Sym024 Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies

Study Overview
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Brief Summary
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The primary purpose of this study is to see if Sym024 is safe and tolerable as monotherapy and in combination with Sym021 in patients with solid tumor malignancies.

Detailed Description
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Part 1 of this study will assess the safety and tolerability to establish the maximum tolerated dose (MTD) (or the maximum administered dose [MAD]) and/or the selected dose(s) of Sym024 in patients with solid tumor malignancies. Part 2 of this study will assess the safety and tolerability to establish the MTD (or the MAD) and/or the selected dose(s) of Sym024 when administered in combination with Sym021 in patients with solid tumor malignancies. Part 2a of this study will assess the safety and tolerability of Sym024 when first administered as a single agent during Cycle 1 (safety lead-in) followed by administration in combination with Sym021 during Cycle 2 and subsequent cycles. Part 3 of this study will assess the safety of Sym024 when administered alone or in combination with Sym021 in expanded cohorts of patients with solid tumor malignancies.

Official Title
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A Phase 1, Open-Label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Antineoplastic Activity of Sym024 (Anti-CD73) as Monotherapy and in Combination With Sym021 (Anti-PD-1) in Patients With Advanced Solid Tumor Malignancies

Conditions
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Solid Tumor, Metastatic Cancer

Intervention / Treatment
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* Drug: Sym021
* Drug: Sym024


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, ≥18 years. Documented (histologically or cytologically proven), locally advanced or metastatic solid tumor malignancy (must be one of the following): Squamous cell carcinoma of the head and neck Non-small-cell lung carcinoma-adenocarcinoma histology subtype Pancreatic ductal adenocarcinoma Cholangiocarcinoma Colorectal carcinoma (microsatellite stable [MSS] and microsatellite instability-high [MSI-H] phenotypes) Gastric carcinoma (includes gastroesophageal carcinoma) Esophageal carcinoma (includes squamous cell and adenocarcinoma) Mesothelioma (pleural and peritoneal) Cervical carcinoma (CC) (includes adeno, squamous and mixed adeno-squamous carcinoma histology subtypes) Malignancy that is not currently amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor. Measurable disease according to RECIST v1.1. Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit. Agreeing to mandatory tumor tissue biopsies (2 total). ECOG PS of 0 or 1. Adequate organ function as indicated by the following laboratory values. Adequate contraception required as appropriate. Exclusion Criteria: Central nervous system (CNS) malignancies. Clinically significant cardiovascular disease or condition. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism within 4 weeks prior to the first dose of study drug(s). Active uncontrolled bleeding or a known bleeding diathesis. Significant ocular disease or condition. Significant pulmonary disease or condition. Current or recent (within 6 months) significant gastrointestinal disease or condition. Active, known or suspected autoimmune disease. History of organ transplantation (i.e., stem cell or solid organ transplant). Known history of human immunodeficiency virus (HIV) or known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Any other serious/active/uncontrolled infection. History of significant toxicities associated with previous administration of immune checkpoint inhibitors. Known or suspected hypersensitivity to any of the excipients of formulated study drug. Unresolved >Grade 1 toxicity associated with any prior antineoplastic therapy. Inadequate recovery from any prior surgical procedure, or patients having undergone any major surgical procedure within 4 weeks prior to the first dose of study drug(s). Any other serious, life-threatening, or unstable preexisting medical condition (aside from the underlying malignancy). Therapeutic Exclusions Prior therapy with Sym024 or other inhibitors of CD73, CD39 or adenosine receptors ADORA2A, ADORA2B. Part II and Part III, prior anti-PD-(L)1 therapy, except for indications where it is approved. Any antineoplastic agent for the primary malignancy (standard or investigational) within 4 weeks or 5 elimination half-lives. Any other investigational treatments within 2 weeks prior to the first dose of study drug(s). Radiotherapy, with exceptions. Live vaccines against infectious diseases 4 weeks prior to the first dose of study drug(s). Immunosuppressive or systemic glucocorticoids therapy (>10 mg daily prednisone or equivalent) within 2 weeks prior to the first dose of study drug(s), with exceptions. Prophylactic use of hematopoietic growth factors within 1 week prior to the first dose of study drug(s).

