Carcinoma, Non-Small-Cell Lung, Colorectal Cancer, Urinary Bladder Neoplasms
Conditions
Keywords
AZD8853, Monoclonal antibody, First-in-Human, Non-Small Cell Lung Cancer, Colorectal cancer, Bladder cancer, Urinary Bladder Neoplasms, Growth Differentiation Factor-15 (GDF-15), CD8-Positive T-Lymphocytes, Urothelial Carcinoma, CD8, ⁸⁹Zr-Df-IAB22M2C, PET, Imaging, CD8 + T cells, Zirconium-89 crefmirlimab berdoxam
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.
Interventions
DRUGAZD8853
Monotherapy given until progressive disease or upon meeting other discontinuation criteria.
DRUGZirconium-89 crefmirlimab berdoxam
CD8+ T cell tracer for positron emission tomography (PET) at two time points in addition to monotherapy AZD8853
Sponsors
ImaginAb, Inc.
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
\*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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
Countries
Canada, United States
Participant flow
Recruitment details
This study was conducted from 07 Jun 2022 to 06 Jun 2023 at multiple centers in the United States of America and Canada.
Pre-assignment details
Participants who met the inclusion criteria and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment. Due to early termination of the study, only Part A was started, Parts B & C were not started.
Participants by arm
| Arm | Count |
|---|---|
| AZD8853 300 mg Participants with advanced/metastatic solid tumors received AZD8853 300 mg every 3 weeks until progressive disease, unacceptable toxicity, or withdrawal of consent. | 3 |
| AZD8853 1000 mg Participants with advanced/metastatic solid tumors received AZD8853 1000 mg every 3 weeks until progressive disease, unacceptable toxicity, or withdrawal of consent. | 6 |
| AZD8853 3000 mg Participants with advanced/metastatic solid tumors received AZD8853 3000 mg every 3 weeks until progressive disease, unacceptable toxicity, or withdrawal of consent. | 7 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 2 | 3 | 3 |
| Overall Study | Study Terminated By Sponsor | 1 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | AZD8853 300 mg | AZD8853 1000 mg | AZD8853 3000 mg |
|---|---|---|---|---|
| Age, Continuous | 63.7 Years STANDARD_DEVIATION 7.3 | 62.0 Years STANDARD_DEVIATION 13.2 | 62.8 Years STANDARD_DEVIATION 4.2 | 65.1 Years STANDARD_DEVIATION 7.4 |
| Race/Ethnicity, Customized Not reported | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 3 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | NA Participants | NA Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | NA Participants | NA Participants | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 3 / 6 | 3 / 7 |
| other Total, other adverse events | 3 / 3 | 4 / 6 | 6 / 7 |
| serious Total, serious adverse events | 2 / 3 | 3 / 6 | 2 / 7 |
Outcome results
Primary
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.
Time frame: From Cycle 1 Day 1 to end of Cycle 1 (21 days)
Population: DLT evaluable set included enrolled participants who completed the DLT evaluation period (defined as 21 days after receiving the first infusion of IP) with at least 75% dosing and had completed safety evaluation requirements during the DLT evaluation period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD8853 300 mg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 Participants |
| AZD8853 1000 mg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 Participants |
Primary
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.
