None listed
Conditions
Brief summary
AXA-042 is a novel toll-like receptor (TLR) 2/6 agonist designed to re-engage the innate immune system and promote anti-tumour immune responses. In this first-in-human study, researchers will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumour activity of AXA-042 administered as monotherapy in participants with advanced solid tumours. This part of the study (Part C) will use a Simon’s two-stage design to identify early signals of clinical activity while minimising exposure to potentially ineffective treatment. Who is it for? You may be eligible for this study if you are 18 years of age or older, have a diagnosis of a locally advanced or metastatic solid tumour, and your cancer has progressed despite standard treatments or you are intolerant to standard of care therapies. Study details Participants will receive AXA-042 as monotherapy, administered as an intravenous infusion on Day 1 of a 21-day treatment cycle. Treatment will continue until disease progression, withdrawal of consent, unacceptable toxicity, investigator decision, or study completion. The dose of AXA-042 used in this part of the study will be selected based on available safety and pharmacokinetic/pharmacodynamic data from earlier parts of the study and confirmed by the Safety Monitoring Committee. Participants will be monitored closely for adverse events throughout treatment and for at least 30 days after the last dose. Blood samples will be collected to assess pharmacokinetics, immunogenicity, and pharmacodynamic biomarkers, including immune response markers and cytokine profiles. Tumour response will be evaluated using RECIST v1.1, iRECIST, and/or PERCIST criteria, as appropriate. Quality-of-life assessments will also be conducted during the study. It is hoped that this study will help determine whether AXA-042 monotherapy demonstrates sufficient biological and clinical activity in selected solid tumour types to support further clinical development.
Interventions
Participants will receive AXA-042 as monotherapy administered by intravenous infusion once every 3 weeks (21-day treatment cycle). The dose administered will be 0.0003 mg/kg, every 3 weeks. Pending evaluation of efficacy and safety by the Safety Monitoring Committee, the dose may be increased to 0.0004 mg/kg, every 3 weeks.
Treatment duration: treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or end of study.
Sponsors
Axelia Oncology Pty Ltd
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of a histologically or cytologically confirmed locally advanced or metastatic cancer (all solid tumours). Subjects must be considered refractory or intolerant to the standard of care therapies or have refused standard therapy. 2. Age greater or equal to 18 years old at the time of Screening (signing the Informed Consent Form [ICF]) 3. Eastern Cooperative Oncology Group (ECOG)9 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 tumour lesion by Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) criteria.10 For suitable subjects, such as subjects that may not have measurable lesions, positron emission tomography (PET) may be implemented in addition to, or in place of, RECIST v1.1, to monitor disease response (PERCIST; PET response criteria in solid tumours version 1.0) on discussion and approval by the sponsor’s medical monitor. 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 enrolment. 7. Subjects who have previously received an immune CPI prior to enrolment must have any immune- related toxicities resolved less than or equal to Grade 1 or baseline (prior to the CPI) with the exception of toxicities not considered a safety risk (e.g., hypothyroidism, alopecia, neuropathy, or asymptomatic laboratory abnormalities). 8. Adequate organ function based on laboratory assessments at Screening, as defined by: a. Haemoglobin greater than or equal to 90 g/L (subjects may be transfused more than 2 weeks before Screening, but should not be transfusion -dependent) b. Platelets greater than or equal to 100 × 109/L c. Absolute neutrophil count greater than or equal to 1.5 × 109/L d. 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 greater than 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. e. 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 (less than 3.0 ×ULN for subjects with liver metastases or Gilbert’s syndrome) f. 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) g. International normalized ratio and activated partial thromboplastin time less than or equal to 1.5 × UL. 9. Available archived tumour 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 (e.g., recently diagnosed subjects or diagnosed with fine -needle aspiration), the subject will have an option to consent for and undergo fresh tumour 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 tumour tissues are not safely accessible as determined by the Investigator or the tumour biopsies have to be obtained from sites that require significant risk procedures. For Part C, subjects may be advised by their study doctor to undergo mandatory pretreatment (during screening period) biopsies and 2 weeks post first treatment cycle. 10. Female subjects must not be pregnant, or must be of non- childbearing potential as defined 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. 11. Non-sterilized male subjects must agree to use contraception as detailed in Appendix 6 of this protocol during the treatment period and for at least 90 days after the last dose of the study treatment for Part A and C and 4 months after the last dose of the study treatment for Part B. 12. 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. 13. Voluntarily agrees to participate by giving written informed consent and is willing and able to comply with this protocol and scheduled visits. Additional eligibility requirements for participants enrolled in each tumour-specific cohort in Part C: 1. Histologically or cytologically proven high-grade serous epithelial ovarian cancer, renal cell carcinoma, appendiceal cancers, undifferentiated pleomorphic sarcoma, and mesothelioma. 2. Must have progressed within 6 months of platinum-based chemotherapy (platinum-resistant disease) or is intolerant to prior treatment with dual immune checkpoint inhibitor therapy or combination of immune checkpoint inhibitor and anti-angiogenic small molecule inhibitor. 3. Must have received no more than 3 prior lines of systemic anti-cancer therapy in the advanced or metastatic disease setting. a. Neoadjuvant and adjuvant not counted as a line of therapy in the advanced disease setting. b. Maintenance therapy, e.g., bevacizumab, PARP inhibitor or hormonal therapy, is considered the same line as / counted as one with the preceding systemic treatment regimen. c. Hormonal therapy is considered its own line of systemic treatment unless given as maintenance. d. On a case-by-case basis in discussion with study Sponsor, therapy change due to toxicity may be considered the same line as / counted as one with the preceding systemic treatment regimen.
