A Phase 1/2, open label, first-in-human, dose escalation and expansion study for the evaluation of safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of SAR445877 administered as monotherapy or in combination with other anticancer therapies in adults with advanced solid tumors

I 01. Participant must be at least 18 years of age inclusive, at the time of
signing the informed consent.
Dose escalation Part 1:
I 02. Participants with advanced unresectable or metastatic solid tumors for
which, in the judgement of the investigator, no standard alternative therapy is
available or is not in the best interest of the participant.
Dose expansion/optimization Part 2:
Cancer diagnosis:
I 03. Participants in Cohorts 1A and A2: Histologically or cytologically
confirmed diagnosis of metastatic NSCLC.
I 04. Participants in Cohort B: Histologically or cytologically confirmed
diagnosis of advanced unresectable or metastatic HCC, or clinically by American
Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic
patients (participants without cirrhosis must have had histological
confirmation of diagnosis).
I 05. Participants in Cohorts C1 and C2: Histologically or cytologically
confirmed diagnosis of advanced unresectable or metastatic GC or Siewert Type 2
& 3 GEJ.
I 06. For participants in Cohorts C1 and C2: Disease with CPS scoring of <1 as
determined at local laboratory with an Agency approved test (for the other
cohorts: Disease with any CPS scoring. No need for CPS determination at local
laboratory).
I 07. For participants in Cohorts C1 and C2: Participants must have MSI or MMR
status known or determined locally and must have non-MSI-H or proficient MMR
(pMMR) disease to be eligible.
I 08. For participants in Cohorts C1 and C2: Participants with unknown HER2/neu
status must have their HER2/neu status determined locally. Participants with
HER2/neu negative are eligible.
Participants with HER2/neu positive tumors must have documentation of disease
progression on treatment containing an approved HER2 targeted therapy to be
eligible.
Prior anticancer therapy (For dose expansion/optimization Part 2 only):
I 09. Participants in Cohorts A1 and A2: Participants must have received at
least 1 systemic therapy for the metastatic setting and must not be amenable to
the available SOC.
Participants in Cohort B: Participants who have received at least 1 prior
anticancer therapy, including an anti-PD1/PD-L1 containing regimen, and for
whom have progressed after a primary or secondary resistance to an
anti-PD1/PD-L1.
Primary resistance: participant must have experienced PD or SD lasting <6
months since the initiation of the anti-PD1/PD-L1 inhibitor-based treatment and
the participant must have received PD1/PD-L1 for at least 6 weeks. Radiographic
confirmation of the PD must be documented after a minimum of 4 weeks after the
initial identification of progression, unless: 1) investigator confirms
clinical progression/deterioration attributed to PD, or 2) the first
radiographic assessment indicated critical tumor growth by imaging (size or
location).
Secondary resistance: participants must have experienced PD, either during or
within 3 months of discontinuing treatment with an anti-PD1 based therapy,
occurring after previous clear benefit (any complete [CR] or partial response
[PR]), or after previous SD of >6 months. There is no requirement for
radiographic confirmation of the progression.
I 10. Participants in Cohorts C1 and C2: Participants should have failed or
relapsed after at least 1 prior line of treatment, which does not include an
anti-PD1/PD-L1-based treatment.
Measurable Disease:
I 11. At least 1 measurable lesion per RECIST 1.1 criteria. Target lesions may
be located in a previously irradiated field if there is a documented
radiographic disease progression in that site.
Provision of tumor tissue:
I 12. Mandatory baseline biopsy for all participants treated in the Escalation
Part from DL3 in Part 1 Q2W schedule and from DL1 QW schedule, and for all
participants in the Expansion Part 2: Biopsies will be obtained if considered
to be an acceptable risk by the treating physician. The slide specifications
are detailed in the Lab Manual. Mandatory on-treatment biopsy for all
participants treated in the Escalation Part from DL3 in Part 1, and for
participants in the Expansion Part 2, if clinically feasible and considered to
be an acceptable risk per investigator's discretion.
Note:
Tumor site used for biopsy must not have been irradiated previously and must
not be the only measurable lesion.
Not applicable to cohort D: The Sponsor may approve the written request to
enroll, on a case-by-case basis, for participants with:
• the location of the tumor not amenable to biopsy due to a significant risk, OR
• less than required number of slides or with an archival tumor tissue sample
collected more than 6 months prior to screening
Weight
I 13. Body weight within 40-150 kg (inclusive).