Time frame: From Day 1 up to 90 (±7 days) days after the last dose of AZD8853 (1 Year)
Population: Safety set included all participants who received any amount of IP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE with outcome death and possibly related to treatment | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any serious adverse event (SAE) | 1 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE leading to discontinuation of IP and possibly related to treatment (IP) | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to discontinuation of IP | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE possibly related to treatment | 1 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE leading to discontinuation of IP | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to discontinuation of IP and possibly related to treatment | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE of >= CTCAE Grade 3 possibly related to treatment | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to interruption of IP | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE possibly related to treatment | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE of >= CTCAE Grade 3 possibly related to treatment | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE | 3 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE with outcome death | 0 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE of >= CTCAE Grade 3 | 1 Participants |
| AZD8853 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE of greater than or equal to (>=) CTCAE Grade 3 | 1 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE of greater than or equal to (>=) CTCAE Grade 3 | 3 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE | 4 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE possibly related to treatment | 0 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any serious adverse event (SAE) | 3 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE possibly related to treatment | 0 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE with outcome death | 1 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE with outcome death and possibly related to treatment | 0 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to discontinuation of IP | 1 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to discontinuation of IP and possibly related to treatment | 0 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to interruption of IP | 1 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE leading to discontinuation of IP | 1 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE leading to discontinuation of IP and possibly related to treatment (IP) | 0 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE of >= CTCAE Grade 3 possibly related to treatment | 0 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE of >= CTCAE Grade 3 | 3 Participants |
| AZD8853 1000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE of >= CTCAE Grade 3 possibly related to treatment | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE with outcome death and possibly related to treatment | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE of >= CTCAE Grade 3 | 2 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE leading to discontinuation of IP and possibly related to treatment (IP) | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE with outcome death | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE possibly related to treatment | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE of greater than or equal to (>=) CTCAE Grade 3 | 4 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any serious adverse event (SAE) | 2 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE | 6 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE of >= CTCAE Grade 3 possibly related to treatment | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to discontinuation of IP and possibly related to treatment | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE possibly related to treatment | 2 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to interruption of IP | 1 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any AE leading to discontinuation of IP | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE of >= CTCAE Grade 3 possibly related to treatment | 0 Participants |
| AZD8853 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any SAE leading to discontinuation of IP | 0 Participants |
Secondary
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.
Time frame: 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)
Population: PK analysis set included all participants who received at least one dose of IP with at least one reportable concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD8853 300 mg | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUCinf) of AZD8853 | 14580 h*ug/mL | Standard Deviation 4136 |
| AZD8853 1000 mg | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUCinf) of AZD8853 | 67480 h*ug/mL | Standard Deviation 18490 |
| AZD8853 3000 mg | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUCinf) of AZD8853 | 223700 h*ug/mL | Standard Deviation 79270 |
Secondary
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.
Time frame: 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)
Population: PK analysis set included all participants who received at least one dose of IP with at least one reportable concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD8853 300 mg | Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUClast) of AZD8853 | 10080 Hours*microgram per milliliter (h*ug/mL) | Standard Deviation 1789 |
| AZD8853 1000 mg | Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUClast) of AZD8853 | 49210 Hours*microgram per milliliter (h*ug/mL) | Standard Deviation 12130 |
| AZD8853 3000 mg | Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUClast) of AZD8853 | 161100 Hours*microgram per milliliter (h*ug/mL) | Standard Deviation 43070 |
Secondary
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.
Time frame: 15 weeks
Population: Response evaluable set included all dosed participants who had measurable disease at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD8853 300 mg | Disease Control Rate (DCR) at 15 Weeks | 1 Participants |
| AZD8853 1000 mg | Disease Control Rate (DCR) at 15 Weeks | 0 Participants |
| AZD8853 3000 mg | Disease Control Rate (DCR) at 15 Weeks | 1 Participants |
Secondary
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.
Time frame: First documented response until date of first documented disease progression or study end (1 Year)
Population: Response evaluable set included all dosed participants who had measurable disease at baseline. Only participants in the response evaluable set who had a response were planned to include. However, data was not evaluated for this outcome measure as there were no objective responses available for any participant at any dose level.
Secondary
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.
Time frame: 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)
Population: PK analysis set included all participants who received at least one dose of IP with at least one reportable concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD8853 300 mg | Maximum Observed Concentration (Cmax) of AZD8853 | 76.70 Micrograms per milliliter (ug/mL) | Standard Deviation 3.439 |
| AZD8853 1000 mg | Maximum Observed Concentration (Cmax) of AZD8853 | 339.5 Micrograms per milliliter (ug/mL) | Standard Deviation 96.74 |
| AZD8853 3000 mg | Maximum Observed Concentration (Cmax) of AZD8853 | 1121 Micrograms per milliliter (ug/mL) | Standard Deviation 225.9 |
Secondary
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.
