Phase I/Ib, open-label, multiple ascending dose, first-in-human study, to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of INT-1B3 in patients with advanced solid tumors

1. Patient provided a signed written informed consent before any screening
procedure
2. Patient with (a) lesion(s) assessable for sequential biopsies (baseline and
on treatment)
3. Patient is male or female, >=18 years of age (adult patients)
4. Patient with histologically or cytologically confirmed advanced and/or
metastatic solid tumor, with progressive disease at baseline, for whom no
standard treatment is available or who have declined standard therapy
5. Patient with evaluable disease per RECIST v1.1, iRECIST or mRECIST (for HCC
patients)
6. Patient with a predicted life expectancy of * 12 weeks
7. Patient with Eastern Cooperative Oncology Group (ECOG) performance status of
Grade 0 - 1
8. Patient with hemoglobin >= 9.0 g/dL, platelet count >= 75×109/L, and absolute
neutrophil count >= 1.0×109/L
9. Patient with adequate renal function (creatinine level within normal
institutional limit defined as CrCl (corrected for body surface area (BSA)) or
calculated creatinine clearance >= 50 mL/min/1.73 m2 (CKD-EPI calculation, see
Appendix 11.1)
10. Patient with adequate liver function (aspartate transaminase and/or alanine
transaminase <3 times institutional upper limit of normal (ULN) (or <= 5 times
ULN for patients with liver metastases), total bilirubin <= 1.5 times ULN (or <=
3 x ULN for patients with Gilbert*s disease)
11. Patient with adequate coagulation tests: international normalized ratio or
prothrombin time (PT) and activated partial thromboplastin time (aPTT) within
1.5 times ULN
12. Female patient of childbearing potential (defined as < 12 continuous months
of amenorrhea with no identified cause other than menopause or not surgically
sterile), must have a negative pregnancy test within 7 days before first
administration of study medication and agree to use highly effective methods of
contraception during the treatment until 60 days after the last administration
of the study medication.
Examples of highly effective contraceptive methods with a failure rate of < 1%
per year include bilateral tubal ligation, male sterilization, hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
and copper intrauterine devices. Hormonal contraceptive methods must be
supplemented by a barrier method
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, or
post ovulation methods) and withdrawal are not acceptable methods of
contraception
13. Male patients with a female partner of childbearing potential must agree to
remain sexually abstinent or use adequate contraception (agreement to use a
barrier method of contraception) during the treatment phase and 60 days after
the last dose of the study medication. In addition, male patients must be
willing to stop sperm donation during this time
14. Patient is able and willing to comply with the protocol and the
restrictions and assessments therein.

Additional inclusion criteria for dose-expansion phase (Phase Ib):
15. Patient with measurable disease per RECIST v1.1, iRECIST or mRECIST (for
HCC) and at least 1 (additional) lesion accessible for sequential biopsies
(baseline and on-treatment)
16. Patient has advanced or metastatic HCC or TNBC with histological or
cytological confirmation (histological confirmation can be obtained per
screening biopsy for HCC)
17. Patient has previously received all systemic standard therapies with proven
clinical benefit, and progressed or relapsed thereafter, or was ineligible for
standard therapies in the judgment of the treating physician
a) Not more than one line of previous therapy with immune checkpoint inhibitor
therapy either alone or in combination is allowed