Exclusion criteria
1. Subjects diagnosed with glioblastoma, other brain tumours, and haematological 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 (e.g., 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 or documented history of autoimmune disease that has caused terminal organ damage or required systemic immunosuppression and/or systemic disease modulating drugs within the past 2 years, or participant is immunocompromised for any other reason (as determined by the Investigator/Medical Monitor). Note that subjects with active or document history of autoimmune disease that has caused terminal organ damage or required systemic immunosuppression and/or systemic disease modulating drugs within the past 2 years or participant is immunocompromised for any other reason may be allowed on case-by-case basis with the approval of the study Sponsor if it is deemed not to put subject at an increased risk of treatment-related toxicities and/or interfere with study data integrity, e.g., hypothyroidism on adequate thyroid hormone replacement therapy. 5. Active or a history of clinically significant atopy (severe or multiple allergic manifestations). Subjects with asthma requiring the administration of regular inhaled steroids, or a history of asthma requiring hospitalisation will be excluded. Note that subjects with active mild asthma requiring intermittent bronchodilator administration and/or short-term inhaled steroids may be allowed on Medical Monitor/Sponsor approval. 6. 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, such as those with arthritis of undiagnosed aetiology and elevated titres of rheumatoid factor, anti-citrullinated antibody or anti-nuclear antibody, final determination can be made as per the discretion of the PI in consultation with the Medical Monitor. 7. Active systemic infection requiring treatment with intravenous antibiotics or a significant infection (minor superficial skin infections or urinary tract infections are not exclusionary). 8. History of drug-induced severe hypersensitivity reaction. 9. History of recurrent or clinically significant syncope.1 10. Have uncontrolled pleural effusion(s), pericardial effusion, or ascites. 11. 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. 12. Received chemotherapy or other anticancer therapy within 4 weeks prior to the first dose of study treatment. Exceptions include concurrent standard of care (SOC) therapies such as the use of hormones for noncancer-related conditions (e.g., insulin for diabetes), hormone deprivation therapy (e.g., androgen deprivation therapy for prostate cancer), antiresorptive therapy (e.g., bisphosphonates, denosumab for prevention of osteoporosis, bone disease etc.), and local treatment of isolated lesions for palliative intent (e.g., by local surgery or local radiotherapy). Subjects on SOC therapy are required to be on a stable dose for a period of at least 1 month prior to enrolment without any foreseeable changes in dose during the duration of this trial. Palliative subjects who have received radiotherapy treatment are allowed after 7 days of their last treatment. Any other concurrent SOC therapies not included here are to be discussed and approved by the MM prior to screening of the subject 13. Received prior TLR agonist therapy. 14. Currently taking chronic systemic glucocorticoid therapy in excess of replacement doses (i.e., greater than 10 mg prednisone/day or equivalent) or other systemic immunosuppressive treatment. 15. 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). For any minor surgical procedures related to the biopsy collection, a less than or equal to 7-day washout will suffice. 16. Received investigational therapy or used an investigational device within 4 weeks prior to the first dose of study treatment. 17. Received a live vaccine within 30 days prior to the first dose of study treatment. Administration of an approved coronavirus disease 2019 (COVID-19) vaccine (both the doses of a 2-dose vaccine or a booster shot) greater than or equal to 14 days prior to the first dose of study treatment is allowed. There can be exceptions on a case-by-case basis as approved by the Medical Monitor. 18. Pregnant or breastfeeding or expecting to conceive a child during the study or within 90 days after the last dose of study treatment. 19. Known history of human immunodeficiency virus infection or active infection with hepatitis B or C. 20. Have a psychiatric or substance use disorder that would interfere with cooperation with the requirements of the study. 21. 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. 22. History of greater than or equal to Grade 2 hypertension. Exception can be made based on MM approval if BP increase is transient due to other reasons like the white coat syndrome or deemed not to put participant at a higher risk of treatment-related toxicity and/or interfere with the integrity of study data.
Outcome results
None listed