A First-in-human Study to Evaluate the Safety and Tolerability of AZD8853 in Participants With Selected Advanced/Metastatic Solid Tumours

Study Overview
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Brief Summary
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A Phase I/IIa First-in-human, Open-label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of AZD8853 in Participants with Selected Advanced/Metastatic Solid Tumours.

Detailed Description
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This study is evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AZD8853 in participants with advanced, unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC), Microsatellite Stable Colorectal Cancer (MSS-CRC), Urothelial Carcinoma (UC). This is a modular study, that includes a master protocol and Substudies. Substudy 1 will be conducted in 3 parts - Part A: Dose escalation, Part B: Safety expansion and exploratory CD8+ T cell radiopharmaceutical tracer with PET imaging, and Part C: Efficacy expansion.

Official Title
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A Phase I/IIa First-in-human, Open-label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of AZD8853 in Participants With Selected Advanced/Metastatic Solid Tumours

Conditions
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Urinary Bladder Neoplasms, Colorectal Cancer, Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: AZD8853
* Drug: Zirconium-89 crefmirlimab berdoxam


Participation Criteria
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Eligibility Criteria
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*Key Inclusion Criteria* All Substudies: At least one measurable target lesions per RECIST 1.1. Eastern Cooperative Group (ECOG) of 0-1. Life expectancy of ≥ 12 weeks Adequate organ and marrow function as defined in the protocol Substudy 1: Histologically or cytologically confirmed locally advanced, unresectable or metastatic NSCLC, MSS-CRC, or UC. Documented progression from previous therapy NSCLC: 3.a. At least 1 line of systemic therapy in the advanced / metastatic setting 3.b.Must have received anti-PD-1/anti-PD-L1 agent with or without chemotherapy 3.c. Part B and C: Documented no sensitizing EGFR mutations or ALK fusions/rearrangements 4. MSS-CRC: 4.a. At least 2 prior lines of systemic therapy in the advanced / metastatic setting, including specific therapies defined in the protocol 5. UC: 5.a. At least 1 prior line of systemic therapy in the advanced / metastatic setting, including either a platinum-containing regimen and/or an anti-PD-1 or anti-PD-L1 drug 6. Provision of archival tissue or unstained slides 7. Part B: Willing to provide mandatory biposies at screening and on study 8. Part B-CD8+ PET: At least 1 non-liver lesion suitable for PET imaging *Key Exclusion Criteria* All Substudies: Unresolved toxicities ≥ Grade 2 per CTCAE 5.0 from prior therapy, with some exceptions defined in the protocol Symptomatic CNS metastases or leptomeningeal disease Active or ongoing infections, or uncontrolled intercurrent illness as defined in the protocol Active or prior documented autoimmune or inflammatory disorder Body weight loss of > 10% within 30 days of screening visit Type 2 diabetes requiring management by metformin, where metformin cannot be switched to another treatment at least 7 days prior to starting study treatment Substudy 1: Must not have had a toxicity from a checkpoint inhibitor that lead to permanent discontinuation of immunotherapy Participants with brain metastases, unless treated, asymptomatic, stable, and not requiring treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Interventional Model Description: Substudy 1: Part A: Part A is an AZD8853 monotherapy dose escalation which may enroll up to 45 participants. Part B: Dose escalation will be followed by Part B, where up to 40 participants will be enrolled to doses determined to be safe during Part A. Additionally, a sub-set of participants will also receive an investigational radiopharmaceutical, Zirconium-89 crefmirlimab berdoxam, to evaluate the presence of CD8+ T cells in and around cancerous tumours. Part C: Part C is an efficacy expansion where up to 80 participants may be enrolled based on doses and indications recommended during Part B.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy 1 - Parts A, B, and C<br>Part A: AZD8853 monotherapy dose escalation Part B1 and Part B2: AZD8853 monotherapy safety expansion at dose levels and indications determined to be safe in Part A Part C1 and Part C2: AZD8853 monotherapy safety and preliminary efficacy expansion at dose levels and indications determined to be safe in Parts A and B | Drug: AZD8853<br>* Monotherapy given until progressive disease or upon meeting other discontinuation criteria.<br>|
