A phase 1/2a, first-in-human, open-label, dose-escalating study with a safety expansion cohort to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of TAX2 in patients with relapsed/refractory advanced/metastatic solid tumours

Prior treatment

• Concurrent enrolment in another clinical trial, unless it is an observational (non-interventional) clinical trial for the duration of this trial or the FU period of an interventional trial.
• Use of any investigational agent within 4 weeks prior to start of trial treatment.
• Any anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 4 weeks or 5 half-lives (for monoclonal antibodies) prior to start of trial treatment; however, the following are allowed: a. Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for prostate cancer.
• Any anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 4 weeks or 5 half-lives (for monoclonal antibodies) prior to start of trial treatment; however, the following are allowed: b. Hormone-replacement therapy or oral contraceptives.
• Any anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 4 weeks or 5 half-lives (for monoclonal antibodies) prior to start of trial treatment; however, the following are allowed: c. Palliative radiotherapy for bone metastases within 2 weeks prior to start of trial treatment.
• Daily requirement for immunosuppressive therapy or corticosteroids (equivalent to > 10 mg/day prednisone) for more than 7 days (except for inhalation corticosteroids).
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of the investigational medicinal product (IMP). Non-live vaccines on routine vaccinations are recommended for the patients and their contacts. Prophylactic vaccination is recommended for influenza A and B virus, pneumococci and Haemophilus influenzae. Ribonucleic acid (RNA)-based vaccination for SARS-CoV-2 is also recommended.
• History or presence of clinically significant cardiovascular disease with at least one of the following criteria: e. Unstable angina pectoris within 6 months prior to start of trial treatment.
• Prior treatment with any anti-CD47 or anti-SIRPα agent.
• Known central nervous system (CNS) metastasis that is either untreated or treated but associated with clinical symptoms (e.g. headache, convulsions). Patients with CNS metastasis who were treated with radiotherapy and/or surgery are eligible if they have been without clinical symptoms and have demonstrated stability on MRI for at least 6 weeks prior to start of trial treatment; if under treatment with corticosteroids (not exceeding 10 mg/day prednisone or equivalent) and/or anticonvulsive agents, patients must be on stable doses for at least 2 weeks prior to start of trial treatment.
• Requirement of therapy for active infections. All anti-infectious therapies must have been completed at least 7 days prior to start of trial treatment.
• Active SARS-CoV-2 infection defined as having a positive SARS-CoV-2 PCR test at screening. The PCR test result must not be older than 72 hours prior to start of trial treatment. Completed vaccination or prior SARS-CoV-2 infection do not exempt from PCR testing.
• History of another primary malignancy except for: a. Malignancy treated with curative intent, with no known active disease for at least 2 years prior to start of trial treatment, and with a relatively low risk for recurrence.
• Prior exposure (for up to 4 months or 5 half-lives, whichever is longer) to PD-1/PD-L1 therapies.

Other illness

• Known intolerance or hypersensitivity to any of TAX2 formulation excipients or to dextrose.
• Any other acute or chronic condition or personal circumstances including medical, clinical, or psychiatric conditions, or with history of substance abuse disorders, that, in the opinion of the investigator, would interfere with understanding the informed consent process, adherence to the protocol requirements and procedures, treatment compliance and/or interpretation of the patient’s data.
• History or presence of autoimmune disease, except for autoimmune endocrinopathies that are stable on hormone replacement therapy.
• History or presence of inflammatory disease such as colitis, liver fibrosis, cirrhosis, interstitial fibrosis or chronic obstructive pulmonary disease.
• History of severe peripheral vascular (arterial or venous) disease, including aneurysm, deep venous thromboembolic disease (DVT) within 6 months from screening, peripheral venous thrombosis within 4 months from screening, arterial thrombosis within 6 months from screening, myocardial infarction, pulmonary embolism or cerebrovascular accident. Patients with a history of DVT, peripheral venous or arterial thrombosis must be controlled under adequate anticoagulation before the beginning of the study.
• History or presence of clinically significant cardiovascular disease with at least one of the following criteria: a. Evidence of poorly controlled arterial hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg).
• History or presence of clinically significant cardiovascular disease with at least one of the following criteria: c. Any cardiac arrhythmia that is not well controlled.
• History of allogeneic tissue and/or solid organ transplantation.
• History or presence of clinically significant cardiovascular disease with at least one of the following criteria: d. Clinically significant valvular heart disease.
• Known acquired immunodeficiency syndrome (AIDS)-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment; known active hepatitis A infection (defined as positive hepatitis A antigen or positive Immunoglobulin M (IgM)); active or chronic hepatitis B (HBV) or hepatitis C (HCV) infection. Participants with chronic HBV or HCV disease that is controlled under antiviral therapy are allowed. Hepatitis B and C serology will be tested at screening in all participants.
• History of another primary malignancy except for: b. Adequately treated non-melanoma skin cancer or lentigo maligna without current evidence of disease.
• History of another primary malignancy except for: Adequately treated carcinoma in situ (including ductal carcinoma of the breast, DCIS) without current evidence of disease.
• History of another primary malignancy except for: d. Cancer subjects with incidental histologic findings of prostate cancer that, in the opinion of the Investigator, does not require active therapy (e.g. incidental prostate cancer identified following cysto-prostatectomy that is tumour/node/metastasis Stage ≤ pT2N0) may be enrolled, pending discussion and approval by the Sponsor.

