Phase 1 Dose Escalation and Expansion to Evaluate AROG4-01 in Patients With Advanced Solid Tumors

First in Human Phase 1 Dose Escalation and Expansion Clinical Trial to Evaluate the Safety, Pharmacokinetics and Antitumor Activity of Intravenous AROG4-01 in Patients With Advanced Solid Tumors

The goal of this clinical trial is to learn if drug AROG4-01 is safe in patients with solid tumors who have no available treatment alternative. Different doses will be tested in order to identify the most suitable one. Once it is identiffied, up to 20 patients will be treated with that dose, to check if thye get clinical benefit.

Participants will: receive intravenous administrations of ARG4-01 twice weekly, and visit the clinic twice every week for checkups and tests.

This study is an open label, Phase 1 dose escalation trial with two expansion cohorts to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of AROG4-01 in patients with mesothelioma and other advanced solid tumors.

This clinical trial is divided into two parts: dose escalation (part A), and dose expansion (part B).

Dose escalation In the present trial, patients will be enrolled sequentially into escalating dose cohorts, and will continue receiving AROG4-01 until disease progression, unacceptable toxicity, withdrawal of consent or otherwise as specified in the investigational medicinal product (IMP) discontinuation criteria.

Patients in a dose cohort will receive AROG4-01 as intravenous (IV) administrations at the same dose in a dosing interval of twice a week, four weeks (equal to one cycle) consecutively without interruption, except when necessary to manage adverse events (AEs).

Six cohorts at escalating dose levels are envisaged. Dose escalation may continue beyond, until the recommended for part B dose, which will be the recommended for phase 2 dose (RP2D), can be defined based on safety, preliminary efficacy, PK and PD data, based on the recommendations of the Safety Review Committee (SRC). The RP2D is defined as the recommended for phase 2 dose, but two cohorts will be treated as part of the phase 1 expansion with that particular dose, in order to get more safety and efficacy data.

Escalation to the next dose level will occur following the SRC meeting for the most recently completed cohort. In considering the appropriate dose level for the next cohort the following will be applied:

• The maximum dose increment will be limited to 100% if patients of a given cohort experience one Grade ≥ 2 AE during the DLT period or if at least one patient decreases >10% weight.
• The maximum dose increment will be limited to 50% if a patient of a given cohort experiences one DLT during the DLT period.

If the prior circumstances do not occur, dose escalation will continue at higher increments (not exceeding three times prior dose level), as determined by the SRC.

Extension phase At the dose expansion part, two cohorts of patients with advanced solid tumor each will be recruited. One cohort of patients with advanced MPM (cohort 1) and a second cohort of patients with other solid tumors (cohort 2). Patients will be treated with AROG4-01 at the RP2D of AROG4-01 resulting from part A.

Inclusion Criteria:

1. Male or female patients, 18 years or older, with a diagnosis (histology or citology) of advanced (unresectable or metastatic) solid tumor for which there is no curative therapy, has progressed on SOC treatment or for whom SOC is no longer an option. In part B patients will be included in different cohorts according to the histology (mesothelioma vs. non-mesothelioma).

2. Evaluable (part A) or measurable disease (part B) as per RECIST v1.1 (part A) or mRECIST v1.1. (part B). Progressive disease to the on or following the last line of antitumor treatment.

3. ECOG performance status ≤ 2.

4. Life expectancy ≥12 weeks.

5. Hematology and clinical chemistry laboratory parameters within acceptable ranges.

6. Adequate organ function as defined below:

   • Hemoglobin ≥9 g/dL
   • Neutrophil count ≥1.000x10/mcL
   • Platelets ≥100.000/mcL
   • Total bilirubin ≤1,5 x Upper Limit of Normal (ULN) (unless Gilbert's Disease)
   • AST (SGOT)/ALT (SGPT) ≤ 2,5 x institutional ULN (or ≤ 5X ULN in the presence of liver metastases)
   • Creatinine ≤1.5 mg/dL and creatinine CL ≥40 mL/min (calculated using the Cockcroft-Gault formula)

7. Adequate coagulation profile as defined below:

   • INR≤ 1,5
   • aPTT ≤ 1,5 x ULN
   • Serum or urine negative pregnancy test for women with childbearing potential.

8. No previous antitumor treatment (radiation therapy, systemic treatment, or surgery) in the previous 28 days and current adverse events from them ≤ grade 1.

Exclusion Criteria:

1. Systemic anti-cancer therapy within 4 weeks prior to study admission.
2. Radiation therapy within 4 weeks prior to study entry.
3. Any major surgery within 4 weeks before first dose of study treatment No major surgery must be planned during the trial expected treatment. receiving study treatment. Participants with recent surgery with only local anesthesia may be included.
4. Non-malignant systemic disease including cerebrovascular accident, myocardial infarction in the last 6 months, unstable angina pectoris, unstable cardiac arrhythmia, New York Heart Association (NYHA) Class III or IV heart failure, coagulation abnormalities and clinically significant pulmonary compromise, .
5. Left ventricular ejection fraction below institutional normal limits.
6. Patients with symptomatic central nervous system (CNS) primary tumor or metastases (including leptomeningeal carcinomatosis). Patients with documented treated CNS metastases stable for at least 4 weeks may be enrolled at the discretion of the investigator.
7. Breast feeding, pregnancy or not willing to adopt safe contraceptive measures by the patient or the patient's partner, to become pregnant during treatment or within 6 months after the end of treatment.
8. Patients with active uncontrolled infection or known to be serologically positive for human immunodeficiency virus (HIV), hepatitis B (except HbsAc after vaccination) or hepatitis C infection.
9. Any other diseases or medical condition that may interfere with the planned treatment, compliance, or place the patient at risk if participating in the study, at investigator criteria.