Pilot Trial of SP-2577 Plus Pembrolizumab in Select Gynecologic Cancers

Study Overview
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Brief Summary
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Open-label study of SF-2577 plus pembrolizumab in advanced, recurrent small cell ovarian cancer as well as select additional ovarian and endometrial cancers within the SWI/SNF pathway.

Detailed Description
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This study is an open-label, non-randomized dose escalation and expansion study of the LSD inhibitor SP-2577 in combination with the anti PD- 1 antibody pembrolizumab in patients with advanced, recurrent small cell ovarian cancer of the hypercalcemic type (SCCOHT) as well as select additional ovarian and endometrial cancers with mutations in the genes within the SWI/SNF pathway (Ovarian Clear Cell Cancers (OCCC), Endometrioid Ovarian Cancers (EOC) and Endometrioid Endometrial Cancers (EEC).

Official Title
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Pilot Feasibility and Efficacy Trial of a Novel Reversible LSD1 Inhibitor SP-2577 (Seclidemstat) Plus Pembrolizumab in Select SWI/SNF-mutant Gynecologic Cancers

Conditions
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SCCOHT, Ovarian Clear Cell Tumor, Ovarian Endometrioid Adenocarcinoma, Endometrial Cancer

Intervention / Treatment
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* Drug: SP-2577
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of small cell carcinoma of the ovary of hypercalcemic type (SCCOHT), ovarian clear cell carcinoma (OCCC), endometrioid ovarian carcinoma (EOC) or endometrioid endometrial carcinoma (EEC) with confirmed mutations in one of the SWI/SNF genes (SMARCA4, ARID1A) will be enrolled in this study. Patients must have received at least one prior regimen in the recurrent or advanced setting and must not be a candidate for other potentially curative treatment options. Not pregnant, breastfeeding and agrees to use contraceptive methods if child-bearing Provides written informed consent Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Have provided archival tumor tissue sample or a newly obtained core or excisional biopsy of a tumor lesion not irradiated. ECOG of 0 to 1 Adequate organ function Exclusion Criteria: A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed as long as patient did not have a serious (≥ Grade 3) immune related AE requiring treatment discontinuation or treatment with systemic steroids. Has received prior therapy with LSD1 targeted agents including monoamine oxidases for cancer therapy. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or 5 half-lives whichever is shorter prior to the first dose of study treatment. Has received prior radiotherapy within 2 weeks of start of study treatment. Has received a live vaccine within 30 days prior to the first dose of study drug. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Has a diagnosis of immunodeficiency or 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 a known additional malignancy that is progressing or has required active treatment within the past 3 years. Has known active CNS metastases and/or carcinomatous meningitis. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Has an active infection requiring systemic therapy. Has a known history of HIV, Hepatitis B, or known active Hepatitis C Has a known history of active TB Has clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality Is currently receiving any of the following substances and cannot be discontinued 14 days, or 5 half-lives for CYP inhibitors (whichever is shorter) prior to Cycle 1 Day 1 Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SP-2577 Plus Pembrolizumab<br> | Drug: SP-2577<br>* Daily oral doses<br>Drug: Pembrolizumab<br>* 200mg Q3W by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incident of AEs | Incidence of Adverse Events (AEs) as measured by NCI CTCAE version 5.0 | First dose to 90 days after last dose | 
| Incident of DLTs | Incidence of dose-limiting toxicities (DLTs) during the dose escalation phase | First dose to 90 days after last dose | 
| Overall Response Rate | Percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), as determined by Investigator according to Response Evaluation in Solid Tumors (RECIST) v 1.1 | Study enrollment until participant discontinuation, occurrence of PD or death (approximately 6 months to 3 years) | 
| Disease Control Rate | Percentage of participants with Disease Control (complete response, partial response, or stable disease) as determined by RECIST v1.1 | Study enrollment until PD or loss of clinical benefit (approximately 6 months to 3 years) | 
| Duration of Response | Duration of Response as determined by the Investigator according to RECIST v1.1 | Date of first occurrence of objective response to first documentation of PD (approximately 6 months to 3 years) | 
| Duration of Stable Disease | Duration of Stable Disease as determined by the investigator according to RECIST v 1.1 | Date of first occurrence of stable disease to first documentation of PD (approximately 6 months to 3 years) | 
| Progression Free Survival | Progression Free Survival (PFS) as determined by the Investigator according to RECIST v1.1 | Start of treatment to first occurrence of PD or death (approximately 6 months to 3 years) | 
| Overall Survival | Overall Survival (OS) as determined by the Investigator according to RECIST v1.1 | Start of treatment to death (approximately 2 to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration of SP-2577 | Plasma concentration of seclidemstat (SP-2577) | 2 months | 
| ctDNA in blood and other body fluids | Proportion of circulating tumor DNA ( ctDNA) in peripheral blood and other body fluids e.g. ascitic fluid | 6 months to 2 years | 
| Target Inhibition in Tumor Biopsies | Percentage of target inhibition by seclidemstat and pembrolizumab in tumor tissue biopsy specimens | 6 months to 2 years |