Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000993796
Ethics application status
Approved
Date submitted
17/06/2022
Date registered
14/07/2022
Date last updated
14/06/2023
Date data sharing statement initially provided
14/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A first-in-human study evaluating the safety of AXA-042 as a single agent in patients with advanced solid tumors
Scientific title
A Phase 1, first-in-human, open-label, non-randomized, multicenter, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AXA-042 as monotherapy in subjects with advanced solid tumors.
Secondary ID [1] 306911 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced solid tumors 326675 0
Condition category
Condition code
Cancer 323914 323914 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will evaluate ascending doses of AXA-042 to investigate its safety, tolerability, pharmacokinetics, immunogenicity and preliminary efficacy in patients with advanced solid tumors.

AXA-042 will be administered as an intravenous infusion over 30 minutes on Day 1 of each 21-Day Treatment Cycle under supervised administration.

Based on a comprehensive analysis of the safety, PD, and PK data from nonclinical studies, the starting FIH dose is proposed to be 0.0001 mg/kg (7 µg for a 70 kg human) of AXA-042. Subsequent dose levels are planned to be calculated as up to a 3-fold increase over the previous dose level.

Approximately 12 to 18 subjects are planned to be enrolled in 5 to 6 sequential dose levels in the study. Additional subjects may be enrolled in further dose levels based on emerging safety, laboratory tests and PK data from this study.

Intrasubject dose escalation is permitted for subjects enrolled at all dose levels if the subject is tolerating their initial dose, the subjects in the next higher dose level have completed the dose-limiting toxicity (DLT) period without evidence of a DLT, and the dose has been declared safe by the Safety Monitoring Committee. It is permitted to escalate the dose twice for each subject as per the discretion of the Principal Investigator and Medical Monitor.

If the safety and tolerability profile of AXA-042 is acceptable, study treatment will continue until disease progression, withdrawal of consent, discontinuation from the study, or toxicity that in the opinion of the Investigator or Sponsor requires study treatment discontinuation or the end of the study, whichever occurs first.
Intervention code [1] 323793 0
Treatment: Drugs
Comparator / control treatment
No control group. This is an open label study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331723 0
Determine incidence of Adverse Events and Dose-limiting toxicities
AXA-042 is an innate immune agonist and adverse events related to the activation of immune system will be monitored, including cytokine release, joint inflammation and infusion related reactions.
Timepoint [1] 331723 0
The incidence of adverse events will be assessed by physical examination or other measurable assessments including ECOG, ECG, vital signs and laboratory results, at each site visit or via telephone calls whenever they occur during the clinical trial participation. All adverse events will be collected from the start of the study treatment (Cycle 1 Day 1) until the end of treatment visit, which is 30 days after the last dose of study treatment or until initiation of a new anti-cancer treatment, whichever occurs first.

Vital signs will be taken at every site visit throughout treatment. For all cycles, on Day 1, vital signs measurements will be performed within 30 minutes before infusion, then every 15 minutes until the EOI, and then at 30 minutes, 1 h, and 2 h after EOI. In addition, vital signs will be performed at 4 h and 6 h after EOI on Cycle 1 Day 1. On other specified days, a single assessment will be performed. Vital signs include systolic and diastolic blood pressure, respiratory rate, pulse rate, and body temperature (tympanic). Blood pressure and pulse rate will be assessed with a completely automated device. Manual techniques will be used only if an automated device is not available.

ECG assessments will be performed during Day 1 of every cycle and EOS. For all cycles, on Day 1, ECG assessments will be performed within 60 minutes prior to dosing and again at 4 h after End of Infusion. At End of Treatment/Early Termination visit, a single assessment will be performed.

Eastern Cooperative Oncology Group (ECOG) will be assessed during screening and within 2 hours of pre-dose on Day 1 cycle 2, Day 1 cycle 3 and every other cycle on day 1 onwards as well as at the end of treatment (EOT) visit.

Physical examination will be performed during screening, within 2 hours of pre-dose on Day 1 and anytime during the visit on Day 8 and Day 15 of cycle 1 and then on Day 1 of subsequent cycles.

