A Study of MEDI5395 in Combination With Durvalumab in Participants With Select Advanced Solid Tumors
- Conditions
- Advanced Solid Tumors
- Interventions
- Biological: MEDI5395Biological: Durvalumab
- Registration Number
- NCT03889275
- Lead Sponsor
- MedImmune LLC
- Brief Summary
The reason for the study is to find out if MEDI5395 and durvalumab will work and be safe for the treatment of solid tumors.
- Detailed Description
This is an Phase 1, first-in-human, open-label, dose-escalation, and dose-expansion study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of MEDI5395 in combination with durvalumab in participants with selected advanced solid tumors.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 39
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1A: MEDI5395 Dose Level 1 + Sequential Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 1 on Days 1, 4, 8, 10, 12, and 15 followed by durvalumab every 4 weeks (Q4W) starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 3B: MEDI5395 Dose Level 3 + Concurrent Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 3 on Days 1, 4, 8, 10, 12, and 15 and durvalumab Q4W, starting from the same day as third dose of MEDI5395, for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 3A Backfill: MEDI5395 Dose Level 3 + Sequential Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 2 on Day 1 and Dose Level 3 on Days 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 4A: MEDI5395 Dose Level 4 + Sequential Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 2 on Day 1 and Dose Level 4 on Days 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 1A: MEDI5395 Dose Level 1 + Sequential Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 1 on Days 1, 4, 8, 10, 12, and 15 followed by durvalumab every 4 weeks (Q4W) starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 2A: MEDI5395 Dose Level 2 + Sequential Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 2 on Days 1, 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 3A: MEDI5395 Dose Level 3 + Sequential Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 3 on Days 1, 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 3A Backfill: MEDI5395 Dose Level 3 + Sequential Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 2 on Day 1 and Dose Level 3 on Days 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 1B: MEDI5395 Dose Level 1 + Concurrent Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 1 on Days 1, 4, 8, 10, 12, and 15 and durvalumab Q4W, starting from the same day as third dose of MEDI5395, for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 2B: MEDI5395 Dose Level 2 + Concurrent Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 2 on Days 1, 4, 8, 10, 12, and 15 and durvalumab Q4W, starting from the same day as third dose of MEDI5395, for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 3B: MEDI5395 Dose Level 3 + Concurrent Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 3 on Days 1, 4, 8, 10, 12, and 15 and durvalumab Q4W, starting from the same day as third dose of MEDI5395, for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 2A: MEDI5395 Dose Level 2 + Sequential Durvalumab Durvalumab Participants will receive IV infusions of MEDI5395 Dose Level 2 on Days 1, 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 4A: MEDI5395 Dose Level 4 + Sequential Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 2 on Day 1 and Dose Level 4 on Days 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 3A: MEDI5395 Dose Level 3 + Sequential Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 3 on Days 1, 4, 8, 10, 12, and 15 followed by durvalumab Q4W starting from 14 days after the last dose of MEDI5395 for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 1B: MEDI5395 Dose Level 1 + Concurrent Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 1 on Days 1, 4, 8, 10, 12, and 15 and durvalumab Q4W, starting from the same day as third dose of MEDI5395, for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first. Cohort 2B: MEDI5395 Dose Level 2 + Concurrent Durvalumab MEDI5395 Participants will receive IV infusions of MEDI5395 Dose Level 2 on Days 1, 4, 8, 10, 12, and 15 and durvalumab Q4W, starting from the same day as third dose of MEDI5395, for maximum of 2 years or until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity; whichever occurs first.
- Primary Outcome Measures
Name Time Method Number of Participants with TEAEs Resulting in Permanent Discontinuation of Durvalumab From first dose of durvalumab through 14.4 months (corresponding to maximum observed duration) Number of participants with TEAEs resulting in permanent discontinuation of durvalumab are reported.
Number of Participants with TEAEs Resulting in Permanent Discontinuation of MEDI5395 From first dose of MEDI5395 through 14.4 months (corresponding to maximum observed duration) Number of participants with TEAEs resulting in permanent discontinuation of MEDI5395 are reported.
