Sac-TMT in Vaginal and Vulvar Cancers

The ARCANA trial (LACOG 1724) is a single-arm, non-randomized, multi-center, parallel, two-cohort Phase II clinical study designed to evaluate the efficacy and safety of sacituzumab tirumotecan (sac-TMT, MK-2870) as a second-line or subsequent treatment in patients with advanced or metastatic vaginal and vulvar squamous cell carcinomas. Given the rarity of these cancers and the lack of standard second-line therapies, this study explores sac-TMT, a novel TROP-2-directed antibody-drug conjugate (ADC). TROP-2 is highly expressed in both vulvar and vaginal squamous cell carcinomas, making it a promising therapeutic target.

Inclusion Criteria: 1. Has a histologically- or cytologically confirmed diagnosis of squamous cell carcinoma of vagina (cohort A) or vulvar (cohort B) origin 2. Advanced disease, defined as presence of metastatic disease or locally advanced disease not amenable to curative therapy in the opinion of the investigator 3. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously-irradiated area are considered measurable if progression has been shown in such lesions. 4. Has received up to 2 prior lines of systemic therapy. Disease progression to first-line or second-line platinum-based chemotherapy for locally advanced/metastatic disease. Previous anti-PD-1/anti-PD-L1 therapy is allowed. Disease progression within 6 months of (neo) adjuvant chemotherapy completion is considered first-line of therapy. The participant may have received prior radiation with or without radio-sensitizing chemotherapy at least \>2 weeks before the start of study treatment. 5. At least 18 years of age at the time of providing informed consent. 6. 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 * Is a POCBP and: - Uses a contraceptive method that is highly effective (with a failure rate of \480 ms, and/or other serious cardiovascular and cerebrovascular diseases within 6 months before the first dose of study intervention. Prior/Concomitant Therapy 3. Received prior treatment with a TROP2-targeted ADC. 4. Received prior treatment with a topoisomerase 1 inhibitor-containing ADC. 5. Received prior systemic anticancer therapy within 2 weeks before the first dose of study intervention. 6. Received prior radiotherapy within 2 weeks before the first dose of study intervention, has radiation-related toxicities, requiring corticosteroids, and/or has had radiation pneumonitis. 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. 7. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. Refer to Section 6.2 for information on COVID-19 vaccines. 8. Is currently receiving a strong inducer/inhibitor of CYP3A4 that cannot be discontinued for the duration of treatment with study intervention. The required washout period before starting study intervention is 2 weeks. Note: A list of strong inducers/inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/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 of CYP3A4. Prior/Concurrent Clinical Study Experience 9. 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. 10. Has received an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention. Diagnostic Assessments 11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 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. 12. History of CNS metastases and/or carcinomatous meningitis. 13. Has an active infection requiring systemic therapy within 4 weeks prior to the first dose of study treatment except those permitted as outlined in Section 5.1. 14. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual's ability to cooperate with the requirements of the study, or interfere with the individual's participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the treating investigator. Other Exclusions 15. Severe hypersensitivity (Grades ≥3) to study intervention, any of their excipients, and/or to another biologic therapy. 16. 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. Note: Participants who underwent major surgery must have adequately recovered from toxicity and/or complications from the surgery before starting study intervention. 17. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 18. 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 participate, in the opinion of the treating investigator.