SL-279252 (PD1-Fc-OX40L) in Subjects With Advanced Solid Tumors or Lymphomas

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 and dose expansion study to evaluate the safety, tolerability, PK, anti-tumor activity and pharmacodynamic effects of SL-279252 in subjects with advanced solid tumors or lymphomas.

Detailed Description
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This is a Phase 1 first in human, open label, multi-center, dose escalation and dose expansion study to evaluate the safety, tolerability, PK, anti-tumor activity and pharmacodynamic effects of SL-279252 in subjects with advanced solid tumors or lymphomas. The study design consists of Dose Escalation and Dose Expansion Cohorts. In the dose escalation phase of the study, subjects will be enrolled into sequential dose levels. During dose escalation, two possible schedules for administration of SL-279252 may be explored. The MTD or MAD may be determined for either schedule. Based on accumulating data from the dose escalation phase, including safety, PK, pharmacodynamic and anti-tumor activity, up to two dose expansion cohorts may be opened. The primary objective of the expansion phase is to further refine the safety and tolerability of SL-279252. The expansion cohorts will evaluate one or two doses of SL-279252 using one selected schedule. At the end of dose escalation and dose expansion, safety, PK, anti-tumor activity, and pharmacodynamic data will be reviewed to identify the RP2D.

Official Title
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Phase 1 Dose Escalation and Dose Expansion Study of an Agonist Redirected Checkpoint Fusion Protein, SL-279252 (PD1-Fc-OX40L), in Subjects With Advanced Solid Tumors or Lymphomas

Conditions
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Squamous Cell Carcinoma of the Head and Neck, Melanoma, Non Small Cell Lung Cancer, Urothelial Carcinoma, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Squamous Cell Carcinoma of the Anus, Squamous Cell Carcinoma of the Cervix, Squamous Cell Carcinoma of the Skin, Renal Cell Carcinoma, Hodgkin Lymphoma, Diffuse Large B Cell Lymphoma, Mismatch Repair Deficient or MSI-High Solid Tumors

Intervention / Treatment
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* Drug: SL-279252


