A First-in-human Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Anti-tumour Activity of TAX2 in Patients With Relapsed/Refractory Advanced/Metastatic Solid Tumours

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

The purpose of this clinical trial is to investigate the treatment for adult patients suffering from advanced or metastatic solid tumours and has 2 parts to the study: the Phase 1 where ascending doses of the experimental study drug, TAX2, will be tested and the Phase 2a where all the participants will receive the study drug at the same dose considered as the recommended Phase 2 dose from Phase 1 part. The participation in the Phase 1 or in the Phase 2a part depends on when the participant is proposed to join the study.

The study purpose is to assess:

• How safe and tolerable TAX2 is. This assessment will be based on the adverse effects collected during the study.
• How well TAX2 enters the body, circulates in the body, and leaves the body (known as pharmacokinetics, PK) by measuring the level of the drug in the blood
• What the drug does with the body and the tumour (known as pharmacodynamics, PD)
• The effect TAX2 has on the tumours (anti-tumour activity)
• Also define the Dose Limiting Toxicity (DLT) and the recommended Phase 2 Dose (RP2D)

Inclusion Criteria:

I.01 Age ≥ 18 years. I.02 Patient capable of and willing to giving signed informed consent, which includes compliance with the requirements and restrictions listed in this protocol.

I.03 Documented diagnosis of:

1. 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.
2. Relapsed/refractory metastatic colorectal cancer (mCRC). All histological types of CRC are eligible.
3. Relapsed/refractory metastatic pancreatic cancer (mPC). All histological types of PC are eligible, with the exception of pancreatic neuro-endocrine tumours.
4. Relapsed/refractory cutaneous metastatic melanoma (MM). All histological types of cutaneous melanoma are eligible.

I.04 Must have received prior therapy for advanced/metastatic disease according to standard of care and have exhausted all therapeutic options.

I.05 Must have documented evidence of progressive disease on or after the last treatment regimen.

I.06 Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

I.07 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.

I.08 Patients willing to use highly effective contraception as described below (in consistency with local regulations regarding the methods of contraception for clinical trial participants):

1. 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.
2. 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.
3. A WOCBP must agree to repeated pregnancy testing during trial participation. She must have a negative serum pregnancy test (beta-HCG) within 48 hours prior to start of trial treatment.
4. 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.

Exclusion Criteria:

E.01 Known intolerance or hypersensitivity to any of TAX2 formulation excipients or to dextrose.

E.02 Prior treatment with any anti-CD47 or anti-SIRPα agent. E.03 Prior exposure (for up to 4 months or 5 half-lives, whichever is longer) to PD 1/PD L1 therapies.

E.04 History or presence of autoimmune disease, except for autoimmune endocrinopathies that are stable on hormone replacement therapy.

E.05 History or presence of inflammatory disease such as colitis, liver fibrosis, cirrhosis, interstitial fibrosis or chronic obstructive pulmonary disease.

E.06 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 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 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 d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN, except in patients with liver metastasis: for these patients, AST or ALT < or equal to 5 x ULN is acceptable for trial participation.

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.

f. Serum albumin < 25 g/L

E.07 History or presence of clinically significant cardiovascular disease with at least one of the following criteria:

1. Evidence of poorly controlled arterial hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg).
2. 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 MUGA scan at screening.
3. Any cardiac arrhythmia that is not well controlled.
4. Clinically significant valvular heart disease.
5. Unstable angina pectoris within 6 months prior to start of trial treatment. E.08 History or presence of severe dyspnoea, pulmonary dysfunction, or need for continuous supportive oxygen inhalation.

E.09 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.

E.10 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.

E.11 Requirement of therapy for active infections. All anti-infectious therapies must have been completed at least 7 days prior to start of trial treatment.

E.12 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.

E.13 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.

E.14 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.

E.15 History of allogeneic tissue and/or solid organ transplantation.

E.16 History of another primary malignancy except for:

1. 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.
2. Adequately treated non-melanoma skin cancer or lentigo maligna without current evidence of disease.
3. Adequately treated carcinoma in situ (including ductal carcinoma of the breast, DCIS) without current evidence of disease.
4. 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 < or equal to pT2N0) may be enrolled, pending discussion and approval by the Sponsor.

E.17 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.

E.18 Use of any investigational agent within 4 weeks prior to start of trial treatment.

E.19 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:

1. Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for prostate cancer.
2. Hormone-replacement therapy or oral contraceptives.
3. Palliative radiotherapy for bone metastases within 2 weeks prior to start of trial treatment.

E.20 Daily requirement for immunosuppressive therapy or corticosteroids (equivalent to > 10 mg/day prednisone) for more than 7