Time frame: From Day 1 up to 90 (±7 days) days after the last dose of AZD8853 (1 year)
Population: Immunogenicity analysis set included all participants who received at least one dose of IP who have a non-missing baseline ADA result and at least 1 non-missing post-baseline ADA result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD8853 300 mg | Number of Participants With Positive Anti-drug Antibody (ADA) of AZD8853 | 1 Participants |
| AZD8853 1000 mg | Number of Participants With Positive Anti-drug Antibody (ADA) of AZD8853 | 1 Participants |
| AZD8853 3000 mg | Number of Participants With Positive Anti-drug Antibody (ADA) of AZD8853 | 0 Participants |
Secondary
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.
Time frame: First dose until progression of disease (PD) or last evaluable assessment in the absence of progression (1 Year)
Population: Response evaluable set included all dosed participants who had measurable disease at baseline. Here, number of participants analyzed specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD8853 300 mg | Objective Response Rate (ORR) | 0 Participants |
| AZD8853 1000 mg | Objective Response Rate (ORR) | 0 Participants |
| AZD8853 3000 mg | Objective Response Rate (ORR) | 0 Participants |
Secondary
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.
Time frame: First dose until study end (1 Year)
Population: Safety set included all participants who received any amount of IP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD8853 300 mg | Overall Survival (OS) | 4.47 Months |
| AZD8853 1000 mg | Overall Survival (OS) | 5.45 Months |
| AZD8853 3000 mg | Overall Survival (OS) | NA Months |
Secondary
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.
Time frame: 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)
Population: PK analysis set included all participants who received at least one dose of IP with at least one reportable concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD8853 300 mg | Partial Area Under the Plasma Concentration-time Curve From Time 0 to 504 Hours Post Dose (AUC[0-504 Hours]) of AZD8853 | 11870 h*ug/mL | Standard Deviation 2385 |
| AZD8853 1000 mg | Partial Area Under the Plasma Concentration-time Curve From Time 0 to 504 Hours Post Dose (AUC[0-504 Hours]) of AZD8853 | 57230 h*ug/mL | Standard Deviation 14760 |
| AZD8853 3000 mg | Partial Area Under the Plasma Concentration-time Curve From Time 0 to 504 Hours Post Dose (AUC[0-504 Hours]) of AZD8853 | 189400 h*ug/mL | Standard Deviation 56040 |
Secondary
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
Time frame: 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
Population: PD analysis set included all participants who received at least one dose of IP with at least one reportable concentration. Here, number of participants analyzed specifies all participants who were evaluated for this outcome measure and n (number analyzed in each raw) signifies the participants with available data that were analyzed for each timepoint for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8853 300 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 1 Day 1: 0 hours post EOI | -97.7850 Percentage change from baseline in GDF15 | Standard Deviation 0.1917 |
| AZD8853 300 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 2 Day 1 (Pre-dose) | 324.2284 Percentage change from baseline in GDF15 | Standard Deviation 103.7778 |
| AZD8853 300 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 3 Day 1 (Pre-dose) | 636.8307 Percentage change from baseline in GDF15 | — |
| AZD8853 300 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | 90 Days Follow-Up: 90 days post EOT | 2164.2547 Percentage change from baseline in GDF15 | — |
| AZD8853 1000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | 90 Days Follow-Up: 90 days post EOT | 1311.2845 Percentage change from baseline in GDF15 | — |
| AZD8853 1000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 1 Day 1: 0 hours post EOI | -99.2637 Percentage change from baseline in GDF15 | Standard Deviation 0.1161 |
| AZD8853 1000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 3 Day 1 (Pre-dose) | 770.4598 Percentage change from baseline in GDF15 | Standard Deviation 520.3336 |
| AZD8853 1000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 2 Day 1 (Pre-dose) | 411.2175 Percentage change from baseline in GDF15 | Standard Deviation 345.6173 |
| AZD8853 3000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | 90 Days Follow-Up: 90 days post EOT | 2513.913 Percentage change from baseline in GDF15 | — |
| AZD8853 3000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 2 Day 1 (Pre-dose) | 165.9668 Percentage change from baseline in GDF15 | Standard Deviation 82.9703 |
| AZD8853 3000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 3 Day 1 (Pre-dose) | 212.5270 Percentage change from baseline in GDF15 | Standard Deviation 111.5861 |
| AZD8853 3000 mg | Percentage Change From Baseline in Circulating Growth Differentiation Factor 15 (GDF15) Serum Levels | Cycle 1 Day 1: 0 hours post EOI | -99.7472 Percentage change from baseline in GDF15 | — |
Secondary
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.
