Phase 1 Study of SL-172154 (SIRPα-Fc-CD40L) in Subjects With Ovarian Cancer

Study Overview
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Brief Summary
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This is a Phase 1 first in human, open label, multi-center, dose escalation study to evaluate the safety, tolerability, PK, anti-tumor activity and pharmacodynamic effects of SL-172154 in subjects with ovarian cancer.

Detailed Description
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This Phase 1 trial will evaluate the safety, tolerability, pharmacokinetics, anti-tumor and pharmacodynamic effects of SL-172154 and identify the dose and schedule i.e., recommended Phase 2 dose for future development (RP2D). Subjects eligible for enrollment are required to have platinum-ineligible ovarian, fallopian tube, and primary peritoneal cancers. The study design consists of dose escalation cohorts, an optional pharmacodynamic cohort, and an optional dose expansion cohort. In the dose escalation phase of the study, subjects will be enrolled into sequential dose levels. The study may also enroll a pharmacodynamic cohort to obtain additional pharmacodynamic data at one or more dose levels that have completed evaluation for safety without exceeding the maximum tolerated dose (MTD). Subjects enrolled in the pharmacodynamic cohort will not inform dose escalation decisions. A dose expansion cohort may be opened to further characterize safety, tolerability, PK, anti-tumor activity, and pharmacodynamic data to inform the selection of a RP2D.

Official Title
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Phase 1 Dose Escalation Study of the Agonist Redirected Checkpoint, SL-172154 (SIRPα-Fc-CD40L) Administered Intravenously in Subjects With Ovarian Cancer

Conditions
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Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Carcinoma

Intervention / Treatment
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* Drug: SL-172154


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if all the following criteria apply: Subject has voluntarily agreed to participate by giving written informed consent in accordance with ICH/GCP guidelines and applicable local regulations. Subject must have a histologically confirmed diagnosis of an unresectable, locally advanced or metastatic ovarian cancer, or primary peritoneal cancer or fallopian tube cancer. Subjects must be refractory or intolerant to existing therapy(ies) known to provide clinical benefit for their condition. Subject must have received platinum-based therapies, and should not be eligible for further platinum therapy, or should be intolerant to such therapy. Subjects with HRD positive disease may participate if they have received prior polyadenosine diphosphate ribose polymerase (PARP) inhibitor therapy given alone or with bevacizumab. Subjects should not be primary platinum refractory as defined by progressing during or within 1 month of upfront platinum therapy. Has measurable disease by RECIST v1.1 using radiologic assessment. Subject age is 18 years and older. Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Has life expectancy of greater than 12 weeks. Has adequate organ function. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 72 hours of D1 of IP. Recovery from prior anti-cancer treatments including surgery, radiotherapy, chemotherapy or any other anti-cancer therapy to baseline or ≤ Grade 1. Willing to consent to mandatory pre-treatment and on-treatment tumor biopsy(ies), unless there is excessive risk as determined by the investigator. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Prior treatment with an anti-CD47 or anti-SIRPα targeting agent or a CD40 agonist. Any anti-cancer therapy within the washout period prior to first dose (D1) of SL-172154. Concurrent chemotherapy, immunotherapy, biologic or hormonal/hormonal suppression therapy for cancer treatment is prohibited. Concurrent use of hormones for non-cancer related conditions is acceptable. Use of corticosteroids or other immunosuppressive medication, current or within 14 days of D1 of SL-172154 treatment. Receipt of live attenuated vaccine within 28 days of D1 of IP. Active or documented history of autoimmune disease. Exceptions include controlled Type I diabetes, vitiligo, alopecia areata or hypo/hyperthyroidism. Hypersensitivity to the active drug substance or to any of the excipients for the agent to be administered or subjects with known hypersensitivity to Chinese hamster ovary cell products. Active pneumonitis (i.e. drug-induced, idiopathic pulmonary fibrosis, radiation-induced, etc.). Ongoing or active infection (e.g., no systemic antimicrobial therapy for treatment of infection within 5 days of D1 of IP). Symptomatic peptic ulcer disease or gastritis, active diverticulitis, other serious gastrointestinal disease associated with diarrhea within 6 months of D1 of IP. Clinically significant or uncontrolled cardiac/thromboembolic disease. Untreated central nervous system or leptomeningeal metastases. Women who are breast feeding. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or compromised ability to provide written informed consent. Another malignancy that requires active therapy and that in the opinion of the investigator and Sponsor would interfere with monitoring of radiologic assessments of response to IP. Has undergone allogeneic stem cell transplantation or organ transplantation. Known history or positive test for human immunodeficiency virus, or positive test for hepatitis B.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SL-172154<br>Intravenous administration | Drug: SL-172154<br>* The investigational product (IP), SL-172154, is a novel fusion protein consisting of human SIRPα and CD40L (SIRPα -Fc-CD40L) linked via a human Fc.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile of SL-172154 | Incidence of all treatment emergent adverse events | From Day 1 to 90 days after Last Dose of SL-172154 | 
| Maximum Tolerated Dose (MTD) of SL-172154 | Defined based on the rate of dose limiting toxicities (DLTs) | From Day 1 to 90 days after Last Dose of SL-172154 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish the recommended Phase 2 dose (RP2D) for SL-172154 | Establish the RP2D for SL-172154 | Approximately 24 months | 
| Assess preliminary evidence of anti-tumor activity of SL-172154 | Disease assessment per investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) | Approximately 24 months | 
| Immunogenicity to SL-172154 | Number and proportion of participants with positive anti-drug antibody titer | Approximately 24 months | 
| Maximum serum concentration (Cmax) of SL-172154 | The Cmax is the maximum observed serum concentration of SL-172154 following single and multiple doses | Approximately 24 months | 
| Minimum serum concentration (Cmin) of SL-172154 | The Cmin is the minimum observed serum concentration of SL-172154 following single and multiple doses | Approximately 24 months | 
| Time at which maximum concentration of SL-172154 is observed (Tmax) | The Tmax is the time at which the maximum concentration of SL-172154 is observed following single and multiple doses | Approximately 24 months | 
| Area under the serum concentration-time curve (AUC) | The AUC is the area under the serum concentration time curve following single and multiple doses of SL-172154 | Approximately 24 months | 
| Terminal elimination half-life (t1/2) | Terminal elimination half-life (t1/2) of SL-172154 | Approximately 24 months | 
| Clearance (CL) | Clearance of Sl-172154 | Approximately 24 months | 
| Volume of distribution | Volume of distribution of SL-172154 | Approximately 24 months |