient enrolment. At the time of protocol update, 6 patients were enrolled in the trial.
Initial HREC approval date, 16 August 2019. HREC approval date with update protocol tittle 22 April 2021.
Patients will receive PAX-1 monotherapy for maximum of 4 cycles (provision for additional cycles based on additional cycle criteria), until intolerance, non compliance, withdrawal of consent.
1. The first cycle will start at a dose of 10 mg/day PAX-1.
2. At the end of the first cycle and for each treatment cycle thereafter, the PI will determine the dose of PAX-1 in the next treatment cycle, taking into account the patient's tolerance of the current dose of PAX-1.
3. If Cycle 1 is well tolerated by the patient, then Cycle 2 of PAX-1 will be at a dose of 12.5 mg/day PAX-1.
4. If Cycle 2 is well tolerated by the patient, then Cycle 3 of PAX-1 will be at a dose of 15 mg/day PAX-1.
5. If 15 mg/day PAX-1 is well tolerated by patients, then this dose will be continued for the rest of the cycles
The patients will have an MRI every 8 weeks for disease assessment.
Intervention code [1] 314185 0
Treatment: Drugs
Comparator / control treatment
There is not control treatment for the study
Control group
Historical

Outcomes
Primary outcome [1] 319744 0
Median progression free survival using RANO (radiographic assessment in neuro-oncology) Response Criteria
Timepoint [1] 319744 0
Patients will be assessed every 8 weeks until progression or death
Secondary outcome [1] 369383 0
Progression Free Survival (12 months). PFS shall be defined as the time from baseline MRI scan until objective tumour progression or death using RANO criteria.
Timepoint [1] 369383 0
12 months. Patients will be evaluated every 8 weeks. Confirmatory scans should be obtained not less than 4 weeks following initial documentation of an objective response.
Secondary outcome [2] 369384 0
Overall survival
Timepoint [2] 369384 0
From date of baseline MRI scan to death (last day of follow-up will be the 12 months from the date the last patient was enrolled in the study).
Secondary outcome [3] 369385 0
• To evaluate the safety and tolerability of PAX-1 when administered to patients with recurrent GBM resistant to SOC
• To estimate the PFS at 12 months after the end of treatment
• To estimate Overall Survival (OS)
• To assess the anti-tumour activity of PAX-1
Timepoint [3] 369385 0
For the duration of the study. Patient will remain on study until they experience confirmed disease progression, are withdrawn due to tolerability, or they withdraw consent

