A Study of ES014 (Anti-CD39/TGF-β Bispecific Antibody) in Patients With Locally Advanced or Metastatic Solid Tumors

An Open-Label, Multicenter, First-in-Human, Dose Escalation and Expansion, Phase 1 Study of ES014 in Subjects With Locally Advanced or Metastatic Solid Tumors

The purpose of this first-in-human, open-label, multicenter, non-randomized study designed to determine the maximum tolerated dose (MTD)/maximum administered dose (MAD), optimal biological dose (OBD), and recommended phase 2 dose (RP2D) of ES014 by evaluating the safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of ES014 administered intravenously to subjects with advanced solid tumors.

Study Overview

• Status: Withdrawn
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: ES014

Detailed Description

Adenosine and transforming growth factor-β (TGF-β) are two key immune suppressors in the tumor microenvironment (TME) that cause broad immune suppression resulting in resistance to current checkpoint inhibitor immunotherapies. The bifunctional antibody-fusion protein ES014 was created by fusing the TGF-β receptor II ectodomain to an antibody targeting human ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1, CD39, UniprotKB: P49961). ES014 simultaneously neutralizes autocrine/paracrine TGF-β and inhibits the enzymatic activity of CD39, which results in the stabilization of pro-inflammatory extracellular adenosine triphosphate (eATP) and the restoration of anti-tumor immunity by impairing the accumulation of immune suppressive adenosine and TGF-β within the TME.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria

1. To be eligible for study entry, subjects must satisfy all of the following criteria:
2. Capable of giving signed informed consent.

3. Part 1: Histological or cytological documentation of unresectable locally advanced or metastatic solid tumors, if 1) disease has progressed despite standard therapy, and no further standard therapy exists; or 2) standard therapy has proven to be ineffective or intolerable.

   Part 2: Histological or cytological documentation of PDAC (Cohort 2A), CRC (Cohort 2B), or NSCLC (Cohort 2C), with unresectable locally advanced or metastatic disease, if 1) disease has progressed despite standard therapy, and no further standard therapy exists; or 2) standard therapy has proven to be ineffective or intolerable.

4. Provide tumor tissue samples (minimum 10 unstained FFPE slides) obtained from the initial diagnosis to study entry.
5. At least one measurable lesion per RECIST v1.1.

6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

   • Part 1: ECOG PS 0-1.
   • Part 2: ECOG PS 0-2.
7. Life expectancy of at least 12 weeks.
8. Adequate hematologic, hepatic, renal and coagulation functions per protocol
9. Male and female subjects of childbearing potential must be willing to completely abstain or agree to use a highly effective method of contraception

Key Exclusion Criteria

1. Any prior therapy targeting CD39, CD73, adenosine A2A receptor, or TGF-β.
2. Receipt of any investigational agents or devices within 4 weeks prior to the first dose of study drug.

3. Prior treatment with the following therapies:

   1. Anticancer therapy within 30 days or 5 half-lives of the drug prior to the first dose of study drug, whichever is shorter. At least 14 days must have elapsed between the last dose of prior anticancer agent and the first dose of study drug is administered. Exception: hormonal and/or hormonal replacement therapy.
   2. A wash out of at least 2 weeks before the start of study drug for radiation to the extremities and 4 weeks for radiation to the chest, brain, or visceral organs is required.
4. Prior allogeneic or autologous bone marrow transplantation or solid organ transplantation.
5. Toxicity from previous anticancer treatment per protocol.
6. Treatment with systemic immunosuppressive medications within 4 weeks prior to the first dose of study drug.
7. Subjects who received transfusion of blood products (including platelets or red blood cells), G-CSF, GM-CSF, recombinant erythropoietin, or recombinant thrombopoietin within 14 days prior to the first dose of study treatment.
8. Major surgery within 4 weeks prior to the first dose of study treatment.
9. Live vaccine therapies within 4 weeks prior to the first dose of study treatment.
10. Recent history of allergen desensitization therapy within 4 weeks prior to the first dose of study treatment.
11. Known allergies to CHO-produced antibodies, which in the opinion of the Investigator suggests an increased potential for an adverse hypersensitivity to ES014.
12. Invasive malignancy or history of invasive malignancy other than disease under study within the last two years per protocol.
13. CNS metastases.
14. Active autoimmune disease or documented history of autoimmune disease that required systemic steroids or other immunosuppressive medications per protocol.
15. Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids or other immunosuppressive medications.
16. Active infection requiring systemic therapy, known human immunodeficiency virus (HIV) infection, or positive test for hepatitis B active infection (HBsAg) or hepatitis C active infection (hepatitis C antibody).
17. Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment).
18. History or evidence of cardiac abnormalities per protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 2 dose expansion; Part 2 of the study will consist of 3 expansion cohorts for pancreatic ductal adenocarcinoma (Cohort 2A), NSCLC (Cohort 2B), and colorectal adenocarcinoma (Cohort 2C) with 10 subjects per expansion cohort respectively at the recommended optimal biological dose determined in Part 1 dose escalation.	Drug: ES014; ES014 is administered via intravenous infusion, once every 14 days, every 28 days as a treatment cycle for a maximum treatment duration per patient of 2 years.
Experimental: Part 1 dose escalation; ES014 doses will be escalated in patients with advanced solid tumors with approximately 30 subjects.	Drug: ES014; ES014 is administered via intravenous infusion, once every 14 days, every 28 days as a treatment cycle for a maximum treatment duration per patient of 2 years.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The frequency and severity of adverse events of ES014	Adverse events will be assessed and assigned by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. [Time Frame: 1-3 years]	1-3 years
Dose Limiting Toxicity of ES014	Evaluation of dose-limiting toxicity (DLT)	Assessed during first 28 days of treatment
Optimal biological dose (OBD) of ES014	The OBD of ES014 will be determined	1-3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed serum concentration (Cmax) of ES014	Maximum observed serum concentration (Cmax) of ES014 will be measured.	1-3 years
Trough observed serum concentration (Ctrough) of ES014	Trough observed serum concentration (Ctrough)of ES014 will be measured.	1-3 years
Area under the serum concentration time curve (AUC) of ES014	Area under the serum concentration time curve (AUC) of ES014 will be measured	1-3 years
Time to Cmax (Tmax) of ES014	Time to Cmax (Tmax) of ES014 will be measured	1-3 years
The terminal elimination half life of ES014	The terminal elimination half-life (t 1/2) of ES014 will be measured	1-3 years
The clearance of ES014	A pharmacokinetic measurement of the volume of plasma from which ES014 is completely removed per unit time	1-3 years
The volume of distribution of ES014	The amount of of ES014 in the body divided by the plasma concentration will be measured	1-3 years
The immunogenicity of ES014	The presence and the frequency of anti-drug antibodies (ADA) against ES014 will be measured	1-3 years
The antitumor activity of ES014	Tumor response will be measured by the revised Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) by Investigator assessment	1-3 years

Collaborators and Investigators

• Sponsor: Elpiscience Biopharma, Ltd.
• Investigators: Study Director: Elpiscience Biopharma, Ltd., Elpiscience Biopharma, Ltd.

Study record dates

Study Major Dates

• Study Start (Anticipated): April 21, 2023
• Primary Completion (Anticipated): April 30, 2026
• Study Completion (Anticipated): April 30, 2026

Study Registration Dates

• First Submitted: May 11, 2022
• First Submitted That Met QC Criteria: May 16, 2022
• First Posted (Actual): May 19, 2022

Study Record Updates

• Last Update Posted (Actual): January 31, 2023
• Last Update Submitted That Met QC Criteria: January 30, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: ES014-1001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No