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

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

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.

Study Overview

• Status: Terminated
• Conditions: Carcinoma, Non-Small-Cell Lung; Urinary Bladder Neoplasms; Colorectal Cancer
• Intervention / Treatment: Drug: AZD8853; Drug: Zirconium-89 crefmirlimab berdoxam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Research Site
    • Toronto, Ontario, Canada, M5G 1X5
      • Research Site
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98109
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

*Key Inclusion Criteria*

All Substudies:

1. At least one measurable target lesions per RECIST 1.1.
2. Eastern Cooperative Group (ECOG) of 0-1.
3. Life expectancy of ≥ 12 weeks
4. Adequate organ and marrow function as defined in the protocol

Substudy 1:

1. Histologically or cytologically confirmed locally advanced, unresectable or metastatic NSCLC, MSS-CRC, or UC.
2. Documented progression from previous therapy
3. 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:

1. Unresolved toxicities ≥ Grade 2 per CTCAE 5.0 from prior therapy, with some exceptions defined in the protocol
2. Symptomatic CNS metastases or leptomeningeal disease
3. Active or ongoing infections, or uncontrolled intercurrent illness as defined in the protocol
4. Active or prior documented autoimmune or inflammatory disorder
5. Body weight loss of > 10% within 30 days of screening visit
6. 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:

1. Must not have had a toxicity from a checkpoint inhibitor that lead to permanent discontinuation of immunotherapy
2. Participants with brain metastases, unless treated, asymptomatic, stable, and not requiring treatment