Lab values

• Inadequate haematological, hepatic and renal functions, as demonstrated by: e. Bilirubin > 1.5 x ULN, except for patients with documented familial hyperbilirubinemia (such as Gilbert's syndrome): for these patients, a total bilirubin of < 3 x ULN is acceptable for trial participation.
• Inadequate haematological, hepatic and renal functions, as demonstrated by: a. Haematology: i. Platelet count ≤ 100,000 cells/mm3 ii. Absolute neutrophil count (ANC) ≤ 1,500 cells/mm3 iii. Haemoglobin ≤ 9 g/dL
• Inadequate haematological, hepatic and renal functions, as demonstrated by: b. Coagulation: i. International normalized ratio (INR) > 1.5 ii. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≥ 1.6 x ULN unless therapeutically warranted
• Inadequate haematological, hepatic and renal functions, as demonstrated by: c. Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance ≤ 50 mL/min based on modification of diet in renal disease (MDRD) glomerular filtration rate estimation
• Inadequate haematological, hepatic and renal functions, as demonstrated by: f. Serum albumin < 25 g/L
• History or presence of clinically significant cardiovascular disease with at least one of the following criteria: b. Documented history of congestive heart failure of New York Heart Association Grade III or IV or presence of left ventricular ejection fraction (LVEF) of < 50% during echocardiography or multigated acquisition (MUGA) scan at screening.
• Inadequate haematological, hepatic and renal functions, as demonstrated by: d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN, except in patients with liver metastasis: for these patients, AST or ALT ≤ 5 x ULN is acceptable for trial participation.

Other

• History or presence of severe dyspnoea, pulmonary dysfunction, or need for continuous supportive oxygen inhalation.
• Body weight >100 kg.

• Age ≥ 18 years.
• Willing to undergo paired tumour biopsies at screening and after 2 treatment cycles (optional: additional biopsy after 6 treatment cycles). Available tumour tissue from a non-irradiated tumour lesion biopsied within 6 weeks to start of trial treatment is acceptable as substitute for the screening biopsy, provided there has been no intervening treatment since the biopsy.
• Patients willing to use highly effective contraception as described below (in consistency with local regulations regarding the methods of contraception for clinical trial participants): a. A male participant must agree to use highly effective contraception (as described below) from the time of screening to at least 3 months after the last dose of trial treatment. During this period, he must refrain from donating sperm.
• Patients willing to use highly effective contraception as described below (in consistency with local regulations regarding the methods of contraception for clinical trial participants): b. A female participant must not be pregnant nor breastfeeding and either is not a woman of childbearing potential (WOCBP; i.e. not post-menopausal for ≥ 1 year and not surgically sterile) or must agree to use highly effective contraception (as described below) from the time of screening to at least 6 months after the last dose of trial treatment. During this period, she must refrain from participation in in vitro fertilisation.
• Patients willing to use highly effective contraception as described below (in consistency with local regulations regarding the methods of contraception for clinical trial participants): c. A WOCBP must agree to repeated pregnancy testing during trial participation. She must have a negative serum pregnancy test (β-HCG) within 48 hours prior to start of trial treatment.
• Patients willing to use highly effective contraception as described below (in consistency with local regulations regarding the methods of contraception for clinical trial participants): d. Highly effective contraception includes combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, and/or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner or sexual abstinence.
• Patient capable of and willing to giving signed informed consent, which includes compliance with the requirements and restrictions listed in this protocol.
• Documented diagnosis of: a. Relapsed/refractory advanced/metastatic ovarian cancer (aOC). All histological types of OC are eligible, including ovarian clear cell carcinoma and with exception of mucinous ovarian subtypes.
• Documented diagnosis of: b. Relapsed/refractory metastatic colorectal cancer (mCRC). All histological types of CRC are eligible.
• Documented diagnosis of: c. Relapsed/refractory metastatic pancreatic cancer (mPC). All histological types of PC are eligible, with the exception of pancreatic neuro-endocrine tumours.
• Documented diagnosis of: d. Relapsed/refractory cutaneous metastatic melanoma (MM). All histological types of cutaneous melanoma are eligible.
• Must have received prior therapy for advanced/metastatic disease according to standard of care and have exhausted all therapeutic options.
• Must have documented evidence of progressive disease (as defined by RECIST version 1.1 criteria) on or after the last treatment regimen.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.