A Single-arm Phase II Trial of Sacituzumab Tirumotecan (Sac-TMT) as Second-line Treatment for Advanced/Metastatic Vaginal and Vulvar Squamous Cell Carcinoma - ARCANA Trial (LACOG 1724)
A Single-arm Phase II Trial of Sacituzumab Tirumotecan (Sac-TMT) as Second-line Treatment for Advanced/Metastatic Vaginal and Vulvar Squamous Cell Carcinoma - ARCANA Trial (LACOG 1724)
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.
RATIONALE AND MOLECULAR TARGETING
Advanced and metastatic vulvar and vaginal squamous cell carcinomas share pathophysiological features with cervical cancer, including high rates of Human Papillomavirus (HPV) driver oncogenesis and robust expression of Trophoblast Cell Surface Antigen 2 (TROP-2). Sacituzumab tirumotecan (sac-TMT, MK-2870) is a novel TROP-2-directed antibody-drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked via a methyl sulfonyl moiety to a potent topoisomerase 1 inhibitor payload (KL610023). Upon binding to TROP-2 on tumor cells, sac-TMT internalizes and releases its payload, inducing cell cycle arrest and apoptosis while exerting bystander-killing and antibody-dependent cellular cytotoxicity.
DREAM STUDY DESIGN AND STATISTICAL CONSIDERATIONS
This Phase II study utilizes a Simon's two-stage Minimax design for each independent cohort (Cohort A: Vagina; Cohort B: Vulva) to control the familywise alpha level at 0.05 (one-sided) with 80% power:
Stage 1: 12 participants per cohort will be enrolled. An interim analysis for futility will be conducted; if 0 responses are observed in Stage 1, enrollment in that cohort will be halted.
Stage 2: If $\ge 1$ objective response is achieved in Stage 1, an additional 10 participants will be accrued (totaling 22 evaluable patients per cohort, expanded to 24 to account for a 10% dropout rate). A cohort is considered positive if $\ge 4$ responses are observed among evaluable participants.
TREATMENT ADMINISTRATION AND MANDATORY PROPHYLAXISSac-TMT is administered intravenously on Days 1 and 15 of 28-day cycles. Mandatory premedication administered 1.5 hours ($\pm30$ minutes) prior to each infusion includes an H1 receptor antagonist (diphenhydramine or equivalent), acetaminophen, dexamethasone (8-10 mg IV), and an H2 receptor antagonist to minimize infusion-related reactions. To prevent oral mucositis, participants receive mandatory daily prophylactic steroid-containing mouthwash (dexamethasone solution) 4 times daily. Prophylactic artificial tears are also strongly recommended to mitigate ocular surface toxicities.
EXPLORATORY BIOMARKER RESEARCH
The trial incorporates a longitudinal biorepository to identify predictive signatures and resistance mechanisms. Mandatory archival or freshly obtained FFPE tumor tissue blocks/slides collected at baseline will undergo TROP-2 immunohistochemistry (IHC), p16/HPV16 profiling, and high-throughput next-generation sequencing (NGS). Serial blood samples (plasma/PBMCs) collected at baseline and prespecified on-treatment timepoints (Weeks 6, 12, 24, and at disease progression) will evaluate circulating tumor DNA (ctDNA) dynamics and immune cell profiling to monitor treatment response and genomic resistance patterns over time.
Inclusion Criteria:
Has a histologically- or cytologically confirmed diagnosis of squamous cell carcinoma of vagina (cohort A) or vulvar (cohort B) origin
Advanced disease, defined as presence of metastatic disease or locally advanced disease not amenable to curative therapy in the opinion of the investigator
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.
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.
At least 18 years of age at the time of providing informed consent.
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:
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 8.4.5.
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.
8. 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. Sites should follow local guidelines regarding fresh tissue collection. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slide. Newly obtained biopsies are preferred to archived tissue (recommended 22-28 slides). 9. 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.
10. Adequate organ function as defined in the following table (Table 2). Specimens must be collected within 14 days before the start of study intervention.
11. Has ECOG performance status of 0 or 1. 12. Be willing and able to comply with study procedures, laboratory tests, and other requirements of the study.
13. HIV testing at screening is not required unless there is a known history of HIV infection. 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 enrollment and agreeing to continue ART throughout the study Note: The ART regimen must not contain any antiretroviral medications that are strong CYP3A4 inducers/inhibitors/substrates. Refer to 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/substrate of CYP3A4.
14. Hepatitis B testing at screening is not required unless there is a known history of HBV infection. 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 enrollment.
Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.
15. Hepatitis C testing at screening is not required unless there is a known history of HCV infection. Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening.
Note: Participants must have completed curative antiviral therapy at least 4 weeks before enrollment.
Exclusion Criteria:
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.
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 diseases within 6 months before the first dose of study intervention. Prior/Concomitant Therapy
Received prior treatment with a TROP2-targeted ADC.
Received prior treatment with a topoisomerase 1 inhibitor-containing ADC.
Received prior systemic anticancer therapy within 2 weeks before the first dose of study intervention.
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.
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.
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
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.
Has received an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention. Diagnostic Assessments
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.
History of CNS metastases and/or carcinomatous meningitis.
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.
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
Severe hypersensitivity (Grades ≥3) to study intervention, any of their excipients, and/or to another biologic therapy.
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.
Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
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.
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