A Phase I First-in-Human Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AZD8701 Administered Intravenously as Monotherapy and in Combination With Durvaluamb (MEDI4736) in Participants With Advanced Solid Tumours.
Overview
- Phase
- Phase 1
- Intervention
- AZD8701
- Conditions
- Clear Cell Renal Cell Cancer
- Sponsor
- AstraZeneca
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- Objective Response Rate according to RECIST 1.1 by investigator assessment in disease specific expansions treated at the MTD/OB/MFD
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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
Detailed Description
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •The study is comprised of 2 main parts Monotherapy (AZD8701) and Combined Therapy (AZD8701 and Durvalumab).
- •Inclusion criteria Dose escalation stages:
- •Histological or cytological confirmation of a solid, malignant tumour including HNSCC, TNBC, NSCLC, ccRCC, gastroesophageal cancer, melanoma, cervical cancer, SCLC, and/or participants with other solid tumours who have demonstrated a response to prior anti-PD-(L)1 treatment
- •Participant with progressive disease that is refractory to standard therapies or for which no standard therapies exist and a clinical trial is the best option for next treatment based on prior response and/or tolerability to standard of care
- •Inclusion Criteria Dose Expansions:
- •Non Small Lung Cancer Participants who have received prior PD(L)1 treatment. Clear Cell Renal Cancer Participants who have not received prior PD(L)1 treatment.
- •Triple negative Breast Cancer participants who have who have not received prior PD(L)1 treatment.
- •General inclusion criteria:
- •Must be 18 year old at the time of screening
- •Body weight \> 35 kg
Exclusion Criteria
- •A condition that, in the opinion of the Investigator, would interfere with evaluation of the study intervention or interpretation of participant safety or study results
- •History of allogeneic organ transplantation.
- •Active or prior documented autoimmune or inflammatory disorders Uncontrolled intercurrent illness
- •Significant cardiac disease
- •History of another primary malignancy except for
- •Malignancy treated with curative intent and with no known active disease ≥ 5 years
- •non-melanoma skin cancer
- •Adequately treated carcinoma in situ without evidence of disease.
- •Participant with previous or confirmed Covid 19 diagnosis requiring significant medical intervention
- •Current clinical signs and symptoms consistent with COVID-19 or confirmed current infection by appropriate laboratory test within the last 4 weeks prior to screening
Arms & Interventions
Monotherapy
Participants will receive AZD8701 intravenously, on Day 1, 3, 5 and 8 and then weekly for a maximum of 2 years.
Intervention: AZD8701
Combination Therapy
Participants will receive AZD8701 (intravenously, on Day 1, 3, 5 and 8 and then weekly) and durvalumab (MEDI4736) intravenously monthly for a maximum of 2 years.
Intervention: AZD8701
Combination Therapy
Participants will receive AZD8701 (intravenously, on Day 1, 3, 5 and 8 and then weekly) and durvalumab (MEDI4736) intravenously monthly for a maximum of 2 years.
Intervention: Durvalumab
Outcomes
Primary Outcomes
Objective Response Rate according to RECIST 1.1 by investigator assessment in disease specific expansions treated at the MTD/OB/MFD
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)
The proportion of subjects achieving a confirmed complete or partial response according to RECIST 1.1 by investigator assessment
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
Time Frame: From screening until 105 days after last dose of study treatment
Determined according to Incidence and treatment related AEs and SAEs
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)
Time Frame: First 28 day cycle
Determined according to Incidence of DLTs (during the 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
Time Frame: From screening until 105 days after last dose of study treatment
Determined according to Incidence of abnormal vital signs and laboratory parameters
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
Time Frame: From screening until 105 days after last dose of study treatment
Safety and tolerability of the MTD/OBD/MFD assessed through incidence of AEs and SAEs
Secondary Outcomes
- Progression-free survival according to RECIST 1.1 by investigator assessment(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(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(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(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(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(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(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(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(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(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(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(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(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(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(Cycle 1, 2, 3, 4 on Day 1 and 105 follow up (up to 28 months))
- Change in FOXP3 mRNA expression(From day 1 to day 29)