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: Substudy 1 - Parts A, B, and C; 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; Monotherapy given until progressive disease or upon meeting other discontinuation criteria.
Experimental: Substudy 1 - Parts B1 and B2 with CD8+ PET; 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; CD8+ T cell tracer for positron emission tomography (PET) at two time points in addition to monotherapy AZD8853; Other Names: 89-Zr-Df-IAB22M2C, 89-Zr-Df-crefmirlimab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	The safety and tolerability of AZD8853 in participants with selected advanced/metastatic solid tumors was assessed. As per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, severity scale ranged from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event. This outcome measure was assessed only for substudy 1 Part A.	From Day 1 up to 90 (±7 days) days after the last dose of AZD8853 (1 Year)
Number of Participants With Dose Limiting Toxicity (DLT)	DLTs (in dose escalation Parts only) of AZD8853 in participants with selected advanced/metastatic solid tumors was assessed. The DLTs are specific adverse events defined as grade 3 (severe), grade 4 (life-threatening), and grade 5 (death) as per NCI-CTCAE version 5.0 non-hematological toxicity or hematological toxicity. This outcome measure was assessed only for substudy 1 Part A.	From Cycle 1 Day 1 to end of Cycle 1 (21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). This outcome measure was assessed only for substudy 1 Part A.	First dose until progression of disease (PD) or last evaluable assessment in the absence of progression (1 Year)
Disease Control Rate (DCR) at 15 Weeks	Disease control was defined as a best overall response (BOR) of confirmed CR or PR or having stable disease (SD) (without subsequent cancer therapy) maintained for greater than or equal to (>=) 14 weeks (study week 15) from first IP. Disease control rate at study week 15 weeks (DCR-15) was defined as the percentage of participants who had disease control at study week 15 weeks. This outcome measure was assessed only for substudy 1 Part A.	15 weeks
Duration of Response (DOR)	The DOR was defined as the time from the date of first documented response (which was subsequently confirmed) until the date of documented progression or death in the absence of disease progression. This outcome measure was assessed only for substudy 1 Part A.	First documented response until date of first documented disease progression or study end (1 Year)
Progression Free Survival (PFS)	The PFS was defined as the time from the start of study intervention until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participant withdraws from study intervention or received another anti-cancer therapy prior to progression. This outcome measure was assessed only for substudy 1 Part A.	First dose until documented disease progression or study end (1 Year)
Percentage Change From Baseline in Tumor Size	Tumor size was the sum of the longest diameters (or short axis measurements for lymph nodes) of the target lesions (TLs). Percentage change in tumor size was determined for participants with measurable disease at baseline. Baseline for Response evaluation criteria in solid tumors (RECIST) version 1.1 was defined as the last evaluable assessment prior to first IP dose. This outcome measure was assessed only for substudy 1 Part A.	Baseline (pre-treatment) up to Week 6 and Week 15
Overall Survival (OS)	Overall survival was defined as the time from the start of treatment until death due to any cause. This outcome measure was assessed only for substudy 1 Part A.	First dose until study end (1 Year)
Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline	Change in ctDNA is defined as the percentage change in ctDNA from baseline to each timepoint for the safety population. This outcome measure was assessed only for substudy 1 Part A.	Baseline (pre-treatment), Day 8 of Cycle 1, Days 1 and 8 of Cycle 2, Day 1 of Cycles 3, 4, 5, 7 (each cycle is equal to 21 days)
Maximum Observed Concentration (Cmax) of AZD8853	The pharmacokinetic (PK) (Cmax) of AZD8853 in serum when administered in participants with selected advanced/metastatic solid tumors were assessed. This outcome measure was assessed only for substudy 1 Part A.	0 hour, 15 minutes, 2 hours, 6 hours, 24 hours, 168 hours and 336 hours post EOI of Cycle 1 (each cycle equals to 21 days)
Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUClast) of AZD8853	The PK (AUClast) of AZD8853 in serum when administered in participants with selected advanced/metastatic solid tumors were assessed. This outcome measure was assessed only for substudy 1 Part A.	0 hour, 15 minutes, 2 hours, 6 hours, 24 hours, 168 hours and 336 hours post EOI of Cycle 1 (each cycle equals to 21 days)
Partial Area Under the Plasma Concentration-time Curve From Time 0 to 504 Hours Post Dose (AUC[0-504 Hours]) of AZD8853	The PK (AUC[t1-t2]) of AZD8853 in serum when administered in participants with selected advanced/metastatic solid tumors were assessed. This outcome measure was assessed only for substudy 1 Part A.	0 hour, 15 minutes, 2 hours, 6 hours, 24 hours, 168 hours and 336 hours post EOI of Cycle 1 (each cycle equals to 21 days)
Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUCinf) of AZD8853	The PK (AUCinf) of AZD8853 in serum when administered in participants with selected advanced/metastatic solid tumors were assessed. This outcome measure was assessed only for substudy 1 Part A.	0 hour, 15 minutes, 2 hours, 6 hours, 24 hours, 168 hours and 336 hours post EOI of Cycle 1 (each cycle equals to 21 days)
Number of Participants With Positive Anti-drug Antibody (ADA) of AZD8853	The immunogenicity of AZD8853 in participants with selected advanced/metastatic solid tumors were assessed. This outcome measure was assessed only for substudy 1 Part A.	From Day 1 up to 90 (±7 days) days after the last dose of AZD8853 (1 year)
Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels	The pharmacodynamics (PD) activity of AZD8853 by assessment of candidate biomarkers in participants with selected advanced/metastatic solid tumors were assessed. This outcome measure was assessed only for substudy1 Part A. End of infusion= EOI; End of treatment= EOT	0 hours post EOI of Cycle 1 Day 1, Day 1 (Pre-dose) of Cycles 2 and 3 (each cycle equals to 21 days) and 90-days post EOT of 90 days follow-up

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: ImaginAb, Inc.

Publications and helpful links

Helpful Links

• CSR Synopsis
• SAP redacted
• CSP redacted

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2022
• Primary Completion (Actual): June 6, 2023
• Study Completion (Actual): June 6, 2023

Study Registration Dates

• First Submitted: May 24, 2022
• First Submitted That Met QC Criteria: May 27, 2022
• First Posted (Actual): May 31, 2022

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 5, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Monoclonal antibody; Imaging; Non-Small Cell Lung Cancer; AZD8853; First-in-Human; Colorectal cancer; Bladder cancer; Urinary Bladder Neoplasms; Growth Differentiation Factor-15 (GDF-15); CD8-Positive T-Lymphocytes; Urothelial Carcinoma; CD8; ⁸⁹Zr-Df-IAB22M2C; PET; CD8 + T cells; Zirconium-89 crefmirlimab berdoxam
• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Urinary Bladder Neoplasms
• Other Study ID Numbers: D9450C00001; 2021-005438-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No