Phase 1b Study of SL-172154 Administered With Combination Agent(s) in Subjects With Ovarian Cancers

Study Overview
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Brief Summary
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SL03-OHD-105 is an open-label, multicenter, phase 1b trial designed to evaluate SL-172154 administered in combination with pegylated liposomal doxorubicin (PLD) or mirvetuximab soravtansine (MIRV) in patients with platinum resistant ovarian cancer. Approximately 102 patients will be enrolled in this study in two phases: dose escalation and dose expansion.

Detailed Description
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Study SL03-OHD-105 is an open-label, multicenter, phase 1b trial designed to evaluate the safety, pharmacokinetics, pharmacodynamic effects, and preliminary anti-tumor activity of SL-172154 administered in combination with either PLD or MIRV in subjects with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers. Patients will be appropriate for combination therapy for their next line of therapy. For the SL-172154 + MIRV cohort, patients' tumors must be positive (defined as PS2+ ≥ 25%) for folate receptor alpha (FRα) as defined by the Ventana FOLR1 (Folate Receptor 1/Folate Receptor Alpha) Assay. The first portion of the study will evaluate the safety of increasing dose levels of SL-172154 in combination with either PLD or MIRV and establish a combination dose for both regimens to be further evaluated in two dose expansion cohorts. The study will consist of a 21-day screening period, a study treatment period until at least one of the study treatment discontinuation criteria is met, and a study follow-up period.

Official Title
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An Open-Label, Phase 1b Study of SL-172154 (SIRPα-Fc-CD40L) Administered With Either Pegylated Liposomal Doxorubicin or Mirvetuximab Soravtansine in Subjects With Platinum-Resistant Ovarian Cancers

Conditions
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Platinum-Resistant Primary Peritoneal Carcinoma, Primary Peritoneal Carcinoma, Platinum-resistant Ovarian Cancer, Fallopian Tube Cancer, Epithelial Ovarian Cancer, Ovarian Cancer, Platinum-Resistant Fallopian Tube Carcinoma

Intervention / Treatment
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* Drug: Pegylated Liposomal Doxorubicin + SL-172154
* Drug: Mirvetuximab + SL-172154


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has voluntarily agreed to participate by giving written informed consent in accordance with ICH/GCP guidelines and applicable local regulations. Age ≥18 years [PLD Cohort] Subject has a histologically confirmed diagnosis of high grade epithelial ovarian cancer, including primary peritoneal cancer or fallopian tube cancer. Non-epithelial tumors and ovarian tumors with low malignant potential are excluded. [PLD Cohort] Subject must have platinum-resistant disease, defined as radiologic disease progression within 180 days (6 months) following the last administered dose of platinum therapy. Subjects who are primary platinum-refractory, defined by progressing during or within 1 month of upfront platinum therapy, are excluded. [PLD Cohort] Subjects may have received any number of prior lines of therapy for epithelial ovarian cancer; however, they may not have received more than 1 prior line of systemic anticancer therapy for platinum-resistant disease. [MIRV Cohort] Subject has a histologically confirmed diagnosis of high grade serous epithelial ovarian cancer, including primary peritoneal cancer or fallopian tube cancer. Non-epithelial tumors and ovarian tumors with low malignant potential are excluded. [MIRV Cohort] Subject must have platinum-resistant disease as defined by: Subjects who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (complete response/remission [CR] or partial response/remission [PR]) and then progressed between >3 months and ≤6 months after the date of the last dose of platinum. Subjects who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum. Subjects who are platinum refractory during front-line treatment are excluded [primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first-line platinum-containing chemotherapy] [MIRV Cohort] Subjects must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy. [MIRV Cohort] Willing to provide an archival tumor tissue block or slides or undergo procedure to obtain new biopsy using a low-risk, medically routine procedure for IHC confirmation of FRα positivity. [MIRV Cohort] Subject's tumor must be positive for FRα expression (defined as PS2+ ≥ 25% by the Ventana FOLR1 Assay). Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. Measurable disease by RECIST v1.1 using radiologic assessment. Adequate organ and hematologic function Subjects must have stabilized or recovered (Grade 1 or baseline) from all prior anti-cancer therapy-related toxicities. [MIRV Cohort, Dose Expansion only] Willing to consent to 1 mandatory pre-treatment and 1 on-treatment tumor biopsy, unless there is excessive risk from the procedure as determined by the investigator Exclusion Criteria: Prior treatment with a signal-regulatory protein alpha (SIRPα) targeting agent, anti-CD47 agent or CD40 agonist. [PLD Cohort] Prior treatment with doxorubicin or PLD [MIRV Cohort] Prior treatment with MIRV or another FRα-targeting agent Any anti-cancer therapy within the time intervals specified per protocol. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment is prohibited. Receipt of live attenuated vaccine (including live attenuated vaccines for COVID-19) within 28 days of the first dose of study treatment. Current or prior use of systemic immunosuppressive medication within 7 days prior to first dose of study treatment. [MIRV Cohort] Requires use of folate-containing supplements (e.g., folate deficiency) Active or documented history of autoimmune disease that has required treatment with a disease modifying agent or immunosuppressive therapy in the past two years, history of multiple sclerosis (MS) or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome). Exceptions include controlled Type I diabetes, vitiligo, alopecia areata or hypo/hyperthyroidism. Ongoing or active infection (e.g., no systemic antimicrobial therapy for treatment of infection within 5 days of D1 of study treatment). Known severe hypersensitivity to the active drug substance or to any of the excipients for the agents to be administered or known hypersensitivity to Chinese hamster ovary cell products. Severe gastrointestinal conditions. Clinically significant or uncontrolled cardiovascular disease [MIRV Cohort] History of cirrhotic liver disease (Child-Pugh Class B or C) [MIRV Cohort] Active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and/or monocular vision. Previous clinical diagnosis of noninfectious interstitial lung disease (ILD), including noninfectious pneumonia. Untreated central nervous system or leptomeningeal metastases. 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 the study treatment. Has undergone allogeneic stem cell transplantation or organ transplantation. Known history or positive test for human immunodeficiency virus (HIV), or positive test for hepatitis B (positive for hepatitis B surface antigen [HBsAg]) or hepatitis C virus ([HCV]