Time frame: Baseline (pre-treatment) up to Week 6 and Week 15
Population: Response evaluable set included all dosed participants who had measurable disease at baseline. Here, n (number analyzed in each raw) signifies the participants with available data that were analyzed for each timepoint for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AZD8853 300 mg | Percentage Change From Baseline in Tumor Size | Week 6 | 10.1 Percentage change in tumor size |
| AZD8853 300 mg | Percentage Change From Baseline in Tumor Size | Week 15 | 46.5 Percentage change in tumor size |
| AZD8853 1000 mg | Percentage Change From Baseline in Tumor Size | Week 6 | 10.9 Percentage change in tumor size |
| AZD8853 1000 mg | Percentage Change From Baseline in Tumor Size | Week 15 | 5.7 Percentage change in tumor size |
| AZD8853 3000 mg | Percentage Change From Baseline in Tumor Size | Week 6 | 14.9 Percentage change in tumor size |
| AZD8853 3000 mg | Percentage Change From Baseline in Tumor Size | Week 15 | 70.0 Percentage change in tumor size |
Secondary
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.
Time frame: 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)
Population: Safety set included all participants who received any amount of IP. Here, number of participants analyzed specifies all participants who were evaluated for this outcome measure and n (number analyzed in each raw) signifies the participants with available data that were analyzed for each timepoint for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD8853 300 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 7 Day 1 | 67.8182 Percentage change from baseline in ctDNA | — |
| AZD8853 300 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 1 Day 8 | 74.3700 Percentage change from baseline in ctDNA | Standard Deviation 103.62 |
| AZD8853 300 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 2 Day 1 | 92.1105 Percentage change from baseline in ctDNA | Standard Deviation 83.4783 |
| AZD8853 300 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 2 Day 8 | 101.0003 Percentage change from baseline in ctDNA | Standard Deviation 63.4941 |
| AZD8853 300 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 3 Day 1 | 64.9807 Percentage change from baseline in ctDNA | Standard Deviation 22.7578 |
| AZD8853 300 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 4 Day 1 | -8.3636 Percentage change from baseline in ctDNA | — |
| AZD8853 300 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 5 Day 1 | 64 Percentage change from baseline in ctDNA | — |
| AZD8853 1000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 2 Day 8 | 84.2143 Percentage change from baseline in ctDNA | Standard Deviation 101.808 |
| AZD8853 1000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 1 Day 8 | 30.2546 Percentage change from baseline in ctDNA | Standard Deviation 98.8909 |
| AZD8853 1000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 3 Day 1 | 131.5277 Percentage change from baseline in ctDNA | Standard Deviation 161.3495 |
| AZD8853 1000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 5 Day 1 | 50.4363 Percentage change from baseline in ctDNA | — |
| AZD8853 1000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 4 Day 1 | 50.2904 Percentage change from baseline in ctDNA | Standard Deviation 54.832 |
| AZD8853 1000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 2 Day 1 | 32.1430 Percentage change from baseline in ctDNA | Standard Deviation 48.906 |
| AZD8853 3000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 2 Day 8 | 116.3071 Percentage change from baseline in ctDNA | Standard Deviation 192.7165 |
| AZD8853 3000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 1 Day 8 | 10.7795 Percentage change from baseline in ctDNA | Standard Deviation 53.1457 |
| AZD8853 3000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 2 Day 1 | 20.7386 Percentage change from baseline in ctDNA | Standard Deviation 78.4507 |
| AZD8853 3000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 3 Day 1 | 26.9231 Percentage change from baseline in ctDNA | — |
| AZD8853 3000 mg | Percentage Change in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Levels From Baseline | Cycle 4 Day 1 | 21.4744 Percentage change from baseline in ctDNA | — |
Secondary
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.
Time frame: First dose until documented disease progression or study end (1 Year)
Population: Safety set included all participants who received any amount of IP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD8853 300 mg | Progression Free Survival (PFS) | 1.31 Months |
| AZD8853 1000 mg | Progression Free Survival (PFS) | 1.23 Months |
| AZD8853 3000 mg | Progression Free Survival (PFS) | 1.25 Months |