Dose Escalation Study of Immunomodulatory Nanoparticles

NCT04751786 | Active Not Recruiting Phase 1 DMC

• 2 other identifiers: NL 72876.091.202017-002568-41
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

PRECIOUS-01 is an immunomodulating agent composed of the invariant natural killer T cell (iNKT) activator threitolceramide-6 (ThrCer6, IMM60) and the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer-testis antigen peptides encapsulated in a poly(lactic-co-glycolic acid) (PLGA) nanoparticle. PRECIOUS-01 is being developed for the treatment of patients with NY-ESO-1-positive cancers.

Conditions

Advanced Solid Tumor

Keywords

Advanced solid tumor; No standard treatment available; Phase I dose escalation study; IHC-confirmed NY-ESO-1 positivity

Outcome Measures

Primary Outcomes (2)

• Safety of PRECIOUS-01

  The incidence of treatment-emerging Adverse Events (AEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 reporting severity and relatedness

  From enrollment up to and including 21 days after last PRECIOUS-01 administration (all AEs). Related AEs and SAEs will be followed up until 17 weeks after end of treatment.

• Multiplex immunohistochemistry assay to gain insight into the composition of immune cell subsets

  To analyze the immunological composition in tumor biopsies using an established immunohistochemistry (IHC) assay for the detection of CD3, CD8, FoxP3, CD45RO and CD20 positive cells; these results will support the decision on the RP2D as part of the planned trial.

  At baseline and at the end of Cycle 3 (each cycle is 21 days)

Secondary Outcomes (2)

• Recommended Phase 2 Dose (RP2D)

  From enrollment up to and including 21 days after last PRECIOUS-01 administration. Side effects will be followed up until 17 weeks after end of treatment.

• Immunological responses in blood

  From study initiation up to and including the database lock, which is estimated to be 24 months later

Other Outcomes (1)

• Best Overall Response

  From study initiation up to and including the database lock, which is estimated to be 24 months later

Study Arms (1)

PRECIOUS-01

EXPERIMENTAL

Eligible subjects will receive three i.v. infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts (low: 0.4 mg/kg, intermediate: 0.8 mg/kg, and high: 1.6 mg/kg fixed doses). Subjects will be monitored for safety and the occurrence of Dose-Limiting Toxicities (DLTs). A 3+3 design is used for the dose escalation steps. Three subjects will be enrolled sequentially per cohort. If the maximum tolerated dose (MTD) is not reached in the planned dose escalation cohorts, the RP2D will be based on the observed safety and immune modulatory activity as pharmacodynamic parameter supporting the RP2D. The sample size is based on the determination of the MTD/RP2D. In order to collect sufficient information regarding changes in immune related parameters as readout for pharmacodynamics of the particles, it is planned to extend the two highest dosing cohorts to a total of six subjects or to extend the highest dosing cohort to a total of nine subjects, depending on observed toxicity

Drug: PRECIOUS-01

Interventions

PRECIOUS-01 DRUG

Subjects will be enrolled in one of three dosing cohorts (three subjects per cohort for the planned dose escalation with a planned extension to a total of six subjects for the two highest dosing cohorts for the evaluation of the pharmacodynamic effects of PRECIOUS-01 for determination of the RP2D, if MTD is not reached).

PRECIOUS-01

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or older at time of signing informed consent.
• Performance status (ECOG 0 or 1).
• Estimated life expectancy of at least 6 months.
• Histologically or cytologically confirmed advanced and /or metastatic solid tumor with progressive disease at baseline, for whom no standard treatment is available.
• IHC-confirmed NY-ESO-1 positivity prior to screening (cut-off value: 1% positive cells) on (archival) tumor tissue, per local laboratory guidelines.
• Subject with evaluable disease per RECIST v1.1.
• Adequate hematologic, renal and liver function as defined by laboratory values performed within 14 days of start of treatment:
• Hemoglobin (Hb) ≥ 6 mmol/L;
• Absolute Lymphocyte Count (ALC) \> 0.8 x 109/L;
• Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L;
• Platelet count \> 100 x 109/L;
• Creatinine level within normal institutional limit;
• Serum bilirubin \< 25 μmol/L;
• Serum Lactic Acid Dehydrogenase (LDH) ≤ Upper Limit of Normal range (ULN);
• Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) ≤ ULN unless related to liver metastasis (in which case levels should be \< 3 ULN).

