Inclusion Criteria:
* Patient, or legally authorized representative (LAR), willing and able to provide written informed consent for the trial
* Patient age ≥ 18 at time of consent
* Pathologically confirmed diffuse pleural mesothelioma
* Must have received at least one prior systemic therapy (platinum/pemetrexed, immunotherapy or a combination thereof)
* Measurable disease as defined primarily by the modified RECIST criteria for mesothelioma (at PI discretion RECIST v1.1 may be used)
* Consent to undergo a biopsy prior to Cycle 1 Day 1 and Cycle 3 Day 1 if deemed medically safe and feasible
* Eastern Cooperative Oncology Group (ECOG) score 0 or Karnofsky Performance Status ≥ 70%
* Adequate organ function, defined as
* Absolute neutrophil count ≥ 1.5K/mcL
* Platelet count ≥ 100K/mcL
* Adequate renal function defined as creatinine clearance ≥ 30ml/min (as calculated by Cockcroft-Gault Formula)
* Hemoglobin \> 9g/dL (prior transfusion permitted if not within 7 days of enrollment)
* Total bilirubin ≤1.5 x upper limit of normal (ULN) if no liver metastases or \<3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases; subjects with Gilbert's syndrome can enroll if conjugated bilirubin is within normal limits
* AST, ALT ≤ 2.5 x ULN (if liver metastases are present, ≤5 × ULN)
* If of childbearing potential, must be willing to use highly effective mode of contraception for at least one month prior, during, and for 2 months after the end of active therapy
Exclusion Criteria:
* Currently participating in another study and receiving another study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks of the first dose of treatment
* Prior hypersensitivity to irinotecan or any components of sacituzumab govitecan-hziy
* Prior cytotoxic/immunologic systemic therapy within 3 weeks prior to study Day 1 or has not recovered (i.e., CTCAE v5 ≥ Grade 1 at baseline; from clinically significant adverse events due to a previously administered agent (excluding Grade 2 neuropathy)
* Known psychiatric or substance abuse disorders that would interfere with the requirements of the trial within the opinion of the investigator
* Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early stage prostate cancer, or in situ cervical cancer after definitive treatment
* Positive hepatitis B (hepatitis B virus \[HBV\]) surface antigen (HBsAg)
o NOTE: Subjects with a prior history of HBV demonstrated by positive hepatitis B core antibody are eligible if they have at Screening 1) a negative HBsAg and 2) a HBV DNA (viral load) below the lower limit of quantification, per local testing. Patients who fit these criteria must use Hep B prophylaxis during treatment. Subjects with a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing
* Positive hepatitis C antibody (anti-HCV)
o NOTE: Subjects with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible
* Participant is positive for human immunodeficiency virus (HIV), with 1 or more of the following:
* Receiving ART that may interfere with study treatment (consult sponsor for review of medication prior to enrollment)
* CD4 count \< 350 cells/mm3 at screening
* AIDS-defining opportunistic infection within 6 months of start of screening
* Not agreeing to start ART and be on ART \> 4 weeks plus having HIV viral load \<400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled)
* Myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), or coronary/peripheral artery bypass graft, or any acute coronary syndrome within 6 months of start of study drug
* Congestive heart failure defined as New York Heart Association (NYHA) Class III-IV or hospitalization for congestive heart failure (any NYHA class) within 6 months of study Day 1
* Pregnant women or women who are breastfeeding or of childbearing potential and not using a highly effective method of birth control for at least one month prior to enrollment. If the risk of contraception exists, male and female subjects must use highly effective contraception throughout the study and for at least 60 days after last treatment. Highly effective contraception includes either 2 barrier methods (diaphragm, condom by the partner, copper intrauterine device, sponge, or spermicide), or 1 barrier method and 1 hormonal method (any oral, subcutaneous, intrauterine, or intramuscular registered and marketed contraceptive agent that contains an estrogen and/or a progesterone agent)
