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.