| Eligibility |
Inclusion Criteria:
1. Signed and dated, written informed consent form (ICF) prior to any trial-specific
procedures.
2. Male or female aged = 18 years (no upper limit of age) at the time of ICF signature.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Life expectancy of at least 3 months.
5. Patients with a SIRPa polymorphism including at least one V1 allele will be selected
(i.e., homozygous V1/V1 or heterozygous V1/V2 in separate cohorts in escalation [Step
1] and only homozygous V1/V1 in expansion cohorts [Step 2]); SIRPa polymorphism will
be assessed in blood sampling (patient DNA) in a central laboratory; V1 allele is
understood to include V1 and V1-like alleles.
6. In Step 1: Patients with histologically or cytologically documented
advanced/metastatic primary or recurrent malignancies who failed or are not eligible
to standard therapy;
In Step 2: Cohort C1: Patients with histologically or cytologically
advanced/metastatic primary or recurrent unresectable documented MSS colorectal
tumors, whose disease relapsed after standard of care and who received no prior
anti-PD-L1 inhibitors.
Cohort C2: Patients with histologically or cytologically advanced or metastatic
documented MSS endometrial carcinoma whose disease relapsed after standard of care and
who received no prior anti-PD-L1 inhibitors.
7. Patients with at least one measurable lesion as per RECIST v1.1.
8. Patients must agree to pre- and on-treatment tumor biopsies. Fresh tumor biopsy may
come either from the primary tumor or from a metastasis. Cytological material is not
accepted. Archival tumor biopsy is acceptable, if done within 4 weeks before the first
treatment administration.
Biopsy sites should be carefully selected by the investigator so that it is safe for
the patient and subsequent biopsy can be performed at the same location; also if
possible should be distinct from the measurable lesion;
9. Adequate biological parameters defined as:
1. Absolute neutrophil count (ANC) = 1.5 x 10^9/L.
2. Hemoglobin (Hb) level = 10 g/dL. (without recent red blood cell transfusion
within 2 weeks prior to study entry)
3. Platelet count = 100 x 10^9/L.
4. Total bilirubin level = 1.5 X Upper Limit Normal (ULN), except for patients with
Gilbert's syndrome from whom total bilirubin < 3.0 x ULN or direct bilirubin <
1.5 x ULN is authorized.
5. Aspartate transaminase (AST) and alanine transaminase (ALT) = 2.5 x ULN.
6. Serum creatinine = 1.5 ULN; or creatinine clearance > 50 mL/min (Chronic Kidney
Disease Epidemiology [CKD-EPI] formula).
7. INR = 1.5 (except if patient treated with anti-vitamin K); anticoagulation with
anti-vitamin K and Low Molecular Weight Heparin [LMWH] is allowed;
10. Prior major treatment-related surgery completed at least 28 days before study drug
administration;
11. In all cohorts :
- An interval of at least 28 days since the last chemotherapy, approved
immunotherapy, biological or investigational therapy, radiation or tyrosine
kinase inhibitor (TKI) therapy (sunitinib, sorafenib) must have elapsed before
the first study drug administration(s);
- And all toxicities related to previous anticancer therapies have resolved to
normal value or = to Grade 1 prior to the study treatment administration, except
alopecia.
12. Women must not be breastfeeding;
13. Women of childbearing potential (WOCB) must agree to use highly effective methods of
contraception (i.e. one that results in a less than 1% per year failure rate when used
consistently and correctly), prior to study entry, during the study and for 5 months
after the last dose of study drug.
Highly effective methods of contraception are defined as one of the following methods:
combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation (oral, intravaginal, 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, sexual abstinence.
14. Male patient with WOCBP partner must be willing to use male contraception (condoms)
during the study and until 5 months after last dose of study drug. WOCBP partners of
male subjects participating in the study may use hormone based contraceptives as one
of the acceptable methods of contraception since they will not be receiving study drug
(i.e.; oral hormonal contraception, cap, diaphragm, or sponge with spermicide).
15. Females of childbearing potential must have a serum negative pregnancy test within 7
days prior to first administration. Females who are postmenopausal for at least 1 year
(defined as more than 12 months since last menses) or are surgically sterilized do not
require this test.
16. Capable of understanding and complying with protocol requirements.
17. Patients must be affiliated to a social security system or an equivalent system.
Exclusion Criteria:
1. Patient with symptomatic/active central nervous system (CNS) metastases; Patient with
previously treated brain metastases are eligible, if there is no evidence of
progression for at least 28 days before the first study treatment administration, as
ascertained by clinical examination and brain imaging (MRI or CT) during the screening
period;
2. Other tumor location necessitating an urgent therapeutic intervention (e.g.,
palliative care, surgery or radiation therapy, such as spinal cord compression, other
compressive mass, uncontrolled painful lesion, bone fracture).
3. Presence of other active invasive cancers, other than the one treated in this trial,
within 5 years prior to screening.
Except appropriately treated basal cell carcinoma of the skin, or in situ carcinoma of
uterine cervix, or other local tumors considered cured by local treatment;
4. Patient with active autoimmune disease or a documented history of autoimmune disease,
that requires systemic treatment (i.e. corticosteroids or immunosuppressive drugs).
Except patients with vitiligo, resolved childhood asthma/atopy, alopecia, or any
chronic skin condition that does not require systemic therapy, patients with
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone
and/or controlled Type 1 diabetes mellitus on a stable insulin regimen may be
eligible.
5. Known severe infusion related reactions to monoclonal antibodies (Grade = 3 NCI-CTCAE
v5.0) and patients removed from previous anti-PD-1 or anti-PD-L1 therapy because of a
severe or life-threatening immune-related adverse event (irAE) (Grade = 3 NCI-CTCAE
v5.0);
6. Patients receiving systemic treatment with any immunosuppressive medication within
one-week prior treatment start; Steroids of max. 10 mg prednisolone equivalent per day
are allowed, topical and inhaled steroids are not considered as immunosuppressive.
7. Patients with interstitial lung disease or active, non-infectious pneumonitis.
8. Patient with uncontrolled disease-related metabolic disorders (e.g., hypercalcemia,
SIADH) or uncontrolled diabetes;
9. Patient with uncontrolled congestive heart failure defined as New York Heart
Association (NYHA) class III or IV, uncontrolled hypertension, unstable heart disease
(e.g., coronary artery disease with unstable angina or myocardial infarction within 6
months before study treatment administration).
10. Patient with significant ECG abnormalities defined as any cardiac dysrhythmia (> Grade
2) (i.e., significant ventricular arrhythmia as persistent ventricular tachycardia
and/or ventricular fibrillation; severe conduction disorders as atrio-ventricular
block 2 and 3, sino-atrial block) or baseline QT/QTc interval >480 milliseconds (ms).
11. Patient with significant chronic liver disease (e.g., significant fibrosis, known
cirrhosis) or active HBV or HCV infection; If HbsAg positive, an effective antiviral
treatment to prevent hepatitis B reactivation is recommended.
12. Patients with known Human Immunodeficiency Virus (HIV) infection or patients with an
active infection requiring specific anti-infective therapy until all signs of
infection have resolved, and this within 2 weeks prior to the first study treatment
administration;
13. Patient whose medical, psychological including alcohol or drug abuse, or surgical
conditions are unstable and may affect the study completion and/or compliance and/or
the ability to give informed consent.
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