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

Phase 1

Terminated

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

Interventions: Drug: AZD8853
Drug: Zirconium-89 crefmirlimab berdoxam

Registration Number: NCT05397171

Lead Sponsor: AstraZeneca

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Substudy 1 - Parts A, B, and C	AZD8853	* 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
Substudy 1 - Parts B1 and B2 with CD8+ PET	Zirconium-89 crefmirlimab berdoxam	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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From Day 1 up to 90 (±7 days) days after the last dose of AZD8853 (1 Year)	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.
Number of Participants With Dose Limiting Toxicity (DLT)	From Cycle 1 Day 1 to end of Cycle 1 (21 days)	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.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	First dose until progression of disease (PD) or last evaluable assessment in the absence of progression (1 Year)	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.
Disease Control Rate (DCR) at 15 Weeks	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.
Duration of Response (DOR)	First documented response until date of first documented disease progression or study end (1 Year)	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.
Progression Free Survival (PFS)	First dose until documented disease progression or study end (1 Year)	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.
Percentage Change From Baseline in Tumor Size	Baseline (pre-treatment) up to Week 6 and Week 15	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.
Overall Survival (OS)	First dose until study end (1 Year)	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.
Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline	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)	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.
Maximum Observed Concentration (Cmax) of AZD8853	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)	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.
Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUClast) of AZD8853	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)	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.
Partial Area Under the Plasma Concentration-time Curve From Time 0 to 504 Hours Post Dose (AUC[0-504 Hours]) of AZD8853	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)	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.
Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels	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	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
Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUCinf) of AZD8853	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)	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.
Number of Participants With Positive Anti-drug Antibody (ADA) of AZD8853	From Day 1 up to 90 (±7 days) days after the last dose of AZD8853 (1 year)	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.