First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours

Study Overview
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Brief Summary
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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
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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).

Official Title
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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.

Conditions
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Clear Cell Renal Cell Cancer, Non-Small-Cell Lung Cancer, Triple Negative Breast Neoplasms, Squamous Cell Cancer of Head and Neck, Small Cell Lung Cancer, Gastroesophageal Cancer, Melanoma, Cervical Cancer, Advanced Solid Tumours

Intervention / Treatment
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* Drug: AZD8701
* Biological: Durvalumab


Participation Criteria
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Eligibility Criteria
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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 Male and Female participants of childbearing potential must use effective methods of contraception Capable of giving signed informed consent ECOG performance status of 0 to 1 A serum albumin > 30g/L Life expectancy of > 12 weeks At least 1 lesion, that qualifies as a RECIST 1.1 target lesion at baseline. Tumour assessment by CT scan or MRI must be performed within 28 days prior to treatment. Participants must provide a new or previous tumour sample Adequate organ system functions 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 Any major unresolved toxicity from previous anticancer therapy Known allergy or hypersensitivity to any of the study interventions or any of the study intervention excipients. Prior/Concomitant Therapy Receipt of the last dose of anticancer therapy within 5 half-lives or ≤ 21 days prior to the first dose of study Prior treatment with potential Treg depletion therapies including agents targeting OX40 or CD357 (GITR) for 90 days prior to enrolment on study. Participants who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4: Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline Must not have experienced a ≥ Grade 3 imAE or a neurologic or ocular imAE of any grade while receiving prior immunotherapy. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE Current or prior use of immunosuppressive medication within 14 days before the first dose of study drug. b. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection). Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study intervention. Major surgical procedure within 28 days prior to the first dose Participants receiving anticoagulation therapy with vitamin K antagonists (eg warfarin) Participation in another clinical study with study intervention administered in the last 30 days Female participants who are pregnant or breastfeeding or male and female participants of reproductive potential who are not willing to employ effective birth control

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 101 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a Phase I, FIH, multicentre, open-label, multiple arm study. Dose-escalation will occur with AZD8701 in monotherapy and in combination with durvalumab in selected participants with HNSCC, TNBC, NSCLC, ccRCC, gastroesophgeal 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 and with a selected dose of AZD8701 and durvalumab in participants with TNBC and clear cell RCC.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy<br>Participants will receive AZD8701 intravenously, on Day 1, 3, 5 and 8 and then weekly for a maximum of 2 years. | Drug: AZD8701<br>* FOXP3 antisense oligonucleotide<br>|
| Experimental: Combination Therapy<br>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. | Drug: AZD8701<br>* FOXP3 antisense oligonucleotide<br>Biological: Durvalumab<br>* anti PDL-1 monoclonal antibody<br>* Other names: MEDI4736;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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) | 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 | 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 | 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 | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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) | 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 | 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) | 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 | 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 | The survival rate of subjects at 18 months from start of treatment | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | From day 1 to day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumours, Durvalumab, MEDI4736, AZD8701, Non Small cell Lung cancer, ccRenal Cancer, TNBC, first time in human, PD-L1, T regulatory cells, FOXP3