Sacituzumab Tirumotecan +/- Pembrolizumab in I/O Exposed Metastatic or Recurrent Ovarian Clear Cell Cancer

The treatment plan consists of Sacituzumab tirumotecan administered at 4 mg/kg on days 1, 15, and 29 as a single agent (Arm 1) or in combination with pembrolizumab 400mg on day 1 (Arm 2). Each cycle will be 42 days. Treatment is administered for a maximum duration of two years on both arms. The interventions are summarized in Table 1.

To avoid the possibility of inappropriate or excessive accrual, an exact Simon minimax two-stage design will guide each arm. Confirmed responses will be determined by investigator-assessed RECIST 1.1 imaging, with the first tumor assessment at Week 6, followed by assessments every 12 weeks and compared to baseline imaging. Based on the results of BrUOG 354 and given the lack of treatment options following immunotherapy for OCCC, an ORR of 15% or lower will be considered insufficiently active, whereas an ORR of 35% or higher will be considered sufficiently promising to warrant further investigation. Fourteen participants will be enrolled in each arm for the first stage; the anticipated duration of accrual is approximately eighteen months. Given this trial evaluates a rare tumor population where we are evaluating a new regimen, our intent is to minimize the trial duration as feasibly as possible. Consistent with the rare-disease trade-off proposed by Khan, Sarker, and Hackshaw, the design was selected using a maximum one-sided type I error of approximately 0.057 and minimum power of 77%.

Stage 1 While both arms are open and each arm has fewer than 14 treated participants, each eligible participant will receive the next concealed allocation from the 1:1 randomization sequence. A participant who receives any amount of assigned study treatment will count toward the applicable arm's Stage 1 treated-participant target. A participant who is assigned but receives no study treatment will not count toward the target and will be excluded from the treated efficacy population. The participant must nevertheless remain in the study disposition and CONSORT flow diagram.

Across both treatment arms and both stages combined, no more than 8 assigned participants who receive no study treatment may be excluded from the treated efficacy population.

If one arm reaches 14 treated participants before the other, that arm will be closed temporarily and the randomization sequence will be suspended. Subsequent eligible participants will then be assigned nonrandomly to the deficient arm until it reaches 14 treated participants. If a participant assigned during this top-up period receives no treatment, another participant will again be assigned nonrandomly to that arm.

Once both arms contain 14 treated participants, enrollment will pause until the Stage 1 responses have been ascertained and the interim decision has been made separately for each arm. An arm will stop for futility if there are no more than 2 responses among its 14 treated participants and will continue to Stage 2 if there are at least 3 responses.

Stage 2 if both arms continue: The concealed 1:1 randomization sequence will resume at the next unused allocation. Randomization will continue while both arms remain open and each contains fewer than 24 treated participants. If one arm reaches 24 treated participants before the other, that arm will close, the randomization sequence will again be suspended, and subsequent participants will be assigned nonrandomly to the deficient arm until it also contains 24 treated participants.

The final Simon decision will be based on the 24 treated participants in each arm. An arm will be considered promising if there are at least 7 responses and insufficiently active if there are no more than 6 responses.

Stage 2 if only one arm continues: The randomization sequence will not be resumed. All participants entering Stage 2 will be assigned nonrandomly to the continuing arm until 10 additional treated participants have been enrolled in that arm.

Inclusion criteria

An individual is eligible for inclusion in the study if the individual meets all of the following criteria:

Type of Participant and Disease Characteristics

• Age ≥18 years (at the time of informed consent).
• Has a histologically-confirmed diagnosis of pure OCCC. Patients with mixed histologies that include a clear cell component will not be eligible for this trial.
• 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.
• Patients must have received at least one prior platinum and taxane-based chemotherapy regimen; maintenance treatment will not be counted as a separate regimen. Radiation therapy (including the use of chemotherapy as a radiosensitizer) will not count as a prior systemic regimen. There is otherwise no line limit for entry in to this trial.
• Patients must have also received one prior line containing an immune checkpoint inhibitor (ICI). More than one prior line of ICI treatment will be exclusionary.
• Participants with known brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• ECOG performance status 0-1
• Is an individual of assigned female sex at birth
• Participant is not pregnant or breastfeeding, and at least one of the following conditions applies:

• Is not a Person of Child-Bearing Potential (POCBP) OR

• Is a POCBP and:

• Agrees to use of 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) beginning at the time of informed consent, during the study treatment, and for at least 210 days after the last dose of study drug. During this period, the participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction.

• The investigator should evaluate the potential for contraceptive method failure (i.e., 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 (e.g., 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 8.3.5.

• 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 have been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.

Informed Consent

• The participant provides written informed consent for the study. Additional Categories
• Has provided an archival tumor tissue sample (slides or block) for pathologic confirmation of diagnosis at Tufts Medical Center.
• 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.
• Adequate organ function as defined in protocol Table 3. Specimens must be collected within 10 days before the start of study intervention.
• Any other medical condition that will prevent the safe administration of study drugs in the opinion of the treating physician.
• Be willing and able to comply with study procedures, laboratory tests, and other requirements of the study.
• HIV-infected participants must have well-controlled HIV on ART, defined as:

a. Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening b. 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.

c. Absence of any AIDS-defining opportunistic infections within the past 12 months d. Being on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before randomization 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.

HIV testing at screening is not otherwise required.

• 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 randomization.

Note: 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:

• There is a known history of HBV infection
• Mandated by local guidelines
• 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 randomization.

Hepatitis C testing at screening is not required unless:

• There is a known history of HCV infection
• Mandated by local guidelines

Exclusion criteria

An individual must be excluded from the study if the individual meets any of the following criteria:

Medical Conditions 18. 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.

• Is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

• Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid) 22. History of stem cell/solid organ transplant. Prior/Concomitant Therapy 23. Received prior treatment with a TROP2-targeted ADC. 24. Received prior treatment with a topoisomerase 1 inhibitor-containing ADC. 25. 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 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.

• 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.

Prior/Concurrent Clinical Study Experience 29. 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 31. 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 of any organ (excluding carcinoma in situ of the bladder) who have undergone potentially curative resection are not excluded.

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.

• Has CNS metastases and/or carcinomatous meningitis. 33. Has an active infection requiring systemic therapy. 34. 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 35. Severe hypersensitivity (Grades ≥3) to study interventions, 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.