Laboratory assessments performed at screening, day 1, day 2, day 8 and day 15 of cycle 1 and cycle 2, and day 1 for subsequent cycles. For all cycles, sampling for safety laboratory tests will be collected prior to dosing on Day 1. Blood samples will be collected to assess chemistry, hematology, liver function, thyroid function, coagulations factors, Urine samples will be collected at each site visit to assess for renal function.
Secondary outcome [1] 410866 0
Concentrations of AXA-042 in plasma, including the concentration-time profile of AXA-042 and plasma PK parameters including (but not limited to) AUC0-336h; AUC0-504h AUC0-last; AUC0-inf, t½, MRT in vivo, Vd, CL, Cmax, and tmax
Timepoint [1] 410866 0
Determine the pharmacokinetics (PK) of AXA-042 in plasma when administered intravenously on Day 1 of a 21-day cycle including the following timepoints: Cycle 1 day 1: pre-dose 0.5 hours prior to infusion, post-dose on the following 0.25, 0.5, 1, 2, 4, and 8 hours; Cycle 1, Day 2 (24 hour), Day 3 (48 hours), Day 4 (72 hours) Day 8 (168 hours) and Day 15 (226 hours) post-dose,

PK assessments will also be taken on Cycle 2 Day 1 during pre-dose at 0.5 hours and post-dose at 4 hours; Day 2 (24 hours), Day 8 (168 hours) and Day 15 (336 hours) post-dose
Secondary outcome [2] 411344 0
Incidence of immunogenicity (ADA) against AXA-042 in serum
Timepoint [2] 411344 0
ADA will be assessed at cycle 1 day 1, cycle 2 day 1 and cycle 3 day 1.
Secondary outcome [3] 411816 0
PD parameters evaluated in blood may include but are not limited to target engagement biomarkers, cytokines, and immune-related gene expression
Timepoint [3] 411816 0
PD markers will be assessed on
Cycle 1 Day 1 pre-dose, and 4 hours post dose
Cycle 1 Day 2, Day 3, Day 4, Day 8 and Day 15 at any time during the visit
Cycle 2 Day 1 pre-dose, and 4 hours post dose
Cycle 2 Day 2, Day 8 and Day 15
Cycle 3 Day 1, pre-dose and 4 hours post dose
Secondary outcome [4] 411817 0
Progression Free Survival as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Timepoint [4] 411817 0
End of study