| Experimental: Substudy 1 - Parts B1 and B2 with CD8+ PET<br>Sub-set of participants from Parts B1 and B2 will also receive investigational CD8+ T cell targeted radioactive tracer, Zirconium-89 crefmirlimab berdoxam with PET scans | Drug: Zirconium-89 crefmirlimab berdoxam<br>* CD8+ T cell tracer for positron emission tomography (PET) at two time points in addition to monotherapy AZD8853<br>* Other names: 89-Zr-Df-IAB22M2C, 89-Zr-Df-crefmirlimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Substudies-Dose Escalation Parts Only: Number of Dose Limiting Toxicities (DLTs) | Incidence of DLTs during the DLT evaluation period per DLT criteria set forth in the protocol. DLTs are assessed per CTCAE v5.0. | From Cycle 1 Day 1 to end of Cycle 1 (21 days) | 
| All Substudies: Number of participants with adverse events (AEs) | Incidence of AEs by evaluation of clinically significant changes from baseline in clinical laboratory parameters, vital signs, ECG results, and other clinical assessments per CTCAE 5.0. | From Informed Consent through 90 days after the last dose of AZD8853 [about 6 months] | 
| All Substudies: Number of participants with serious adverse events (SAEs) | Incidence of SAEs by evaluation of clinically significant changes from baseline in clinical laboratory parameters, vital signs, ECG results, and other clinical assessments per CTCAE 5.0. | From Informed Consent through 90 days after the last dose of AZD8853 [about 6 months] | 
| All Substudies: Incidence of AEs leading to discontinuation of AZD8853 | Assessed per CTCAE v5.0 | From Cycle 1 Day 1 through 90 days after the last dose of AZD8853 [about 6 months] [Each cycle is of 21 Days] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Substudies: Overall response rate (ORR) per RECIST 1.1 |  | From Screening through End of Treatment (Approximately 6 months) | 
| All Substudies: Disease control rate (DCR) per RECIST 1.1 |  | From Screening through End of Treatment (Approximately 6 months) | 
| All Substudies: Duration of response (DoR) per RECIST 1.1 |  | From first documented response to Disease Progression or other End of Study criteria are met (Approximately 1 year) | 
| All Substudies: Progression Free Survival (PFS) per RECIST 1.1 |  | From Cycle 1 Day 1 through Disease Progression or other End of Study qualifying event occurs (Approximately 1 year) [Each cycle is of 21 Days] | 
| All Substudies: Percent change in target lesion tumor size from baseline per RECIST 1.1 |  | From Screening to End of Treatment (Approximately 6 months) | 
| All Substudies: Overall survival (OS) |  | From Cycle 1 Day 1 until Death or End of Study (Approximately 2 years) [Each cycle is of 21 days] | 
| All Substudies: Change in ctDNA from baseline through post-treatment |  | Baseline through 90 days after the last dose of study drug (Approximately 9 months) | 
| All Substudies: Maximum observed serum concentration (Cmax) of AZD885 |  | From Cycle 1 Day 1 through 90 days after the last dose of study drug (Approximately 9 months) [Each cycle is of 21 Days] | 
| All Substudies: Area Under the Curve (AUC) of AZD8853 |  | From Cycle 1 Day 1 through 90 days after the last dose of study drug (Approximately 9 months) [Each cycle is of 21 Days] | 
| All Substudies: Number and percentage of participants with detectable antidrug antibodies (ADAs) against AZD8853 |  | From Cycle 1 Day 1 through 90 days after the last dose (Approximately 9 months) [Each cycle is of 21 Days] | 
| Substudy 1-Parts A & B: Change in circulating GDF15 serum levels |  | Screening through 90 days after the last dose of study drug (Approximately 9 months) | 
| Substudy 1 - Part B: Change in CD8 tumor infiltration in paired biopsies |  | Screening and Cycle 2 Day 8 (Approximately 2 months) [Each cycle is of 21 Days] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD8, CD8-Positive T-Lymphocytes, Urothelial Carcinoma, ⁸⁹Zr-Df-IAB22M2C, PET, Imaging, CD8 + T cells, Zirconium-89 crefmirlimab berdoxam, AZD8853, Monoclonal antibody, First-in-Human, Non-Small Cell Lung Cancer, Colorectal cancer, Bladder cancer, Urinary Bladder Neoplasms, Growth Differentiation Factor-15 (GDF-15)