Phase 1 Study Of SAR445877 In Combination With FOLFOX6 And Bevacizumab As First-Line Treatment For Microsatellite Stable Metastatic Colorectal Cancer

Primary Objective •To determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of SAR445877 + FOLFOX6 and bevacizumab in patients with MSS metastatic CRC.

Secondary Objective

•To evaluate the antitumor efficacy of SAR445877 + FOLFOX6 and bevacizumab in participants with MSS metastatic CRC.

Eligibility Criteria

• Ability to understand and willingness to sign informed consent form prior to initiation of the study and any study procedures.
• Capable of and willing to comply with scheduled visits, treatment plans, laboratory tests, and other study-related tests and procedures.
• Age ≥18 years.
• Participants with histologically documented CRC with metastatic disease who have not received prior treatment in the metastatic setting. Participants who have received adjuvant FOLFOX must be 6 months from treatment at the time of enrollment.
• CRC documented as MSS by immunohistochemistry, next-generation sequencing, or polymerase chain reaction assay at any time prior to screening.
• Measurable disease per the RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ and marrow function as defined below within 28 days of study treatment initiation:

• Hemoglobin >9.0 g/dL
• Absolute neutrophil count ≥1500/mL
• Platelets ≥100,000/mL
• Total bilirubin ≤1.5 × institutional upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is ≤3 × ULN.
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 × institutional ULN. Transaminases up to 3 × ULN in the presence of liver metastases.
• Estimated glomerular filtration rate ≥50 mL/min/1.73 m² (Modification of Diet in Renal Disease Formula)
• For participants not receiving therapeutic anticoagulation: international normalized ratio or activated partial thromboplastin time ≤1.5 × ULN. For participants receiving therapeutic anticoagulation: stable anticoagulant regimen.
• Life expectancy ≥ 3 months.
• The effects of SAR445877 and FOLFOX/bevacizumab on the developing human fetus are unknown. For this reason, women of childbearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of the study treatment period, and for 9 months after completion of study treatment.

(Refer to Pregnancy Assessment Policy MD Anderson Cancer Center [MDACC] Institutional Policy # CLN1114). WOCBP includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the participant presents with an applicable exclusionary factor which may be one of the following:

• Postmenopausal (no menses in ≥12 consecutive months)
• History of hysterectomy or bilateral salpingo-oophorectomy
• Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range and have received whole pelvic radiation therapy)
• History of bilateral tubal ligation or another surgical sterilization procedure
• Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation or hysterectomy, patient/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the duration of the study treatment period and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Male participants must agree to use adequate contraception throughout the duration of the study treatment period and for 6 months after the last dose of study treatment
• WOCBP must have a negative serum pregnancy test within 3 days prior to first administration of study treatment.

Exclusion criteria

• Pregnant or breastfeeding.
• Ongoing or recent (within 2 years) evidence of significant autoimmune disease that requires/required treatment with systemic immunosuppressive treatments, which may suggest risk for 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.
• Participants who are receiving any other investigational agents.
• Receipt of a live-virus vaccination within 28 days prior to study treatment initiation. Non-live COVID vaccines will be allowed on study, but it is recommended to avoid their use during the first treatment cycle (from 3 days prior to Cycle 1 Day 1 through Cycle 2 Day 3).
• Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 1 week prior to the first administration of study treatment. 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 they are not for the treatment of an autoimmune disorder. 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.
• Known history of positive test for human immunodeficiency virus or known acquired immunodeficiency syndrome, unless most recent CD4 count exceeds 500 cells/mm3.
• Acute or chronic hepatitis B virus or hepatitis C virus infection.
• Previous solid organ or allogeneic hematopoietic stem cell transplant.
• Active brain or leptomeningeal metastases.
• Active infection requiring IV antibiotics or other uncontrolled intercurrent illness requiring hospitalization.
• History of interstitial lung disease or severe obstructive pulmonary disease.
• Clinically significant cardiovascular/cerebrovascular disease.
• Left ventricular ejection fraction <50% as measured by echocardiogram or multigated acquisition scan.
• Serious, non-healing wound, ulcer, or bone fracture.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to first administration of study treatment.
• Evidence of bleeding or coagulopathy.
• Uncontrolled hypertension (>150/100 mmHg).
• Urine dipstick of proteinuria >2+. Participants with >2+ proteinuria on dipstick analysis will undergo a 24-hour urine collection and must demonstrate <1.0 g protein/24 hours to be eligible.
• Known severe hypersensitivity reactions to monoclonal antibodies, any history of or recent (within 6 months) anaphylaxis.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
• Known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.

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