Phase 2 Trial Of Sacituzumab Tirumotecan For Treatment Of Refractory Metastatic Or Unresectable Squamous Cell Carcinoma Of The Anus/Rectum

Eligibility Criteria 1. Participants must have histologically or cytologically confirmed squamous cell carcinoma of the anus or rectum that is metastatic or unresectable at the discretion of the treating investigator. 2. Participants must have measurable disease according to the standard RECIST version 1.1 as assessed by the local site investigator/radiology. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions. 3. Participants must have been treated with at least one, but no more than three, prior line(s) of systemic treatment, including prior cytotoxic chemotherapy and immunotherapy, for incurable advanced or metastatic SCC of the anal canal. Prior cytotoxic chemotherapy for metastatic disease is not required for participants who develop new metastatic lesions during or within 6 months of completion of chemoradiation for limited-stage disease. 4. Participants must be ≥18 years old. 5. ECOG performance status 0 or 1. 6. Ability to understand and the willingness to sign a written informed consent document. 7. For male participants, if capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. The length of time required to continue contraception for Sacituzumab tirumotecan is 120 days. o Refrains from donating sperm o Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive method (refer to Section 14.3.3), as a condom may break or leak. 8\. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed. 9\. Note: If the participant is azoospermic (vasectomized or secondary to medical cause, documented from the site personnel's review of the participant's medical records, medical examination, or medical history interview), no contraception is required. 10\. For female participants, a participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a POCBP, OR OR o Is a POCBP and: * Uses a contraceptive method that is highly effective (with a failure rate of 1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 4 during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. The participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for sacituzumab tirumotecan is 210 days. * The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed. * Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention are in Section 6.3.1. * Abstains from breastfeeding during the study intervention period and for at least 10 days after study intervention. * Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy. 11\. Has provided an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion from any site not previously irradiated. Tumors that have grown following previous radiotherapy are permitted. Sites should follow local guidelines regarding fresh tissue collection. Tissue is required for determination of TROP2 status by the supporting company's (Merck) central laboratory. 12\. Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline (except for alopecia and vitiligo). Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible. 13\. Adequate laboratory evaluation (within 10 days before the start of study intervention), defined as: * ANC ≥1,500/mcL * Hemoglobin ≥ 9.0 gm/dL * Platelet count ≥100,000/mcL * Total bilirubin ≤ 1.5x \~ institutional upper limit of normal (ULN) OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN * AST(SGOT)/ALT(SGPT) ≤ 2.5x\~ ULN (≤5 × ULN for participants with liver metastases) * Creatinine clearance (CrCl) ≥ 30 mL/min * INR or PT and aPTT ≤ 1.5x\~ ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Criteria must be met without colony-stimulating factors, erythropoietin dependency, and without pRBC transfusion within the preceding 2 weeks. * Criteria must be met without albumin supplementation within the last 72 hours. * CrCl is calculated by the Cockcroft-Gault CrCl formula = \[\[140 - age (years)\] × weight (kg)\] / \[72 × serum Cr (mg/dL) × 0.85 for female participants\]. As an alternative, CrCl can be determined from a 24-hour urine collection. 14\. Be willing and able to comply with study procedures, laboratory tests, and other requirements of the study. 15\. HIV-infected participants must have well-controlled HIV on ART, defined as: * Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening * Having achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 or the LLOQ using the locally available assay, at the time of screening and for at least 12 weeks before screening * Absence of any AIDS-defining opportunistic infections within the past 12 months * Being on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before start of treatment and agreeing to continue ART throughout the study. The ART regimen must not contain any antiretroviral medications that are strong CYP3A4 inducers/inhibitors/substrates. Refer to https://www.fda.gov/drugs/drug-interactionslabeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Please note that this list is not exhaustive and that investigators should review the locally approved label for all concomitant therapy to ensure it is not a strong inducer/inhibitor/substrate of CYP3A4. HIV testing at screening is not required unless: * There is a known history of HIV infection * Mandated by local guidelines 16. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load before start of treatment. Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention. Hepatitis B testing at screening is not required unless: o There is a known history of HBV infection o Mandated by local guidelines 17. Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. Participants must have completed curative antiviral therapy at least 4 weeks before start of treatment. Hepatitis C testing at screening is not required unless: o There is a known history of HCV infection o Mandated by local guideline Exclusion Criteria 1. Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing. 2. Has active inflammatory bowel disease requiring immunosuppressive medication or previous history or inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea). 3. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to \>480 ms, and/or other serious cardiovascular and cerebrovascular disease within 6 months before the first dose of study intervention. 4. Exposure to prior systemic anticancer therapy or radiotherapy within 2 weeks before the first dose of study intervention, has radiation-related toxicities, requiring corticosteroids, and/or has had radiation pneumonitis. 5. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention. 6. Receipt of any other investigational agent(s) or investigational device within 4 weeks before the first dose of study intervention. 7. Is currently enrolled on another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited. 8. Prior treatment with a topoisomerase 1 inhibitor-containing ADC. 9. Prior treatment with irinotecan or topotecan. 10. Prior treatment with a TROP2-targeted ADC. 11. Receipt of a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. 12. Treatment with strong inhibitors or inducers of cytochrome P450 3A4 enzyme (CYP3A4) within 2 weeks prior to the first dose and during the study treatment. 13. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 14. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) who have undergone potentially curative resection are not excluded. 15. Note: Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA \<10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded. 16. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable, and have not required steroid treatment for at least 14 days before the first dose of study intervention. 17. Has an active infection requiring systemic therapy other than those permitted in Section 4.1. 18. Severe hypersensitivity (Grades ≥3) to study intervention, any of their excipients, and/or to another biologic therapy. 19. Has had major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention. Anticipation of the need for major surgery during the course of treatment with study intervention is also exclusionary. 20. Note: Participants who underwent major surgery must have adequately recovered from toxicity and/or complications from the surgery before starting study intervention. 21. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 22. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to particip