I 17. For participants in Cohort D: Participants with tumors that are usually
considered immunogenic "hot" tumors infiltrated by T cells as any of the
following: histologically or cytologically confirmed diagnosis of advanced
unresectable or metastatic melanoma, non-small cell lung cancer, bladder, head
and neck, kidney, and liver cancer or other indications known to be immunogenic
at the discretion of the investigator with agreement of the study medical
monitor.
I 18. Participants in Cohort D: Participants must have received at least 1
systemic therapy for their advanced/ metastatic setting and must not be
amenable to the available SOC.
I 19. Participants in Cohorts E1, E2 and E3: Histologically or cytologically
confirmed diagnosis of advanced unresectable or metastatic colorectal cancer.
I 20. Participants in Cohorts E1, E2 and E3 MSI status: Participants must have
MSI status known or determined locally and must have non-MSI-H disease to be
eligible.
I 21. Participants in Cohorts E1, E2 and E3: Participants with RAS-mutant and
BRAF-mutant colorectal cancer are eligible for enrollment.
I 22. Prior anticancer therapy: Participants in cohorts E1 and E2 should have
failed or relapsed on at least 2 prior regimens.
I 23. Participants in cohort E3 should have failed or relapsed on at least 1
prior regimen. Participants who have received cetuximab or other anti-EGFR
therapy as part of their prior line of treatment are eligible.

E 01. Eastern Cooperative Oncology Group (ECOG) performance status of >=2.
E 02. Predicted life expectancy <=3 months.
E 03. For participants with HCC- Cohort B (Part 2): Child Pugh Class B or C
liver score. Participants with Child Pugh Class B-7 score are allowed for Part
1.
E 04. Diagnosed of any other malignancies, either progressing or requiring
active treatments, within 2 years prior to enrollment, except for basal cell
carcinoma or squamous cell carcinoma of the skin, which are in-situ
malignancies, as well as superficial bladder carcinoma, or low risk prostate
cancer, and any tumors that have been deemed as effectively treated with
definitive local control.
E 05. Active brain metastases or leptomeningeal metastases:
• Participants with previously treated brain metastases are eligible, provided
they are clinically stable for at least 4 weeks with no evidence of new or
enlarging brain metastases, and have not received corticosteroids for at least
2 weeks prior to the first IMP administration.
• Participants with asymptomatic brain metastases (ie, no neurological
symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) are
eligible but will require regular imaging of the brain at the site of the
disease.
E 06. History of treatment-related immune-mediated (or immune-related) AEs from
immune modulatory agents (including but not limited to anti-PD1/PD-L1 agents
and anti-cytotoxic T lymphocyte associated protein 4 monoclonal antibodies)
that caused permanent discontinuation of the agent, or that were Grade 4 in
severity, or have not resolved to Grade <=1.
E 07. Has any condition requiring ongoing/continuous corticosteroid therapy
(>10 mg prednisone/day or an anti-inflammatory equivalent) within 1 week prior
to the first dose of the study medicine. Physiologic replacement doses are
allowed even if they are >10 mg of prednisone/day or equivalent, as long as
they are not being administered for immunosuppressive intent. Inhaled or
topical steroids are permitted, provided that they are not for treatment of an
autoimmune disorder. Note: Participants who require a brief course of steroids
(up to 2 days in the week before enrollment) or physiologic replacement are
eligible to be enrolled in the study.
E 08. Any clinically significant cardiac (including valvular) or vascular
(thromboembolic disorders) disease, within 6 months prior to the first IMP
administration, such as:
• Congestive heart failure (New York Heart Association Class II to IV, or left
ventricular ejection fraction <50%).
• Increased troponin (higher than upper limit of normal [ULN] per local
laboratory) at screening. Participants with a higher troponin may be allowed
upon cardiologist consultation and discussion with the Study Medical Monitor on
a case-by-case basis.
• Unstable or poorly controlled angina, myocardial infarction, coronary artery
revascularization procedure (eg, coronary artery bypass graft, percutaneous
coronary intervention).
• Transient ischemic attack, cerebral infarction (stroke), symptomatic
pulmonary embolism, and peripheral artery revascularization procedure.
• Uncontrolled cardiac arrhythmia requiring medication (>= Grade 2, according to
the NCI-CTCAE V5.0).