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pegylated Liposomal Doxorubicin + SL-172154 (SIRPα-Fc-CD40L)<br>Pegylated Liposomal Doxorubicin (PLD) will be administered via intravenous administration + SL-172154 (SIRPα-Fc-CD40L) will be administered via intravenous administration. | Drug: Pegylated Liposomal Doxorubicin + SL-172154<br>* The investigational product, SL-172154, is a novel fusion protein consisting of human SIRPα and CD40L (SIRPα -Fc-CD40L) linked via a human Fc.<br>* Other names: Caelyx;|
| Experimental: Mirvetuximab + SL-172154 (SIRPα-Fc-CD40L)<br>Mirvetuximab (MIRV) will be administered via intravenous administration + SL-172154 (SIRPα-Fc-CD40L) will be administered via intravenous administration | Drug: Mirvetuximab + SL-172154<br>* The investigational product, SL-172154, is a novel fusion protein consisting of human SIRPα and CD40L (SIRPα -Fc-CD40L) linked via a human Fc.<br>* Other names: MIRV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate safety and tolerability of SL-172154 when administered with PLD | Incidence and severity of adverse events (AE) per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 | first dose up to 3 years | 
| Evaluate safety and tolerability of SL-172154 when administered with MIRV | Incidence and severity of adverse events (AE) per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 | first dose up to 3 years | 
| Establish the recommended Phase 2 dose (RP2D) for SL-172154 when administered with PLD | Establish the recommended Phase 2 dose (RP2D) for SL-172154 when administered with PLD for the dose expansion phase | first dose up to 1 year | 
| Establish the recommended Phase 2 dose (RP2D) for SL-172154 when administered with MIRV | Establish the recommended Phase 2 dose (RP2D) for SL-172154 when administered with MIRV for the dose expansion phase | first dose up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess preliminary evidence of anti-tumor activity of SL-172154 when administered with PLD | Overall response rate per investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) | first dose up to 3 years | 
| To assess preliminary evidence of anti-tumor activity of SL-172154 when administered with MIRV | Overall response rate per investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) | first dose up to 3 years | 
| Immunogenicity to SL-172154 | Number and proportion of participants with positive anti-drug antibody titer | first dose up to 3 years | 
| Immunogenicity to MIRV | Number and proportion of participants with positive anti-drug antibody titer | first dose up to 3 years | 
| Maximum serum concentration (Cmax) of SL-172154 | The Cmax is the maximum observed serum concentration of SL-172154 following single and multiple doses | first dose up to 3 years | 
| Maximum serum concentration (Cmax) of MIRV | The Cmax is the maximum observed serum concentration of MIRV following single and multiple doses | first dose up to 3 years | 
| Maximum serum concentration (Cmax) of Total Antibody | The Cmax is the maximum observed serum concentration of Total Antibody following single and multiple doses | first dose up to 3 years | 
| Maximum serum concentration (Cmax) of DM4 Payload | The Cmax is the maximum observed serum concentration of DM4 Payload following single and multiple doses | first dose up to 3 years | 
| Maximum serum concentration (Cmax) of S-Methyl DM4 Payload | The Cmax is the maximum observed serum concentration of S-Methyl DM4 Payload following single and multiple doses | first dose up to 3 years | 
| Area under the serum concentration-time curve (AUC) of SL-172154 | The AUC is the area under the serum concentration time curve of SL-172154 following single and multiple doses | first dose up to 3 years | 
| Area under the serum concentration-time curve (AUC) of MIRV | The AUC is the area under the serum concentration time curve of MIRV following single and multiple doses | first dose up to 3 years | 
| Area under the serum concentration-time curve (AUC) of Total Antibody | The AUC is the area under the serum concentration time curve of Total Antibody following single and multiple doses | first dose up to 3 years | 
| Area under the serum concentration-time curve (AUC) of DM4 Payload | The AUC is the area under the serum concentration time curve of DM4 Payload following single and multiple doses | first dose up to 3 years | 
| Area under the serum concentration-time curve (AUC) of S-Methyl DM4 Payload | The AUC is the area under the serum concentration time curve of S-Methyl DM4 Payload following single and multiple doses | first dose up to 3 years | 
| Terminal elimination half-life (t1/2) of SL-172154 | Terminal elimination half-life (t1/2) of SL-172154 | first dose up to 3 years | 
| Terminal elimination half-life (t1/2) of MIRV | Terminal elimination half-life (t1/2) of MIRV | first dose up to 3 years | 
| Terminal elimination half-life (t1/2) of Total Antibody | Terminal elimination half-life (t1/2) of Total Antibody | first dose up to 3 years | 
| Terminal elimination half-life (t1/2) of DM4 Payload | Terminal elimination half-life (t1/2) of DM4 Payload | first dose up to 3 years | 
| Terminal elimination half-life (t1/2) of S-Methyl DM4 Payload | Terminal elimination half-life (t1/2) of S-Methyl DM4 Payload | first dose up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Platinum-resistant, Ovarian, Peritoneal, High grade serous EOC, primary peritoneal cancer, Fallopian, Combination, Mirvetuximab Soravtansine, SL-172154, SIRPα-Fc-CD40L, Pegylated Liposomal Doxorubicin