This is a phase II, two-arm, noncomparative screening study of Sacituzumab tirumotecan, an intravenous antibody-drug conjugate (ADC) that targets Trop-1, administered alone or in combination with pembrolizumab, a monoclonal antibody to PD-1 in patients with relapsed clear cell cancers that originated in the ovary, fallopian tube or peritoneal cavity, inclusive of endometriosis (collectively referred to as OCCC throughout the protocol) after previous treatment with anti-PD1 therapy. The regimens will be evaluated separately, and the study is not designed or powered to compare the regimens.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Sacituzumab tirumotecan
pembrolizumab
Tufts Medical Center
Boston, Massachusetts, United States
RECRUITINGObjective response rate for sacituzumab tirumotecan alone and sacituzumab tirumotecan plus pembrolizumab, defined as the proportion of treated participants with a best overall response of complete response or partial response.
Responses will be confirmed by serial imaging (CT or MRI), conducted at least 4 weeks apart. Initial tumor scans at Screening must be performed within 28 days before randomization. The first on-study scan should be performed 6 weeks (42 days+7 days) from the date of randomization. Subsequent tumor scans should be performed every 12 weeks (84 days±7 days) or more frequently if clinically indicated for the first two years of treatment (Week 104). After Week 104 (±7 days), tumor scans should be performed every 16 weeks (112 days±7 days) until documentation of disease progression. Response will be evaluated by the investigator using RECIST 1.1 criteria, confirmed by repeat imaging performed at least 4 weeks after the initial documentation of response. Scans are to be performed until disease progression is identified by the investigator or until any of these conditions are met: * start of a new anticancer therapy * pregnancy * death * withdrawal of consent * the end of the study
Time frame: First scan collected within 28 days prior to randomization, then according to the schedule above until disease progression, new anticancer therapy, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first, up to ten years.
Clinical benefit rate (Response+Stable disease at 6 months)
Clinical benefit rate is determined by confirmed resopnse or stable disease maintained for at least 6 months. Responses will be confirmed by serial imaging (CT or MRI), conducted at least 4 weeks apart. Initial tumor scans at Screening must be performed within 28 days before randomization. The first on-study scan should be performed 6 weeks (42 days+7 days) from the date of randomization. Subsequent tumor scans should be performed every 12 weeks (84 days±7 days) or more frequently if clinically indicated for the first two years of treatment (Week 104). After Week 104 (±7 days), tumor scans should be performed every 16 weeks (112 days±7 days) until documentation of disease progression. Scans are to be performed until disease progression is identified by the investigator or until any of these conditions are met: • start of a new anticancer therapy • pregnancy • death • withdrawal of consent • the end of the study
Time frame: Baseline imaging assessment will be collected within 28 days before randomization. All scans obtained thereafter through the first six months after randomization.
Toxicity of Treatment (Adverse Events)
All AEs, SAEs, and other reportable safety events that occur after the participant provides documented informed consent, but before intervention randomization, must be reported by the investigator if the participant is receiving placebo run-in or other run-in treatment, if the event causes the participant to be excluded from the study, or is the result of a protocol-specified intervention, including, but not limited to washout or discontinuation of usual therapy, diet, or a procedure. * All AEs (including those meeting serious criteria) from the time of intervention randomization through 90 days after cessation of study intervention must be reported by the investigator. * Pregnancies (as described in protocol section 8.4.1) * Any SAE brought to the attention of an investigator at any time outside the time specified above must be reported immediately to the Sponsor/Principal Investigator if the event is considered related to study intervention.
Time frame: Safety information will be collected according to protocol guidelines from the time of patient signing of informed consent or treatment randomization (as applicable) through 90 days after cessation of study intervention or until resolution.
Progression-Free Survival (Time to progression of disease)
Disease progression event will be defined as progressive disease according to investigator RECIST 1.1 assessment or death. Responses will be confirmed by serial imaging (CT or MRI), conducted at least 4 weeks apart. Initial tumor scans at Screening must be performed within 28 days before randomization. The first on-study scan should be performed 6 weeks (42 days+7 days) from the date of randomization. Subsequent tumor scans should be performed every 12 weeks (84 days±7 days) or more frequently if clinically indicated for the first two years of treatment (Week 104). After Week 104 (±7 days), tumor scans should be performed every 16 weeks (112 days±7 days) until documentation of disease progression. Scans are to be performed until disease progression is identified by the investigator or until any of these conditions are met: * start of a new anticancer therapy * pregnancy * death * withdrawal of consent * the end of the study
Time frame: First scan collected within 28 days prior to randomization, then according to the schedule above until disease progression, new anticancer therapy, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first, up to ten years.
Overall Survival (Time to death from any cause)
Participant survival follow-up status will be assessed approximately every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. The first survival follow-up assessment should be scheduled as described below: * For participants who discontinue treatment intervention and who will not enter Efficacy Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last). * For participants who completed assessments in Efficacy Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up visit has been performed.
Time frame: Survival status will be assessed beginning after the discontinuation, safety follow-up or final efficacy follow-up visit, approximately every 12 weeks until death, withdrawal of consent, or the end of the study, whichever occurs first, up to 10 years.
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