1. Patient on any other anti-cancer therapy (cytotoxic, biologic or
investigational agents), unless at least 4 weeks (or 5 half-lives, whichever is
shorter, 6 weeks for mitomycin-C or nitrosoureas), have elapsed since the last
dose before the first administration of INT-1B3 At least 2 weeks should have
elapsed since receiving non-palliative radiotherapy. Chronic treatment with
non-investigational gonadotropin-releasing hormone analogs or other hormonal or
supportive care is permitted
2. Patient with known central nervous system (CNS) metastases, unless
previously treated and well-controlled for at least 1 month (defined as
clinically stable, no edema, no steroids and stable in 2 scans at least 4 weeks
apart)
3. Patient with concomitant second malignancies unless curatively treated at
least 2 years before study entry with no additional therapy required or
anticipated to be required during the study period
4. Patient with major surgery within 5 weeks before initiating treatment or
with minor surgical procedure within 7 days before initiating treatment (except
for port-a-cath placement or biopsy)
5. Patient with active autoimmune disease or persistent immunemediated
toxicity caused by immune checkpoint inhibitor therapy of grade >= 2 (patients
with autoimmune-related hyperthyroidism, autoimmune-related hypothyroidism in
remission, or with a stable dose of hormone-replacement, vitiligo, or psoriasis
not requiring systemic therapy (>10mg prednisone equivalent) or controlled Type
1 diabetes mellitus, may be included)
6. Patient with toxicity (except for alopecia) related to prior anti-cancer
therapy and/or surgery, unless the toxicity is either resolved, returned to
baseline or Grade 1 (or are allowed according to other in/exclusion criteria)
7. Patient with any active neuropathy > Grade 2 (National Cancer Institute
Common Terminology Criteria for Adverse Events [CTCAE] v5.0)
8. Patient with a history of life-threatening (Grade 4) toxicity related to
prior immune therapy or severe (Grade 3) toxicity that resulted in permanent
discontinuation after rechallenge with immune therapy
9. Patient with any condition requiring concurrent use of systemic
immunosuppressants or corticosteroids at a daily dose > 10 mg prednisone
equivalent or other immunosuppressive medications within 14 days of study
medication administration (permitted: premedication for i.v. contrast,
treatment with a short course of steroids (< 5 days) up to 7 days before
initiating study medication, and topical glucocorticoids, or steroid
replacement doses for adrenal or pituitary insufficiency)
10. Patient with evidence of active infection that requires systemic
antibacterial, antiviral, or antifungal therapy <= 7 days before the first dose
of study medication
11. Patient with uncontrolled or significant cardiovascular disease including,
but not limited to, any of the following:
a) Left ventricular ejection fraction (LVEF) <= 50 % determined by
echocardiogram or multi-gated acquisition (MUGA) scan
b) High risk or uncontrolled clinically significant arrhythmias (such as atrial
fibrillation and conduction disorders, ventricular tachycardia, ventricular
fibrillation, or torsade de pointes)
c) Treatment with drugs that are generally considered to have a high risk of
causing torsade de pointes (it will be at the discretion of the treating
physician to discontinue or substitute as appropriate; if discontinued, the
washout period needs to be at least 5 half-lives of the drug)
d) QT interval corrected using Fridericia*s formula (QTcF) prolongation > 480
msec
e) Cerebral vascular accident/stroke or myocardial infarction < 6 months prior
to enrollment
f) Uncontrolled hypertension (systolic > 150 millimeter of mercury [mmHg]
and/or diastolic > 100 mmHg)
g) Unstable angina within the past 6 months, congestive heart failure (CHF)
defined as New York Heart Association (NYHA) class II -IV, hospitalization for
CHF (any NYHA class) within 6 months before the start of trial treatment
h) Medical history of deep vein thrombosis or pulmonary embolism
12. Patient with active or chronic hepatitis B (positive for HBsAg or
anti-HBsAg and anti-HBcAg antibodies) or C (positive for anti-HCV antibody or
HCV RNA quantitation)
a) For the dose escalation phase, serology testing may be omitted at the
investigator*s discretion if there are no clinical signs suggestive of
hepatitis infections.
b) Subjects with positive HBV serology are eligible if quantitative PCR for
plasma HBV-DNA is negative and the subject will be receiving prophylaxis for
potential HBV reactivation.
c) Subjects with positive HCV serology are eligible if quantitative PCR for
plasma HCV RNA is negative.
13. Patient with known history of presence of human immunodeficiency virus
(HIV), patients are NOT required to be tested for the presence of HIV before
therapy on this protocol)
14. Patient with any known or underlying medical, psychiatric condition, and/or
social situations that, in the opinion of the investigator, would limit
compliance with study requirements
15. Patient with history of allergy to the study medication or any of its
excipients
16. Patient that received packed red blood cells or platelet transfusion within
2 weeks of the first dose of study medication
17. Female patient: pregnant or breastfeeding
18. Involvement in the planning and/or conduct of the study (applies to Sponsor
staff, contract research organization (CRO) staff, and/or staff at study site)