Eligibility
Key inclusion criteria
1. Diagnosis of a histologically or cytologically confirmed locally advanced or metastatic cancer (all solid tumors). Subjects must be considered refractory or intolerant to the standard of care therapies or have refused standard therapy.
2. Age greater than or equal to 18 years old at the time of Screening (signing the Informed Consent Form [ICF]).
3. Eastern Cooperative Oncology Group performance status 0 to 1.
4. The estimated life expectancy of at least 3 months as per the Investigator's judgment.
5. At least one measurable disease tumor lesion by Response Evaluation Criteria in Solid Tumors Version 1.1
6. Subjects who have undergone treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody must have a gap of at least 4 weeks from the last dose of antibody and evidence of disease progression per the Investigator's assessment before enrollment.
7. Subjects who have previously received an immune CPI prior to enrollment must have any immune-related toxicities resolved to less than or equal to Grade 1 or baseline (prior to the CPI) with the exception of toxicities not considered a safety risk (eg, alopecia, neuropathy, or asymptomatic laboratory abnormalities).
8. Adequate organ function based on laboratory assessments at Screening, as defined by:
• Hemoglobin greater than or equal to 90 g/L (subjects may be transfused >2 weeks before Screening, but should not be transfusion-dependent)
• Platelets greater than or equal to 100 × 109/L
• Absolute neutrophil count greater than or equal to 1.5 × 109/L
• Serum creatinine less than or equal to 1.5 × upper limit of normal (ULN); or a calculated creatinine clearance (Cockcroft-Gault method) greater than or equal to 50 mL/minute if serum creatinine >1.5 × ULN. Lower calculated creatinine clearance values may be allowed at the Investigator’s discretion and in consultation with the Medical Monitor and Sponsor.
• Total bilirubin less than or equal to ULN; or conjugated bilirubin less than or equal to ULN and total bilirubin less than or equal to 1.5 × ULN (<3.0 × ULN for subjects with liver metastases or Gilbert’s syndrome)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 × ULN (AST and ALT less than or equal to 5 × ULN if liver metastases present)
• International normalized ratio and activated partial thromboplastin time less than or equal to 1.5 × ULN.
9. Available archived tumor tissue sample (block of formalin-fixed paraffin-embedded [FFPE] tissues) to allow for exploratory biomarker studies. In the setting where archival material is unavailable or unsuitable for use (eg, recently diagnosed subjects or diagnosed with fine-needle aspiration), the subject will have an option to consent for and undergo fresh tumor biopsy (at acceptable risk as judged by the Investigator). The requirement for fresh biopsy collected from a given subject could be waived after the discussion with the Medical Monitor if the tumor tissues are not safely accessible as determined by the Investigator or the tumor biopsies have to be obtained from sites that require significant risk procedures.
10. Female subjects must not be pregnant, or must be of non-childbearing potential; or if of childbearing potential, must agree to use highly effective birth control methods during the study treatment period and for at least 90 days after the last dose of the study treatment.
Non-sterilized male subjects must agree to use contraception during the treatment period and for at least 90 days after the last dose of the study treatment.
11. For women of childbearing potential (WOCBP) only: A negative serum pregnancy test during Screening and a negative serum or urine pregnancy test within 24 hours of the first dose of study treatment.
12. Voluntarily agrees to participate by giving written informed consent and is willing and able to comply with this protocol and scheduled visits.
Minimum age
18 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subjects diagnosed with glioblastoma, other brain tumors, and hematological cancer. In the case of rare cancers, there may be some exceptions at the Investigator’s discretion in consultation with the Medical Monitor.
2. Prior malignancies active within previous 3 years, except the cancer for which the subject is enrolled in the current study or locally curable cancers that have been cured (eg, basal cell skin cancer, squamous cell carcinoma, or carcinoma in situ of the cervix or breast).
3. Known active central nervous system metastases or carcinomatous meningitis.
4. Active autoimmune disease or a history of autoimmune disease, except for vitiligo, resolved childhood asthma/atopy, current mild asthma (treated with intermittent bronchodilators only), mild atopic dermatitis (treated with topical medications only), and endocrine deficiency following immunotherapy.
5. Current or known history of rheumatoid arthritis, ankylosing spondylitis, or any other joint inflammatory conditions that have systemic and/or organ involvement, and/or involve disease flares affecting joint function. Osteoarthritis alone is not exclusionary. For uncertain cases, final determination can be made as per the discretion of the PI in consultation with the Medical Monitor.
6. Active systemic infection requiring treatment with intravenous antibiotics or a significant infection (minor superficial skin infections or urinary tract infections are not exclusionary).
7. History of a severe hypersensitivity reaction to another biological therapy.
8. History of syncope.
9. Have uncontrolled pleural effusion(s), pericardial effusion, or ascites.
10. Evidence of abnormal cardiac function as defined by any of the following:
• Myocardial infarction within 6 months of Cycle 1 Day 1.
• Symptomatic congestive heart failure (New York Heart Association Class II or greater).
• Unstable angina.
11. Received chemotherapy, radiation therapy, or other anticancer therapy within 4 weeks prior to the first dose of study treatment. Exceptions include concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and HRT), androgen deprivation therapy for prostate cancer, and local treatment of isolated lesions for palliative intent (eg, by local surgery or local radiotherapy).
12. Received prior TLR agonist therapy.
13. Currently taking chronic systemic glucocorticoid therapy in excess of replacement doses (ie, >10 mg prednisone/day or equivalent) or other systemic immunosuppressive treatment.
14. Have undergone major surgery in the 4 weeks prior to Screening or minor surgical procedures less than or equal to 7 days (no waiting required following port-a-cath placement or for venous access).
15. Received investigational therapy or used an investigational device within 4 weeks prior to the first dose of study treatment.
17. Pregnant or breastfeeding or expecting to conceive a child during the study or within 90 days after the last dose of study treatment.
18. Known history of human immunodeficiency virus infection or active infection with hepatitis B or C.
19. Have a psychiatric or substance use disorder that would interfere with cooperation with the requirements of the study.
20. History of any condition or treatment which could confound the results of the study, interfere with the subject’s participation in the study, or make study participation not in the subject’s best interests, in the opinion of 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
18/07/2022
Actual
15/11/2022
Date of last participant enrolment
Anticipated
31/10/2023
Actual
Date of last data collection
Anticipated
29/03/2024
Actual
Sample size
Target
18
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA,VIC
Recruitment hospital [1] 22559 0
Linear Clinical Research - Nedlands
Recruitment hospital [2] 22560 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 22561 0
Dandenong Hospital- Monash Health - Dandenong
Recruitment hospital [4] 22562 0
Scientia Clinical Research - Randwick
Recruitment postcode(s) [1] 37812 0
2031 - Randwick
Recruitment postcode(s) [2] 37810 0
3000 - Melbourne
Recruitment postcode(s) [3] 37811 0
3175 - Dandenong
Recruitment postcode(s) [4] 37809 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 311222 0
Commercial sector/Industry
Name [1] 311222 0
Axelia Oncology Pty Ltd
Country [1] 311222 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Axelia Oncology Pty Ltd
Address
31 Queen st,
Melbourne Vic 3000
Country
Australia
Secondary sponsor category [1] 313094 0
None
Name [1] 313094 0
Address [1] 313094 0
Country [1] 313094 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310749 0
Bellberry Limited
Ethics committee address [1] 310749 0
123 Glen Osmond Road, Eastwood South Australia 5063
Ethics committee country [1] 310749 0
Australia
Date submitted for ethics approval [1] 310749 0
06/04/2022
Approval date [1] 310749 0
14/06/2022
Ethics approval number [1] 310749 0
2022-04-349
Ethics committee name [2] 311107 0
Royal Melbourne Hospital
Ethics committee address [2] 311107 0
300 Grattan Street (corner of Royal Parade)
Parkville, Victoria 3050
Australia
Ethics committee country [2] 311107 0
Australia
Date submitted for ethics approval [2] 311107 0
Approval date [2] 311107 0
Ethics approval number [2] 311107 0

