Clinical Trials /

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

NCT03894618

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Anal Canal Squamous Cell Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Diffuse Large B-Cell Lymphoma
  • Gastric Adenocarcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Hodgkin Lymphoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Renal Cell Carcinoma
  • Skin Squamous Cell Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: SL-279252 (PD1-Fc-OX40L) in Subjects With Advanced Solid Tumors or Lymphomas
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: SL01-DEL-101
  • NCT ID: NCT03894618

Conditions

  • 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

Interventions

DrugSynonymsArms
SL-279252SL-279252

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
SL-279252ExperimentalIntravenous administration; Two possible dosing schedules for SL-279252 may be evaluated
  • SL-279252

Eligibility Criteria

        Inclusion Criteria:

        Participants are eligible to be included in the study only if all the following criteria
        apply.

          1. Subject has voluntarily agreed to participate by giving written informed consent in
             accordance with ICH/GCP guidelines and applicable local regulations.

          2. 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.

          3. 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.

          4. Age 18 years and older.

          5. Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

          6. 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.

          7. Has life expectancy of greater than 12 weeks.

          8. 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 %.

          9. 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.

         10. 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.

         11. 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

         12. 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:

          1. 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.

          2. 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.

          3. 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

          4. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy is prohibited.
             Concurrent use of hormones for non-cancer related conditions is acceptable.

          5. 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)

          6. Receipt of live attenuated vaccine within 28 days of D1 of IP.

          7. 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.

          8. Active pneumonitis (i.e. drug-induced, idiopathic pulmonary fibrosis,
             radiation-induced, etc.).

          9. Ongoing or active infection (e.g., no systemic antimicrobial therapy for treatment of
             infection within 5 days of D1 of IP).

         10. Symptomatic peptic ulcer disease or gastritis, active diverticulitis, other serious
             gastrointestinal (GI) disease associated with diarrhea within 6 months of D1 of IP.

         11. 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)

         12. 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.

         13. Women who are breast feeding.

         14. 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.

         15. 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.

         16. Has undergone allogeneic stem cell transplantation or organ transplantation.

         17. 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety profile of SL-279252 - Incidence of all treatment emergent adverse events
Time Frame:From Day 1 to 90 days after Last Dose of SL-279252 (approximately 1 year)
Safety Issue:
Description:Incidence of all treatment emergent adverse events

Secondary Outcome Measures

Measure:Establish the recommended phase 2 dose of SL-279252
Time Frame:Approximately 32 months
Safety Issue:
Description:Establish the recommended phase 2 dose of SL-279252
Measure:Overall Response Rate of SL-279252
Time Frame:Approximately 32 months
Safety Issue:
Description: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
Measure:Immunogenicity to SL-279252
Time Frame:Approximately 32 months
Safety Issue:
Description:Number and proportion of participants with positive anti-drug antibody titer
Measure:Maximum serum concentration (Cmax) of SL-279252
Time Frame:Approximately 32 months
Safety Issue:
Description:The Cmax is the maximum observed serum concentration of SL-279252 following single and multiple doses
Measure:Minimum serum concentration (Cmin) of SL-279252
Time Frame:Approximately 32 months
Safety Issue:
Description:The Cmin is the minimum observed serum concentration of SL-279252 following single and multiple doses
Measure:Time at which maximum concentration of SL-279252 is observed (Tmax)
Time Frame:Approximately 32 months
Safety Issue:
Description:The Tmax is the time at which the maximum concentration of SL-279252 is observed following single and multiple doses
Measure:Area under the serum concentration-time curve (AUC)
Time Frame:Approximately 32 months
Safety Issue:
Description:The AUC is the area under the serum concentration time curve following single and multiple doses of SL-279252
Measure:Terminal half life (t1/2)
Time Frame:Approximately 32 months
Safety Issue:
Description:The t1/2 elimination half-life of SL-279252
Measure:Clearance
Time Frame:Approximately 32 months
Safety Issue:
Description:Clearance of SL-279252
Measure:Volume of distribution
Time Frame:Approximately 32 months
Safety Issue:
Description:Volume of distribution of SL-279252

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Shattuck Labs, Inc.

Last Updated

January 20, 2021