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 has a histologically confirmed diagnosis of one of the following unresectable locally advanced or metastatic malignancies: melanoma, non-small cell lung cancer (squamous, adeno, or adeno-squamous), urothelial cancer, squamous cell carcinoma of the head and neck, squamous cell cervical cancer, gastric or gastro-esophageal junction adenocarcinoma, squamous cell carcinoma of the anal canal, squamous cell carcinoma of the skin, renal cell cancer, Hodgkin's lymphoma, and microsatellite instability high (MSI-H) or mismatch repair deficient (MMRD) solid tumors excluding CNS malignancies. MSI and MMRD testing results as per institution is acceptable. Head and neck cancers: Subjects must have primary tumor locations in the oropharynx, oral cavity, hypopharynx, or larynx. Primary tumor sites of nasopharynx, maxillary sinus, paranasal, and unknown primary are excluded. Non-small cell lung cancers: Subjects with a known EGFR sensitizing (activating) mutation or an ALK fusion are excluded. Subject must have received, been intolerant to, or is ineligible for standard therapy (per local guidelines and approvals) or have a malignancy for which there is no approved therapy considered standard of care. Age 18 years and older. Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. Has measurable disease by iRECIST (solid tumors) or RECIL 2017 (lymphoma). Refer to Appendix Sections 16.6 and 16.7 for details on criteria of measurable disease. Has life expectancy of greater than 12 weeks. Laboratory values must meet the following criteria. Laboratory parameter Threshold value Absolute lymphocyte count (ALC) ≥ 0.8 x 109/liter (L) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support Platelet count ≥ 50 x 109/L Laboratory parameter Threshold value Hemoglobin (Hgb) > 9.0 g/dL with no blood transfusions for at least 5 days prior to D1 of investigational product (IP; SL-279252) Creatinine clearance (CrCl) ≥ 30 milliliter (mL)/min (modified Cockcroft-Gault) ALT/AST ≤ 3 x ULN Total bilirubin ≤ 1.5 x ULN; subjects with isolated indirect hyperbilirubinemia are permitted if direct bilirubin ratio is <35% and total bilirubin is ≤ 3.0 x ULN Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) ≥ lower limit of normal (LLN) per institutional threshold. If LLN is not defined for a given institution, then ejection fraction must be ≥50 %. Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test within 72 hours of D1 of IP. NOTE: FCBP unless they are surgically sterile (i.e., have undergone a complete hysterectomy, bilateral tubal ligation/occlusion, bilateral oophorectomy or bilateral salpingectomy), have a congenital or acquired condition that prevents childbearing or are naturally postmenopausal for at least 12 consecutive months (see Appendix Section 16.2 for additional details). Documentation of postmenopausal status must be provided. FCBP should use an acceptable method of contraception (see Appendix Section 16.2) to avoid pregnancy during treatment and for 30 days (which exceeds 5 half-lives) after the last dose of IP. FCBP must start using acceptable contraception at least 14 days prior to D1 of IP. Male subjects with female partners must have azoospermia from a prior vasectomy or underlying medical condition or agree to use an acceptable method of contraception during treatment and for 30 days (which exceeds 5 half-lives) after last dose of SL-279252 (see Appendix Section 16.2). Male subjects of reproductive potential must start using acceptable contraception at least 14 days prior to D1 of treatment with SL-279252 as per Appendix Section 16.2. All AEs resulting from prior anti-cancer immunotherapy have resolved (NOTE: exceptions include alopecia, vitiligo, and endocrinopathies adequately treated with hormone replacement). • Subjects that were discontinued from prior PD-1/L1 therapy due to immune-related adverse events are not eligible Recovery from toxicities from prior anti-cancer treatments including surgery, radiotherapy, chemotherapy or any other anti-cancer therapy to baseline or ≤ Grade 1. (NOTE: Low-grade toxicities (e.g., alopecia, ≤ Grade 2 lymphopenia, ≤ Grade 2 hypomagnesemia, ≤ Grade 2 neuropathy) may be allowed at the discretion of the investigator if considered clinically insignificant. Please consult the Sponsor Medical Monitor to discuss these cases). Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Has received more than two prior checkpoint inhibitor containing treatment regimens (regimen refers to either monotherapy or combination immunotherapies) or has had prior treatment with an OX40 agonist. • Prior PD-1/L1 therapy is not required. Refractory to last PD-1/L1 inhibitor-based therapy which is defined as disease progression within 3 months of treatment initiation. • Subjects must have had clinical benefit (stable disease or response) to last PD-1/L1 inhibitor-based therapy for at least three months to be eligible. Any anti-cancer therapy within the time intervals noted below prior to first dose (D1) of SL-279252. Therapy Washout period Chemotherapy 3 weeks Hormonal therapy 3 weeks PD-1/L1 inhibitor and other immunotherapies not otherwise specified 3 weeks Tumor vaccine 4 weeks Cell-based therapy 8 weeks Other mAbs or biologic therapies 3 weeks Major surgery 2 weeks Radiation (except palliative intent which does not require washout) 2 weeks Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy 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 IP with the following exceptions (i.e., the following are allowed during treatment with or within14 days of D1 of IP): Topical, intranasal, inhaled, ocular, intraarticular corticosteroids Physiological doses of replacement steroid (e.g., for adrenal insufficiency) provided ≤ 10 mg/day of prednisone or equivalent Steroid premedication for hypersensitivity reactions (HSRs; e.g., reaction to IV contrast) Receipt of live attenuated vaccine within 28 days of D1 of IP. Active or documented history of autoimmune disease (autoimmune disease does not refer to irAEs; for irAEs see inclusion criteria #11). Exceptions include Type I diabetes, vitiligo, alopecia areata or hypo/hyperthyroidism. 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 (GI) disease associated with diarrhea within 6 months of D1 of IP. Clinically significant or uncontrolled cardiac disease including any of the following: Myocarditis Unstable angina within 6 months from D1 of IP Acute myocardial infarction within 6 months from D1 of IP Uncontrolled hypertension New York Heart Association (NYHA) Class II, III or IV congestive heart failure Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, second- or third- degree atrioventricular block without a pacemaker, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia requiring therapy) Untreated central nervous system (CNS) or leptomeningeal metastases. Subjects with treated CNS metastases must have completed definitive treatment (radiotherapy and/or surgery) > 2 weeks prior to D1 of IP and no longer require steroids. 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 (positive for hepatitis B surface antigen [HBsAg]) or hepatitis C virus ([HCV]; if HCV antibody (Ab) test is positive check for HCV ribonucleic acid [RNA]). (NOTE: Hepatitis B virus (HBV): Subjects who are hepatitis B core antibody [HBcAb] positive, but HBsAg negative are eligible for enrollment. HCV: Subjects who are HCV Ab positive, but HCV RNA negative are eligible for enrollment).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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-279252<br>Intravenous administration; Two possible dosing schedules for SL-279252 may be evaluated | Drug: SL-279252<br>* The investigational product (IP), SL-279252, is a first-in-class agonist redirected checkpoint (ARC) fusion protein (FP) consisting of the extracellular domains of human programmed cell death 1 (PD- 1) and OX40L, linked by a central Fc domain (PD1-Fc-OX40L).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile of SL-279252 - Incidence of all treatment emergent adverse events | Incidence of all treatment emergent adverse events | From Day 1 to 90 days after Last Dose of SL-279252 (approximately 1 year) | 
| Maximum Tolerated Dose (MTD) of SL-279252 | Defined based on the rate of dose limiting toxicities (DLTs) | From Day 1 to 90 days after Last Dose of SL-279252 (approximately 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish the recommended phase 2 dose of SL-279252 | Establish the recommended phase 2 dose of SL-279252 | Approximately 32 months | 
| Overall Response Rate of SL-279252 | Response assessment according to immune response evaluation criteria in solid tumors (iRECIST) for solid tumors or response evaluation criteria in lymphoma (RECIL) 2017 for lymphomas Objective response rate (ORR; proportion of participants whose best overall response is a complete response [CR] or partial response [PR] evaluated via iRECIST. Clinical benefit rate (CBR; proportion of participants whose best overall response is an iCR, iPR or stable disease (iSD) of >12 weeks); minor response (MR) will be included for lymphomas | Approximately 32 months | 
| Immunogenicity to SL-279252 | Number and proportion of participants with positive anti-drug antibody titer | Approximately 32 months | 
| Maximum serum concentration (Cmax) of SL-279252 | The Cmax is the maximum observed serum concentration of SL-279252 following single and multiple doses | Approximately 32 months | 
| Minimum serum concentration (Cmin) of SL-279252 | The Cmin is the minimum observed serum concentration of SL-279252 following single and multiple doses | Approximately 32 months | 
| Time at which maximum concentration of SL-279252 is observed (Tmax) | The Tmax is the time at which the maximum concentration of SL-279252 is observed following single and multiple doses | Approximately 32 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-279252 | Approximately 32 months | 
| Terminal half life (t1/2) | The t1/2 elimination half-life of SL-279252 | Approximately 32 months | 
| Clearance | Clearance of SL-279252 | Approximately 32 months | 
| Volume of distribution | Volume of distribution of SL-279252 | Approximately 32 months |