Summary
Brief summary
AXA-042 functions through a multi-cellular mechanism to re-engage the innate immune response. This first-in-human study is planned to evaluate the safety, tolerability, pharmacokinetics (PK), preliminary efficacy, and pharmacodynamics (PD) of AXA-042 as monotherapy in subjects with advanced solid tumors.

Who is it for?
You may be eligible for this study if you are aged 18 years or over, have a diagnosis of a locally advanced or metastatic solid tumor, and are refractory or intolerant to standard of care therapies.

Study details
All participants will receive AXA-042 as an intravenous infusion over 30 minutes on day 1 of each 21-day treatment cycle. This will continue until disease progression, withdrawal of consent, discontinuation from the study, or toxicity that in the opinion of the Investigator or Sponsor requires study treatment discontinuation, or up to study completion, whichever occurs first. Participants will be enrolled in one of the estimated 4-5 cohorts of 1 participant in each cohort for the accelerated portion of the study where the first cohort will receive 0.0001 mg/kg of AXA-042 for the duration of their treatment, while the dose will be increased by 3-fold in each subsequent cohort, after review of safety data, to determine the maximum tolerated dose. It is anticipated that there will be additional 1-2 cohorts in the 3+3 portion of the study where 3 participants will be enrolled in each cohort. Participants will be monitored for adverse events throughout their treatment until at least 30 days after their last dose of study drug. Participants will also have blood samples taken throughout day 1 of treatment after receiving AXA-042 to study the time course of drug absorption, distribution, metabolism, and excretion. Preliminary efficacy and pharmacodynamics will be determined through objective response rate, progression-free survival, time to response and overall survival and pharmacodynamics data on cytokines and other immune response biomarkers in response to AXA-042 treatment.

It is hoped that this study may show that AXA-042 is safe and effective for the treatment of advanced solid tumors, which may lead the way for larger efficacy trials in future.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118730 0
Prof Michael Millward
Address 118730 0
Prof, Michael Millward
Ground Floor, B Block, QEII Medical Centre, Hospital Avenue
Nedlands WA 6009
Country 118730 0
Australia
Phone 118730 0
+61 1300546327
Fax 118730 0
Email 118730 0
michael.millward@uwa.edu.au
Contact person for public queries
Name 118731 0
Mr Ardian Latifi
Address 118731 0
Ardian Latifi
Axelia Oncology
31 Queen St, Melbourne, VIC, 3000
Country 118731 0
Australia
Phone 118731 0
+61 421814712
Fax 118731 0
Email 118731 0
al@axeliaoncology.com
Contact person for scientific queries
Name 118732 0
Dr Phil Kearney
Address 118732 0
Phil Kearney
Axelia Oncology
31 Queen St, Melbourne Australia
Country 118732 0
Australia
Phone 118732 0
+61 414795133
Fax 118732 0
Email 118732 0
pk@axeliaoncology.com

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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16396Ethical approval    383918-(Uploaded-16-06-2022-13-26-33)-Study-related document.pdf



Results publications and other study-related documents

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