Eligibility
Key inclusion criteria
Inclusion Criteria:
1. Patients with recurrent GBM (based on radiological or histological evidence of recurrence) who are resistant to SOC (radiation, second-line treatments including re surgery, or any other treatment deemed appropriate by the PI)
2. Male or female patients >18 years of age (or age of legal adult, whichever is older) and <70 years of age
3. Patients with an ECOG status 0-2
4. RANO criteria defined measurable disease as bidimensional contrast-enhancing lesions with clearly defined margins, with 2 perpendicular diameters of at least 10 mm by MRI imaging at baseline
5. Patients must have adequate haematological, hepatic and renal functions:
• Absolute neutrophil count (ANC) = 1.5 x109/L
• Platelet count = 100 x109/L
• Haemoglobin = 90 g/L (> 9.0 g/dL)
• Total bilirubin = 1.5 upper limit of normal (ULN) (< 2.5 ULN if patient has Gilbert’s syndrome)
• AST/ALT = 2.5 x ULN; = 5 x ULN for patients with liver metastases
• Serum creatinine within normal range or calculated creatinine clearance > 50 mL/min
• Albumin = 33 g/L
• International normalised ratio (INR) and activated partial thromboplastin time (APTT) < 1.5 ULN
• Serum magnesium 0.70 to 1.10 mmol/L (magnesium replacement strategies may be used in case of deficiency)
• Serum potassium = 3.5 mmol/L (potassium replacement strategies may be used in case of deficiency)
• Serum electrolyte levels (e.g. calcium, phosphorus) within normal range or deemed not clinically significant by the Investigator.
6. The patient is able to take oral medication
7. Recovery from the effects of prior therapy, including minimum washout before enrolment in the study is as below:
• 4 weeks from non-nitrosoureas cytotoxic agents (3 weeks from procarbazine, 2 weeks from vincristine)
• 2 weeks from daily or metronomic chemotherapy (the patient must have recovered from the expected toxic effects of such therapy to their baseline or to grade 1)
• 6 weeks from nitrosoureas cytotoxic agents
• 4 weeks from any investigational agents
• 1 week from non-cytotoxic agents
12 weeks from radiotherapy to minimize the potential for MRI changes related to radiation necrosis that might be misdiagnosed as progression of disease, or 4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside the primary radiation field
8. Women of childbearing potential (WOCBP) must have a negative serum beta- human chorionic gonadotrophin (HCG) pregnancy test documented within 7 days prior to IP initiation.
9. Women of childbearing potential and sexually active male patients must agree to use two reliable methods of contraception i.e., oral contraceptives, double barrier methods, hormonal injectable, transdermal, or implanted contraceptives, intrauterine device (IUD), tubal ligation, or vasectomy of their sexual partner(s) for > 30 days before Screening and up to 90 days after discontinuation of study treatment
10. Male subjects with female partners of child-bearing potential must agree to meet 1 of the following contraception for > 30 days before Screening and up to 90 days after discontinuation of study treatment.
• Documentation of successful vasectomy or azoospermia.
• Male condom plus partner use of 1 of the contraceptive options listed above for contraception for WOCBP (oral contraceptives, hormonal injectable, transdermal, or implanted contraceptives, IUD, tubal ligation)
• Male subjects must also agree not to donate sperm up to 90 days after discontinuation of study treatment

11. Female patients without childbearing potential (spontaneous amenorrhea for > 12 months or surgically sterilised by tubal ligation, hysterectomy, or bilateral oophorectomy > 6 months before Screening) are eligible for inclusion without contraceptive use restriction
12.
Female patients must agree not to restart breastfeeding until at least 6 months after last IP administration
13. Patients agrees not to participate in another interventional study while participating in the present clinical study
14. If receiving glucocorticoid therapy, the dose must be stable (or decreasing) over at least 7 days prior to commencing IP
15. Able to undergo gadolinium-enhanced magnetic resonance imaging (Gd-MRI) scans
16. Patients must be competent to understand the nature of the study and capable of giving written informed consent. Patients who understand the nature of the study but are unable to sign may have their next of kin provide written consent
17. A known molecular pathological finding related to prognosis of GBM (e.g. O-6-methylguanine-DNA methyltransferase [MGMT] methylation status; Isocitrate dehydrogenase 1 [IDH-1) mutation) or any other molecular pathology.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Presence of leptomeningeal disease
2. Patients with documented history of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
3. Active autoimmune disorder or known history of an autoimmune neurologic condition (e.g. Guillain-Barre syndrome). Patients with vitiligo, type 1 diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement therapy, psoriasis not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are permitted to enrol
4. Female patients who have been pregnant within the 6 months prior to Screening or breastfeeding within the 3 months prior to Screening
5. Patients with ECG evidence of a QTcF > 450 ms in men and > 470 ms in women and patients with any other risk factors for torsade de pointes (TdP) (such as hypokalaemia, hypomagnesaemia or hypocalcaemia or family history of long QT syndrome)
6. Patients with uncontrolled cardiac disease (e.g. uncontrolled hypertension: diastolic blood pressure [DBP] >100 mmHg, or systolic blood pressure [SBP] >180 mmHg)
7. Myocardial infarction within 6 months before enrolment, unstable angina, New York Heart Association (NYHA) class III or greater congestive heart failure, history of uncontrolled seizures, oxygen dependent chronic diseases, and active psychiatric disorder
8. Stroke or transient ischaemic attack within 6 months before enrolment
9. Clinically significant chronic obstructive pulmonary disease or uncontrolled asthma
10. A history of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer or other solid tumours curatively treated with no evidence of disease for = 2 years
11. Patients with known or suspected to have hypersensitivities, allergies to sodium meta arsenite, related compounds or any of the excipients of the IP
12. Unresolved toxicity > Grade 2, using Common Terminology Criteria for Adverse Events (CTCAE), attributed to any prior therapies (excluding haemoglobin, alopecia, pigmentation, and chemotherapy-induced neurotoxicity)
13. Patients with use of doses of paracetamol in excess of 4 g/day over the 6 months prior to Screening, or with severe malnutrition which may lead to glutathione depletion
14. Current anticoagulant or antiplatelet therapy, except for prophylactic doses of low molecular weight heparins or low-dose aspirin
15. Patients with an inability to comply with study procedures or any condition which in the Investigator's opinion makes the patient unsuitable for study participation
16. Patients with a psychiatric illness who the Investigator deems will have difficulty adhering to the study requirements
17. History of psychotic symptoms requiring antipsychotic treatment or history of a suicidal attempt/s within the prior 6 months
18. History or evidence of any other clinically significant condition including post-operative complications that, in the opinion of the Investigator, would pose a risk to patient safety or interfere with study procedures, evaluation or completion
19. Subjects with pseudoprogression will be excluded based upon imaging and the opinion from the Investigator.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis
Statistical Analysis Plan (SAP) will be produced between finalisation of the CRF and database lock. This will include detailed descriptions of all statistical methodology to be utilised, planned analyses (with any ‘sensitivity’ analyses), together with master table and listing shells and outline figures for reporting. The SAP will be approved and signed prior to clean file.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/02/2020
Actual
10/02/2020
Date of last participant enrolment
Anticipated
Actual
14/10/2022
Date of last data collection
Anticipated
12/09/2023
Actual
6/10/2023
Sample size
Target
40
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,VIC
Recruitment hospital [1] 20729 0
Scientia Clinical Research - Randwick
Recruitment hospital [2] 20730 0
Gallipoli Medical Research Foundation - Greenslopes
Recruitment hospital [3] 20731 0
The Canberra Hospital - Garran
Recruitment hospital [4] 20732 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 35537 0
4120 - Greenslopes
Recruitment postcode(s) [2] 35538 0
2605 - Garran
Recruitment postcode(s) [3] 35539 0
3168 - Clayton
Recruitment outside Australia
Country [1] 24207 0
Korea, Republic Of
State/province [1] 24207 0