You may not qualify if:

• Second malignancy in the previous 2 years, with the exception of adequately treated in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin,
• Clinical suspicion or radiological evidence of active brain metastases. Patients with brain metastases that have been treated previously and are proven stable (computed tomography \[CT\] or magnetic resonance imaging \[MRI\] \< 30 days) and without steroids for \> 3 months are allowed.
• Subjects with thromboembolic events within the past year.
• Subjects on any other anticancer therapy (cytotoxic, biologic or investigational agents), unless at least 4 weeks (or 5 half-lives, whichever is shorter, 6 weeks for mitomycin-C or nitrosoureas), have elapsed since the last dose before the first administration of PRECIOUS-01. At least 4 weeks should have elapsed since receiving palliative radiotherapy. Chronic treatment with non-investigational gonadotropin-releasing hormone analogs or other hormonal or supportive care is permitted.
• Subjects with major surgery within 4 weeks before initiating treatment or with minor surgical procedure within 7 days before initiating treatment (except for port-a-cath or central line i.v. placement, or biopsy), or anticipation of the need for major surgery during the course of the trial treatment.
• Concomitant use of oral or i.v. immunosuppressive drugs. Inhaled, topical or intranasal steroids and adrenal replacement steroids \< 10 mg/day (prednisone equivalent) are permitted in the absence of auto-immune disease.
• Uncontrolled infectious disease, i.e. negative testing for human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and syphilis (Treponema Pallidum Hemagglutination Assay \[TPHA\]).
• (Systemic) autoimmune disease such as, but not limited to, inflammatory bowel disease, multiple sclerosis and lupus. Subjects with type 1 diabetes mellitus, hypothyroidism after autoimmune thyroiditis and skin disorders (eczema and psoriasis) are not excluded.
• History of clinically significant cardiovascular disease (≤ 6 months prior to Day 1 on trial) such as stroke, Transient Ischemic Attack (TIA), unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, myocardial infarction, uncontrolled hypertension, cardiac arrhythmia requiring medication, relevant pathological ECG findings or uncontrolled hypertension (systolic \> 150 mm Hg and/or diastolic \> 100 mm Hg).
• Serious (bleeding and clotting) condition(s) that may interfere with safe administration of PRECIOUS-01.
• Abnormal or clinically significant coagulation parameters at the discretion of the Clinical Investigator, i.e.:
• Prothrombin Time - International Normalized Ratio (PT-INR)
• Activated Partial Thromboplastin Time (APTT)
• Subjects being treated with anticoagulants are excluded if the coagulation parameters are outside the therapeutic intervals as described in the Summary of Product Characteristics (SmPC) for the administered treatment.
• Evidence of any other conditions (such as psychological/familial sociological/geographical issues, psychiatric illness, infectious diseases, physical examination or laboratory findings) that may interfere with the planned treatment, affect subject compliance or place the subject at high risk from treatment-related complications. These conditions must be discussed with the subject before registration in the trial.

Sponsors & Collaborators

• Radboud University Medical Center: lead
• CATO-SMS: collaborator

Study Sites (1)

Radboudumc

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Related Publications (2)

• Dolen Y, Kreutz M, Gileadi U, Tel J, Vasaturo A, van Dinther EA, van Hout-Kuijer MA, Cerundolo V, Figdor CG. Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses. Oncoimmunology. 2015 Aug 12;5(1):e1068493. doi: 10.1080/2162402X.2015.1068493. eCollection 2016.

  PMID: 26942088 BACKGROUND

• Creemers JHA, Pawlitzky I, Grosios K, Gileadi U, Middleton MR, Gerritsen WR, Mehra N, Rivoltini L, Walters I, Figdor CG, Ottevanger PB, de Vries IJM. Assessing the safety, tolerability and efficacy of PLGA-based immunomodulatory nanoparticles in patients with advanced NY-ESO-1-positive cancers: a first-in-human phase I open-label dose-escalation study protocol. BMJ Open. 2021 Nov 30;11(11):e050725. doi: 10.1136/bmjopen-2021-050725.

  PMID: 34848513 DERIVED

Study Officials

• Petronella B. Ottevanger, MD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Eligible subjects will receive three i.v. infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts (low: 0.4 mg/kg, intermediate: 0.8 mg/kg, and high: 1.6 mg/kg fixed doses). Subjects will be monitored for safety and the occurrence of Dose-Limiting Toxicities (DLTs). A 3+3 design is used for the dose escalation steps. Three subjects will be enrolled sequentially per cohort. If the maximum tolerated dose (MTD) is not reached in the planned dose escalation cohorts, the RP2D will be based on the observed safety and immune modulatory activity as pharmacodynamic parameter supporting the RP2D. The sample size is based on the determination of the MTD/RP2D. In order to collect sufficient information regarding changes in immune related parameters as readout for pharmacodynamics of the particles, it is planned to extend the two highest dosing cohorts to a total of six subjects or to extend the highest dosing cohort to a total of nine subjects, depending on observed toxicity.

Study Record Dates

• First Submitted: December 11, 2020
• First Posted: February 12, 2021
• Study Start: January 11, 2021
• Primary Completion: July 1, 2025
• Study Completion: December 1, 2025
• Last Updated: April 4, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

NL (1)