The purpose of this study is to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Antitumor Activity of AZD8701 Alone and in Combination with Durvalumab (MEDI4736) in Adult Subjects with Select Advanced Solid Tumors
This is a Phase I, First in Human, multicentre, open-label, multiple arm study with dose escalations and expansions at selected doses. Dose-escalation will occur with AZD8701 in monotherapy (Part 1) and in combination with durvalumab (Part 3) in selected participants with HNSCC, TNBC, NSCLC, ccRCC, gastroesophageal cancer, melanoma, cervical cancer, small-cell lung cancer and/or participants with solid tumours who have demonstrated a response to prior PD-(L)1 treatment. Disease specific expansions will occur with a selected dose of AZD8701 in participants with NSCLC (Part 2) and with a selected dose of AZD8701 and durvalumab in participants with TNBC and clear cell RCC (Part 4).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
FOXP3 antisense oligonucleotide
anti PDL-1 monoclonal antibody
Research Site
Baltimore, Maryland, United States
Research Site
St Louis, Missouri, United States
Research Site
Huntersville, North Carolina, United States
Research Site
Franklin, Tennessee, United States
Research Site
Houston, Texas, United States
Research Site
Madison, Wisconsin, United States
Research Site
Toronto, Ontario, Canada
Research Site
Rennes, France
Research Site
Villejuif, France
Research Site
Barcelona, Spain
...and 3 more locations
Maximum Tolerated dose (or optimal dose or maximum feasible dose) and RP2D of AZD8701 as monotherapy and in combination with Durvalumab assessed through evaluation of AEs and SAEs
Determined according to Incidence and treatment related AEs and SAEs
Time frame: From screening until 105 days after last dose of study treatment
Maximum Tolerated dose (or optimal dose or maximum feasible dose) and RP2D of AZD8701 as monotherapy and in combination with Durvalumab assessed through evaluation of Dose Limiting Toxicities (DLTs)
Determined according to Incidence of DLTs (during the first 28 day cycle)
Time frame: First 28 day cycle
Maximum Tolerated dose (or optimal dose or maximum feasible dose) and RP2D of AZD8701 as monotherapy and in combination with Durvalumab assessed through evaluation of vital signs and abnormal laboratory parameters
Determined according to Incidence of abnormal vital signs and laboratory parameters
Time frame: From screening until 105 days after last dose of study treatment
Incidence of AEs and SAEs related to AZD8701 as monotherapy and in combination with Durvalumab in disease specific expansions treated at the MTD/OBD/MFD
Safety and tolerability of the MTD/OBD/MFD assessed through incidence of AEs and SAEs
Time frame: From screening until 105 days after last dose of study treatment
Objective Response Rate according to RECIST 1.1 by investigator assessment in disease specific expansions treated at the MTD/OB/MFD
The proportion of subjects achieving a confirmed complete or partial response according to RECIST 1.1 by investigator assessment
Time frame: Every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death, start of subsequent anti-cancer therapy or end of study (for max 42 months)
Progression-free survival according to RECIST 1.1 by investigator assessment
Time from start of study treatment to the date of objective disease progression or death (by any cause in the absence of progression)
Time frame: every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death or end of study (for max 42 months)
Duration of Response according to RECIST 1.1 by investigator assessment
Time from first documented response (that is subsequently confirmed) to the date of objective disease progression or death (by any cause in the absence of progression)
Time frame: every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death or end of study (for max 42 months)
Disease Control Rate at 16 weeks according to RECIST 1.1 by investigator assessment
The proportion of subjects with a best response of CR or PR in the first 16 weeks or SD for at least 16 weeks according to RECIST 1.1 by investigator assessment
Time frame: Every 8 weeks from start of treatment until earlier of progression, death or start of subsequent anti-cancer therapy (for up to 24 weeks). Subjects followed to 24 weeks for assessment of SD for 16 weeks from first tumour assessment at 8 weeks
Time to Response according to RECIST 1.1 by investigator assessment
Time from the start of study treatment until the date of first documented response (which is subsequently confirmed)
Time frame: Every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death or end of study (for max 42 months)
Best percentage change in tumour size according to RECIST 1.1 by investigator assessment
Best percentage change from baseline in sum of the diameters of target lesions
Time frame: Every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death, start of subsequent anti-cancer therapy or end of study (for max 42 months)
Overall Survival at 18 months
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The survival rate of subjects at 18 months from start of treatment
Time frame: From start of treatment until the earlier of death or end of study (for max of 42 months). Each subject is followed for a minimum of 18 months and the landmark OS rate at 18 months will be estimated using a Kaplan-Meier analysis
Maximum concentration (Cmax) of AZD8701 in plasma when administered as monotherapy and in combination with Durvalumab
Maximum concentration (Cmax) of AZD8701 in plasma
Time frame: Cycle 1: Day 1, 2, 3, 5, 8. Cycle 2: Day 1, 22, 23. Cycle 3 & 4: Day 1 and at 105 day follow up (up to 28 months)
Time to maximum concentration (tmax) of AZD8701 in plasma when administered as monotherapy and in combination with Durvalumab
Time to maximum concentration (tmax) of AZD8701 in plasma
Time frame: Cycle 1: Day 1, 2, 3, 5, 8. Cycle 2: Day 1, 22, 23. Cycle 3 & 4: Day 1 and at 105 day follow up (up to 28 months)
Exposure to AZD8701 through measurement of area under the curve (AUC) in plasma when administered as monotherapy and in combination with Durvalumab
Exposure to AZD8701 through measurement of area under the curve (AUC) in plasma
Time frame: Cycle 1: Day 1, 2, 3, 5, 8. Cycle 2: Day 1, 22, 23. Cycle 3 & 4: Day 1 and at 105 day follow up (up to 28 months)
Maximum concentration (Cmax) of AZD8701 in urine when administered as monotherapy and in combination with Durvalumab
Maximum concentration (Cmax) of AZD8701 in urine
Time frame: Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Time to maximum concentration (tmax) of AZD8701 in urine when administered as monotherapy and in combination with Durvalumab
Time to maximum concentration (tmax) of AZD8701 in urine
Time frame: Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Exposure to AZD8701 through measurement of area under the curve (AUC) in urine when administered as monotherapy and in combination with Durvalumab
Exposure to AZD8701 through measurement of area under the curve (AUC) in urine
Time frame: Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Urine concentrations of AZD8701 to assess renal clearance when administered as monotherapy and in combination with Durvalumab
Urine samples will be collected to assess urine concentrations of AZD8701 at a series of timepoints to derive renal clearance
Time frame: Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Maximum concentration (Cmax) of Durvalumab in serum when administered in combination with AZD8701
Maximum concentration (Cmax) of Durvalumab in serum
Time frame: Cycle 1, 2, 3, 4 on Day 1 and 105 follow up (up to 28 months)
Minimum concentration (Cmin) of Durvalumab in serum when administered in combination with AZD8701
Minimum concentration (Cmin) of Durvalumab in serum
Time frame: Cycle 1, 2, 3, 4 on Day 1 and 105 follow up (up to 28 months)
Change in FOXP3 mRNA expression
Percentage change in FOXP3 mRNA expression from pre-treatment (baseline) to post treatment
Time frame: From day 1 to day 29