Solid Tumors
Conditions
Keywords
Solid Tumors
Brief summary
Study D7880C00001 is a first-in-human (FIH), Phase 1, open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of MEDI9253 in combination with durvalumab in adult participants with select advanced/metastatic solid tumors.
Detailed description
Up to approximately 192 participants may be assigned to study intervention in the study across approximately 30 sites globally.
Interventions
BIOLOGICALMEDI9253
Participants will receive either single or multiple dose of MEDI9253; sequentially or concurrent with Durvalumab
BIOLOGICALDurvalumab
Participants will receive durvalumab treatment sequentially or concurrently with MEDI9253
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 101 Years
Healthy volunteers
No
Inclusion criteria
1. Participant must be at least 18 years old at signing of informed consent. 2. Body weight \> 35 kg at screening.
Exclusion criteria
1 Primary central nervous system (CNS) disease is excluded, as well as untreated or uncontrolled metastatic CNS involvement, leptomeningeal disease, or cord compression. NOTE: CNS disease that has been treated and stable/controlled for at least 3 months is permitted. Participants with CNS disease controlled via systemic steroids are not permitted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Day 1 through 76.14 weeks (maximum observed duration) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, important medical event, congenital anomaly/birth defect (in the offspring of the subject). The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. |
| Number of Participants With Dose-limiting Toxicities (DLTs) | From the first dose of MEDI9253 through Day 14 (single dose cohorts) or Day 28 (multiple dose cohorts) | DLT: Any study drug-related Grade (G) 3 or higher toxicity; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) together with total bilirubin (TBL) ≥ 2 × ULN; Grade ≥ 2 myocarditis; Grade 2 non-infectious pneumonitis that does not resolve to ≤ G 1 within 7 days; any ≥ G 2 MEDI9253-related toxicity that prevents the administration of more than 1 dose of MEDI9253; in the sequential dosing cohorts, any ≥ Grade 2 MEDI9253-related toxicity that prevents administration of the first dose of durvalumab; any AE that after consultation with the sponsor and investigators, is deemed to be a DLT. |
| Number of Participants With TEAEs Leading to Discontinuation | Day 1 through 76.14 weeks (maximum observed duration) | Participants were permanently discontinued (PED) due to TEAE if: an AE that in the opinion of the investigator or the sponsor, warrants discontinuation of further dosing; an AE that met the criteria for a DLT during the DLT-evaluation period (from the first dose of MEDI9253 through Day 14 \[single dose cohorts\] or Day 28 \[multiple dose cohorts\]) unless criteria for initiation of durvalumab are met; an AE that required permanent discontinuation of study drug per toxicity management guidelines. |
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | Day 1 through 76.14 weeks (maximum observed duration) | Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, blood pressure, pulse oximetry \[on MEDI9253 dosing days only\], pulse rate, and respiratory rate). |
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs | Day 1 through 76.14 weeks (maximum observed duration) | Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, and urinalysis. |
| Number of Participants With Abnormal Electrocardiogram (ECG) Parameters Reported as TEAEs | Day 1 through 76.14 weeks (maximum observed duration) | Number of participants with abnormal ECG reported as TEAEs are reported. |
| Number of Participants With Abnormal Physical Examination Reported as TEAEs | Day 1 through 76.14 weeks (maximum observed duration) | Number of participants with abnormal physical examination reported as TEAEs are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Interleukin (IL)-12 Concentrations for Single Dose Cohorts | Pre-dose, 1, 2, 4, 6, 9, 12, 24, 32, 40, 48, 72 hours and Days 7, 14, 21, 42 post end of infusion, and Durvalumab Cycle 3 (each cycle is 28 days) pre-dose | The plasma IL-12 concentrations for single dose cohorts are reported. |
| Plasma IL-12 Concentrations for Multiple Dose Cohorts | Pre-dose, end of infusion, 1 day post dose on Days 1, 8, and 15; and 7 days post Dose 3; Durvalumab Cycle 1 (each cycle is 28 days)-Days 29, 36; Cycle 2-Days 36, 57; Cycle 3 Pre-dose Days 64, 85 | The plasma IL-12 concentrations for multiple dose cohorts are reported. |
| Cluster of differentiation (CD) 8 T cell Density as Assessed by Immunohistochemistry (IHC) | Baseline (Day -28 to -Day 1) and on Days 8, 15, 36, and 57 | The mean CD8 T cell density by IHC is reported. |
| Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks) | The OR is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 criteria that occurs prior to the initiation of subsequent anticancer treatment and prior to progression. The CR is defined as disappearance of all target lesions (TLs) and non-target lesions (NTLs) present at baseline, any pathological lymph nodes selected as TLs or non-pathological lymph nodes of NTLs must have a reduction in short axis to \< 10mm. The PR is defined as at least a 30% decrease in the sum of diameters of TLs, taking as reference the baseline sum of diameters as long as criteria for progressive disease (PD) are not met. PD is defined as ≥ 20% increase in the sum of diameters of TLs and an absolute increase of ≥ 5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters and unequivocal progression of existing NTLs. Percentage of participants with OR is reported. |
| Percentage of Combined Tumor and Immune PD-L1 Positive Tumor Cells in Tumor Areas as Assessed by IHC | Baseline (Day -28 to -Day 1) and on Days 8, 15, 36, and 57 | The percentage of combined tumor and immune PD-L1 positive tumor cells in tumor areas as assessed by IHC is reported. |
| Number of Participants with Positive Neutralizing Antibody (nAb) Response to MEDI9253 | Baseline (pre-dose Day 1), Cycle 1 (each cycle is 28 days) Day 22, Cycle 2 Day 1, Cycle 3 Day 1, and 28 days after the last dose (7.47 weeks) | Number of participants with positive nAb response to MEDI9253 is reported. Persistent positive is defined as positive at ≥ 2 post-baseline assessments (with ≥ 16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive is complement of persistent positive. Treatment boosted nAb is defined as baseline nAb titer that was boosted to a 4-fold or higher-level following study drug administration. Treatment emergent nAb is defined as the sum of treatment-induced nAb (post-baseline positive only) and treatment-boosted nAb. |
| Percentage of Programmed Cell Death Ligand 1 (PD-L1) Positive Tumor Cells by IHC | Baseline (Day -28 to -Day 1) and on Days 8, 15, 36, and 57 | The percentage of PD-L1 positive tumor cells by IHC is reported. |
| Time to Response (TTR) According to RECIST V1.1 | Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks) | The TTR is defined as the time from first dose until the first documentation of a subsequently confirmed OR. The OR is defined as confirmed CR or PR based on RECIST v1.1 criteria that occurs prior to the initiation of subsequent anticancer treatment and prior to progression. Only participants who have achieved confirmed CR or PR were evaluated for TTR. TTR was assessed using Kaplan-Meier methods. |
| Percentage of Participants With Disease Control Rate (DCR) at 16 Weeks According to RECIST v1.1 | Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks) | The DCR at 16 weeks is defined as a best overall response of confirmed CR or PR or having stable disease (SD) (without subsequent cancer therapy) maintained for ≥ 15 weeks from first dose. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as a ≥ 20% increase in the sum of diameters of TLs and an absolute increase of ≥ 5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Percentage of participants who have disease control at 16 weeks is reported. |
| Progression Free Survival (PFS) According to RECIST v1.1 | Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks) | The PFS is defined as the time from first dose until the date of first documented PD or death (by any cause in the absence of disease progression), regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy. Median number of months of PFS assessed via Kaplan-Meier method is reported. Here, number of participants analyzed denotes those participants who had PFS event. |
| Overall Survival (OS) | Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks) | The OS is defined as the time from the date of first dose until death due to any cause regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy. Median number of months of OS assessed using Kaplan-Meier method is reported. Here, number of participants analyzed denotes those participants who had an event. |
| Whole Blood Viral Genome Concentrations of MEDI9253 for Single Dose Cohorts | Pre-dose, end of infusion (EOI); 1, 2, 4, 6, 9, 12, 24, 32, 40, 48, 72 hours and Days 7, 14, 21, 42 post EOI in Cycle 1 (each cycle is 28 days); and Durvalumab Cycle 3 pre-dose | The whole blood viral genome concentrations of MEDI9253 for single dose cohorts are reported. |
| Whole Blood Viral Genome Concentrations of MEDI9253 for Multiple Dose Cohorts | Pre-dose, end of infusion, 1 day post dose on Days 1, 8, and 15; and 7 days post Dose 3; Durvalumab Cycle 1 (each cycle is 28 days)-Days 29, 36; Cycle 2-Days 36, 57; Cycle 3 Pre-dose Days 64, 85 | The whole blood viral genome concentrations of MEDI9253 for multiple dose cohorts are reported. |
Countries
France, United States
Outcome results
None listed