Maximum Reduction From Baseline in Global Longitudinal Strain (GLS) Values From first dose of MEDI5395 through 14.4 months (corresponding to maximum observed duration) Maximum reduction from baseline in GLS values are reported. The GLS \< 16% is abnormal, GLS \> 18% is normal, and GLS 16% to 18% is borderline.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) From first dose of MEDI5395 through 14.4 months (corresponding to 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; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. 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 Abnormal Electrocardiogram (ECG) Parameters Reported as TEAEs From first dose of MEDI5395 through 14.4 months (corresponding to maximum observed duration) Number of participants with abnormal ECG parameters reported as TEAEs are reported.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) From first dose of MEDI5395 through 14.4 months (corresponding to maximum observed duration) Change from baseline in LVEF values are reported.
Number of Participants with Dose-limiting Toxicities (DLT) Day 1 to Day 28 of first dose of MEDI5395 A DLT is defined as any toxicity not clearly and directly related to the primary disease or to another etiology and included: any Grade 3 or higher toxicity that occurs during the DLT evaluation period, aspartate aminotransferase or alanine aminotransferase \>= 3 × upper limit of normal (ULN) together with total bilirubin \>= 2 × ULN, where no other reason other than the study drugs, can be found to explain the combination of increases, Grade ≥ 2 myocarditis, Grade 2 non infectious pneumonitis that does not resolve to Grade ≤ 1 within 7 days of the initiation of maximal supportive care, any Grade \>= 2 MEDI5395 related toxicity that prevents administration of more than 1 dose of MEDI5395 within the 18-day dosing period, in sequential dosing cohorts, any Grade \>= 2 MEDI5395 related toxicity that prevents administration of the first dose of durvalumab, and any AE that, after consultation with the Sponsor and investigators, is deemed a DLT.
Number of Participants With Abnormal Vital Signs Reported as TEAEs From first dose of MEDI5395 through 14.4 months (corresponding to maximum observed duration) Number of participants with abnormal vital signs (blood pressure, pulse rate, respiration rate, oxygen saturation, and body temperature) reported as TEAEs are reported.
Number of Participants With Abnormal Laboratory Parameters Reported as TEAEs From first dose of MEDI5395 through 14.4 months (corresponding to maximum observed duration) Laboratory assessment included hematology, clinical chemistry, coagulation, cardiac parameters, and urinalysis. Participants with abnormal laboratory parameters reported as TEAEs are reported.
Number of Participants With at Least 1-Grade Shift From Baseline to Worst Post-baseline in Eastern Co-operative Oncology Group Performance Status (ECOG-PS) Score From first dose of MEDI5395 through 14.4 months (corresponding to maximum observed duration) ECOG performance status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. The scores are: 0 = Fully Active, able to carry out all pre-disease performance without restrictions; 1 = Restricted activity but ambulatory and able to carry out light work or work of a sedentary nature; 2 = Ambulatory and capable of self-care but unable to carry out work activities; 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely Disabled, unable to carry out any self-care and totally confined to bed or chair; 5 = Dead.
- Secondary Outcome Measures
Name Time Method Percentage of Participants with Disease Control (DC) per RECIST v1.1 Baseline (Day -28 to Day -1) through 24.5 months (corresponding to maximum observed duration) The DC is confirmed CR, PR, or stable disease (SD) per RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions (TLs and NTLs), normalization of tumor marker level, all lymph nodes (target and non-target) must be non-pathological in size (\<10 mm in short axis), and no new lesions. The PR is defined as at least a 30% decrease in sum of diameters (SoD) of TLs, taking as reference the baseline SoD and no new NTL. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. The SD is defined as neither sufficient shrinkage of TLs to qualify for PR nor sufficient increase of TLs to qualify for progressive disease (PD), taking as reference the smallest SoD while on study and no new lesions. The PD is defined as at least a 20% increase in SoD of TLs, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of SoD, or the appearance of new lesions.
Percentage of Programmed Cell Death Ligand 1 (PD-L1) Positivity in Tumor Cells Baseline (Pre-treatment) and on the Day of Dose 4 of MEDI5395 (Post-treatment) The PD-L1 expression was assessed by validated IHC assays using tumor tissue from an archival or newly obtained biopsy. Tumor cells were analyzed for PD-L1 expression to determine the tumor cells positivity for PD-L1.