E 09. History of congenital long QT syndrome, torsades de pointes or prolonged
QTc interval >480 msec using Fridericia*s formula (unless a pacemaker is in
place).
E 10. Ongoing AEs >=Grade 2 (NCI CTCAE V5.0) caused by any prior anti-cancer
therapy with the exception of Grade 2 alopecia, vitiligo, fatigue, and active
hypothyroidism, and stable neuropathy.
E 11. Ongoing or recent (within 2 years) evidence of significant autoimmune
disease that required treatment with systemic immunosuppressive treatments,
which may suggest risk for immune-related AEs (irAEs). Participants with the
following conditions are eligible: vitiligo, childhood asthma that has
resolved, residual hypothyroidism that required only hormone replacement or
psoriasis that does not require systemic treatment.
E 12. Has a known history or any evidence of interstitial lung disease or
active, non-infectious pneumonitis within 3 years prior to the first dose of
the study drug. A history of radiation pneumonitis in the radiation field is
permitted.
E 13. Organ transplant requiring immunosuppressive treatment.
E 14. Uncontrolled or active infection with human immunodeficiency virus (HIV),
hepatitis B, or hepatitis C infection, or has a diagnosis of immunodeficiency.
• Participants will be tested for hepatitis C virus (HCV) and hepatitis B virus
(HBV) at screening.
• Participants with a known HIV infection, if controlled (undetectable viral
load [HIV RNA PCR] and CD4 count above 350, either spontaneously or on a stable
antiviral regimen), are permitted. For participants with a controlled HIV
infection, monitoring will be performed per local standards.
• Participants with a controlled hepatitis B (HBsAg+) infection (serum HBV DNA
PCR that is below the limit of detection and receiving anti-viral therapy for
hepatitis B) are permitted. Participants with controlled infections must
undergo periodic monitoring of the HBV DNA. Participants must remain on
anti-viral therapy throughout the study treatment.
• Participants who are hepatitis C virus antibody positive (HCV Ab+), and whose
infection is controlled (undetectable HCV RNA by PCR either spontaneously or in
response to a successful prior course of anti-HCV therapy), may be enrolled
into the study.
E 15. Clinically not controlled chronic or ongoing infectious disease requiring
hospitalization or treatment within the 14 days prior first IMP administration.
E 16. Known severe hypersensitivity (>= Grade 3) to or contraindication for the
use of any study intervention or components thereof, including premedication
that may be administered in this study. Otherwise, sensitivity of any grade or
allergies that, in the opinion of the investigator contraindicates
participation in the study. For Cohort E3 (receiving cetuximab) Participant has
a history of allergic reactions attributed to compounds of chemical or biologic
composition similar to those of cetuximab, or if the participant had red meat
allergy/tick bite history.
Prior/concomitant therapy
E 17. Is unable or unwilling to take the premedication that may be used.
E 18. Last administration of prior antitumor therapy within 21 days or less
than 5 times the half-life, whichever is shorter; major surgery or local
therapy within 21 days prior to first dose of IMP. Participants who received
anti-PD-1 therapy require an interval of 90 days prior to first dose.
E 19. Washout period of less than 2 weeks prior to radiotherapy. A 1-week
washout is permitted for palliative radiation for a non-central nervous system
disease.
E 20. Receipt of a live-virus vaccination within 28 days of the planned
treatment start date.
E 21. For participants in Cohorts C1 and C2: Prior treatment with an agent
(approved or investigational) that blocks the PD1/PD-L1 pathway (participants
who had joined a study with an anti-PD1/PD-L1 but have a written confirmation
they were on the control arm are allowed).
Prior/concurrent clinical study experience
E 22. Participation in any other clinical study in which the last
investigational study treatment administration was within 5 half-lives from
this study*s intervention initiation ie, prior to the first IMP administration.
Diagnostic assessments
E 23. Inadequate organ and bone marrow functions as evidenced by:
• Absolute neutrophil count (ANC) <1500 cells/µL (1.5 × 109/L). No granulocyte
colony stimulating factor (G-CSF) is permitted in order to reach this value.
• Platelets <100 × 10³/µL or <100 × 109/L. Platelet transfusion is not allowed
within 3 days prior to the screening hematological test.
• Hemoglobin <9 g/dL (transfusion support within prior 2 weeks i