Funding & Sponsors
Funding source category [1] 302484 0
Commercial sector/Industry
Name [1] 302484 0
Komipharm International Australia
Country [1] 302484 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Novotech (Australia) Pty Limited
Address
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country
Australia
Secondary sponsor category [1] 302383 0
None
Name [1] 302383 0
Address [1] 302383 0
Country [1] 302383 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303146 0
South Eastern Sydney Local Health District HREC
Ethics committee address [1] 303146 0
Ethics committee country [1] 303146 0
Australia
Date submitted for ethics approval [1] 303146 0
16/01/2019
Approval date [1] 303146 0
16/08/2019
Ethics approval number [1] 303146 0
2019/ETH00016

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

Contacts
Principal investigator
Name 92634 0
Dr Charlotte Lemech
Address 92634 0
The address for Scientia Clinical Research is;

5 Bright Building Corner High, Avoca st Randwick NSW 2031.
Country 92634 0
Australia
Phone 92634 0
+61 02 9382 5820
Fax 92634 0
Email 92634 0
charlotte [email protected]
Contact person for public queries
Name 92635 0
Indira Mismit
Address 92635 0
Indira Mismit

Komipharm International Australia .62-64 Burwood Road, Burwood. NSW 2134
Country 92635 0
Australia
Phone 92635 0
+61 0450301833
Fax 92635 0
Email 92635 0
[email protected]
Contact person for scientific queries
Name 92636 0
Indira Mismit
Address 92636 0
Indira Mismit
Komipharm International Australia. 62-64 Burwood Road, Burwood. NSW 2134
Country 92636 0
Australia
Phone 92636 0
+61 044450301833
Fax 92636 0
Email 92636 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
Clinical trial data for this study is confidential. The Sponsor will use the data for publication purposes and regulatory activities but not share IPD publicly.


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
No additional documents have been identified.