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sym024 Dose Level 1<br>Part I, Sym024 monotherapy dose level 1 | Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym024 Dose Level 2<br>Part I, Sym024 monotherapy dose level 2 | Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym024 Dose Level 3<br>Part I, Sym024 monotherapy dose level 3 | Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym024 Dose Level 4<br>Part I, Sym024 monotherapy dose level 4 | Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym024 Dose Level -1<br>Part I, Sym024 monotherapy dose level -1. Evaluate only if needed based on tolerability | Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym021+Sym024 Dose Level 2<br>Part II, Sym021 in combination with dose level 2 of Sym024 | Drug: Sym021<br>* Sym021 is a humanized anti-PD-1 antibody.<br>* Other names: Anti-PD-1;Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym021+Sym024 Dose Level 3<br>Part II, Sym021 in combination with dose level 3 of Sym024 | Drug: Sym021<br>* Sym021 is a humanized anti-PD-1 antibody.<br>* Other names: Anti-PD-1;Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym021+Sym024 Dose Level 4<br>Part II, Sym021 in combination with dose level 4 of Sym024 | Drug: Sym021<br>* Sym021 is a humanized anti-PD-1 antibody.<br>* Other names: Anti-PD-1;Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym021+Sym024 Dose Level 5<br>Part IIa, Sym024 monotherapy and in combination with Sym021 | Drug: Sym021<br>* Sym021 is a humanized anti-PD-1 antibody.<br>* Other names: Anti-PD-1;Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Sym021+Sym024 Dose Level 1<br>Part II, Sym021 in combination with dose level 1 of Sym024. Evaluate only if needed based on tolerability | Drug: Sym021<br>* Sym021 is a humanized anti-PD-1 antibody.<br>* Other names: Anti-PD-1;Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|
| Experimental: Dose Expansion Sym021 (+Sym024)<br>Part III, dose expansion Sym024 and/or Sym021+Sym024 | Drug: Sym021<br>* Sym021 is a humanized anti-PD-1 antibody.<br>* Other names: Anti-PD-1;Drug: Sym024<br>* Sym024 is an anti-CD73 antibody.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: To evaluate the incidence, severity and relationship of (S)AEs to establish the MTD/MAD of Sym024 monotherapy. | Assess the safety and tolerability of Sym024 monotherapy on a Q2W schedule (every two weeks). Assessment based on the occurrence of AEs meeting DLT criteria measured during Cycle 1 | 28 days | 
| Part II: To evaluate the incidence, severity and relationship of (S)AEs to establish MTD/MAD of Sym024 in combination with Sym021. | Assess the safety and tolerability of the sequential escalating doses of Sym024 in combination with Sym021 on a Q2W schedule. Assessment based on the occurrence of AEs meeting DLT criteria measured during Cycle 1 | 28 days | 
| Part III: To evaluate the incidence, severity and relationship of (S)AEs to further assess safety of Sym024 when administered alone or in combination with Sym021. | Assess the safety and tolerability of Sym024 and/or Sym021+Sym024 on a Q2W schedule. Assessment based on the occurrence of AEs | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the immunogenicity of Sym024 as a single agent and in combination with Sym024 | Serum sampling to assess the potential for anti-drug antibody (ADA) formation | 24 months | 
| Evaluation of objective response (OR) or stable disease (SD) | Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) and Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST) | 24 months | 
| Time to progression (TTP) of disease | Based on time of enrollment to first evidence of progression on imaging studies, as assessed by RECIST v1.1 and iRECIST | 24 months | 
| Area under the concentration-time curve in a dosing interval (AUC) | Will be estimated using non-compartmental methods and actual timepoints | 24 months | 
| Maximum concentration (Cmax) | Will be derived from observed data | 24 months | 
| Time to reach maximum concentration (Tmax) | Will be derived from observed data | 24 months | 
| Trough concentration (Ctrough) | Will be derived from observed data | 24 months | 
| Terminal elimination half-life (T½) | Will be estimated using non-compartmental methods and actual timepoints | 24 months | 
| Clearance (CL) | Will be estimated using non-compartmental methods and actual timepoints | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic solid tumor, Anti-PD-1, PD1, CD73, Squamous cell carcinoma of the head and neck (SCCHN), Non-small-cell lung carcinoma-adenocarcinoma histology subtype (NSCLC-Adeno), Pancreatic ductal adenocarcinoma (PDAC), Cholangiocarcinoma (CCA), Colorectal carcinoma (CRC), Gastric carcinoma (GC), Esophageal carcinoma (EsoCA), Mesothelioma (Meso), Sym021, Sym024, Locally advanced/unresectable, PD-1, Head and neck squamous cell carcinoma (HNSCC), Cervical carcinoma (CC)