Conditions

• Non-Small Cell Lung Cancer
• ICI-refractory

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Eligibility Criteria

1. Ability to understand and willingness to sign informed consent form (ICF) prior to
initiation of the study and any study procedures.

2. Age ≥18 years. Because no dosing or adverse event data are currently available on
the use of SAR445877 in participants <18 years of age, children are excluded from
this study.

3. Participants with histologically documented locally advanced or metastatic NSCLC who
have had disease progression after treatment with all available therapies for
metastatic disease that are known to confer clinical benefit, or are intolerant to
treatment, or refuse standard treatment:

4. Prior immune checkpoint inhibitor (anti-PD-(L)1) exposure. Participants need to have
received at least 6 weeks of exposure to anti-PD-(L)1 and developed disease
progression. Treatment with neoadjuvant or adjuvant ICI is acceptable if participant
developed progression within one year of start of ICI therapy.

5. One lesion suitable for repeat biopsy without significant risk to the participant.

6. Measurable disease per RECIST v1.1.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

8. Adequate organ and marrow function as defined below, obtained before study treatment
initiation:

1. Hemoglobin >9.0 g/dL

2. Absolute neutrophil count ≥1000/mcL

3. Platelets ≥75,000/mcL

4. Total bilirubin ≤1.5 institutional upper limit of normal (ULN). Documented
Gilbert syndrome is allowed if total bilirubin is ≤3 × ULN.

5. AST/ALT ≤2.5 × institutional ULN. Transaminases up to 5 × ULN in the presence
of liver metastases.

6. Measured or calculated creatinine clearance (CrCl; glomerular filtration rate
can also be used in place of creatinine or CrCl) ≥30 mL/min (CrCl should be
calculated per institutional standard).

7. 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.

9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
result at screening.

10. WOCBP must agree to use highly effective contraception for the duration of study
participation and for 60 days after completion of study treatment. A woman is
considered to be of childbearing potential if she is postmenarcheal, has not reached
a post-menopausal state (≥12 continuous months of amenorrhea with no identified
cause other than menopause), and is not permanently infertile due to surgery (i.e.,
removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined
by the investigator (e.g., Müllerian agenesis). 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. Men treated or enrolled on this
study must also agree to use adequate contraception for the duration of study
participation and for 60 days after completion of study treatment. In addition, male
participants must be willing to refrain from sperm donation during this time.

11. Willing to undergo mandatory biopsies and blood collections as required by the
study.

12. Participants with treated brain metastases are eligible if follow-up brain imaging
after central nervous system (CNS)-directed therapy shows no evidence of progression
and participant is clinically stable without requirement of steroid treatment for ≥
7 days prior to the first dose of study treatment.

13. Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial.

Exclusion Criteria

1. History of allergic reactions attributed to compounds of similar chemical or
biologic composition to the study drugs.

2. Participants who are pregnant or breastfeeding.

3. Participants with an active, known or suspected autoimmune disease. Participants
with type I diabetes mellitus, hypothyroidism only requiring hormone replacement,
skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are permitted to enroll.

4. Participants with a condition requiring systemic treatment with either
corticosteroid (>10 mg daily prednisone equivalent) or other immunosuppressive
medications within 14 days of study treatment initiation. Inhaled or topical
steroids, and adrenal replacement steroid doses, are permitted in the absence of
active autoimmune disease.

5. History of interstitial lung disease (ILD) or checkpoint inhibitor-induced
pneumonitis.

6. Known history of positive test for human immunodeficiency virus or known acquired
immunodeficiency syndrome.

7. Acute or chronic hepatitis B virus or hepatitis C virus infection. Prior viral
exposure with cleared or fully treated infection based on negative HCV viral load is
permitted.

8. Previous solid organ or allogeneic hematopoietic stem cell transplant.

9. Active infection requiring IV antibiotics or other uncontrolled intercurrent illness
requiring hospitalization.

10. Significant cardiovascular/cerebrovascular disease, including stroke, myocardial
infarction, or prolonged QTc (> 480msec) within 3 months. Participants on beta
blockers must be able to stop beta blockers for duration of their time on study
treatment period when applicable.

11. Participants who have not recovered from AEs due to prior anticancer therapy (i.e.,
have residual toxicities > Grade 1) with the exception of alopecia, hearing loss,
grade 2 neuropathy or endocrinopathy managed with hormone replacement therapy.

12. Participants who have previously been treated with PD-1, PD-L1, or CTLA-4 inhibitors
and required permanent discontinuation or systemic immunosuppression (e.g. immune
inhibitory monoclonal antibodies) due to irAEs.

13. Participants who are receiving any other investigational agents.

14. Treatment with a live, attenuated vaccine within 4 weeks prior to study treatment
initiation, or anticipation of need for such a vaccine during the course of the
study or within 5 months after the last dose of study treatment. 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).

15. Participants must have adequate washout from prior therapy at the time of study
treatment initiation: 4 weeks from major surgery; 4 weeks from antibody-based
therapy; 3 weeks from prior PD-(L)1 inhibitor exposure; 2 weeks or 5 half-lives
(whichever is shorter) from any targeted therapy or small molecule therapy; 3 weeks
or 5 half-lives (whichever is shorter) from chemotherapy or 6 weeks in the case of
certain therapies (e.g., extensive radiotherapy, mitomycin C, and nitrosoureas); and
2 weeks from radiation therapy. Palliative radiotherapy is permitted for a
preexisting lesion, provided it does not interfere with the assessment of tumor
target lesions (e.g., the lesion to be irradiated must not be a site of measurable
disease).

16. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, ductal carcinoma in situ,
squamous cell carcinoma of the skin that has undergone potentially curative therapy,
or in situ cervical cancer.

17. Has a known psychiatric or substance abuse disorder that would interfere with
cooperation with the requirements of the study.

18. Inability to comply with the study and follow-up procedures.

Recruiting Locations

Study Contact

Detailed Description

Primary Objectives - To identify early efficacy signals for SAR445877 in ICI-exposed NSCLC participants - Identify biomarkers related to the mechanism of action in SAR445877 and predictive of response/resistance in ICI-exposed NSCLC participants