Duration of Response (DoR) per RECIST v1.1 Baseline (Day -28 to Day -1) through 24.5 months (corresponding to maximum observed duration) DoR: Time from first documentation of OR to first documented PD or death due to any cause, whichever occurred first. OR: Confirmed CR or confirmed PR based on RECIST v1.1 guidelines. CR: Disappearance of all target and non-target lesions, normalization of tumor marker level, all lymph nodes (target and non-target) must be non-pathological in size (\< 10 mm in short axis), and no new lesions. PR: At least a 30% decrease in the SoD of target lesions, taking as reference the baseline sum diameters and no new lesions. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. PD: At least a 20% increase in SoD of target lesion, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of sum of diameters, or the appearance of new lesions. The DOR is estimated using the Kaplan-Meier method.
Tumoral Cluster of Differentiation 8 Positive (CD8+) Cell Density in Tumor Tissue Baseline (Pre-treatment) and on the Day of Dose 4 of MEDI5395 (Post-treatment) The CD8+ cells were assessed by validated immunohistochemical (IHC) assays using tumor tissue from an archival or newly obtained biopsy. The results of CD8+ cell density was reported as number of CD8+ positive cells per mm\^2.
Percentage of PD-L1 Positvity in Whole Biopsy Sample Baseline (Pre-treatment) and on the Day of Dose 4 of MEDI5395 (Post-treatment) The PD-L1 expression was assessed by validated IHC assays using tumor tissue from an archival or newly obtained biopsy. The whole biopsy sample (without differentiation between tumor or stromal/immune compartments) was analyzed for PD-L1 expression to determine total tissue positivity (TIP) for PD-L1.
Percentage of Participants with Objective Response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Baseline (Day -28 to Day -1) through 24.5 months (corresponding to maximum observed duration) The OR is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level and all lymph nodes (target and non-target) must be non-pathological in size (\< 10 mm in short axis). The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between.
Progression-Free Survival (PFS) per RECIST v1.1 Baseline (Day -28 to Day -1) through 24.5 months (corresponding to maximum observed duration) The PFS is defined as the time from the start of treatment with any study drug until the first documentation of disease progression or death due to any cause, whichever occurred first. Disease progression is defined as at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of sum of diameters, or the appearance of one or more new lesions. The PFS is estimated using the Kaplan-Meier method.
Time to Response (TTR) per RECIST v1.1 Baseline (Day -28 to Day -1) through 24.5 months (corresponding to maximum observed duration) The TTR is defined as the time from the start of treatment with any study drug until the first documentation of a subsequently confirmed OR. The OR is defined as confirmed CR or confirmed PR based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions, normalization of tumor marker level, all lymph nodes (target and non-target) must be non-pathological in size (\< 10 mm in short axis), and no new lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters and no new lesions. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. The TTR is assessed using the Kaplan-Meier method.
Overall Survival (OS) Baseline (Day -28 to Day -1) through 24.5 months (corresponding to maximum observed duration) The OS is defined as the time from the start of treatment with study drug until death due to any cause. The OS is estimated using the Kaplan-Meier method.
Viral Genome Concentration of MEDI5395 in Whole Blood Predose and end of infusion; on dose 1,2,3,4,5,6, 1 day(D) post Dose 1 and 6, 7 D post Dose 6 of MEDI5395/Cycle(C)1D15, C2D1, C3D1,C4D1, and C5D1 pre dose of durvalumab in both sequential and concurrent dosing; C1D1, C1D8, and C1D15 in sequential dosing Viral genome concentration of MEDI5395 in whole blood is reported.
Number of Participants With Positive Neutralizing Antibodies (nAbs) to MEDI5395 Day (D) of MEDI5395 (MEDI) Dose 1, 4, 6, D1 C1 and C2 of durvalumab in sequential dosing; on day of MEDI Dose 1, 4, 6; C1D15, C2D1 C3D1, C4D1 of durvalumab dose in concurrent dosing; within 28 days of last dose (LD) and 90 days post LD (14.4 months) Number of participants with positive nAbs to MEDI5395 are reported. Persistent positive is defined as positive at \>=2 post-baseline assessments (with \>=16 weeks between first and last positive assessment) or positive at last post-baseline assessment. Transient positive is defined as negative at the last post-baseline assessment and positive at only 1 post-baseline assessment or at \>= 2 post-baseline assessments (with \< 16 weeks between the first and last positive assessment).
Trial Locations
- Locations (1)
Research Site
🇬🇧London, United Kingdom