Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours

Study Overview
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Brief Summary
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The proposed study is designed to examine the effects of AZD0171 and durvalumab in combination with standard-of-care chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC).

Detailed Description
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This is a Phase II, open-label, single arm, multicentre study to assess the safety, preliminary antitumour activity, immunogenicity, pharmacodynamics (PD), and pharmacokinetics (PK) of AZD0171 in combination with durvalumab and standard-of-care chemotherapy (gemcitabine and nab-paclitaxel) in participants with first line (1L) metastatic pancreatic ductal adenocarcinoma (mPDAC). All participants will be treated until progressive disease or unacceptable toxicity or withdrawal of consent or another discontinuation criterion is met.

Official Title
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A Phase II Study to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumours

Conditions
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Locally Advanced or Metastatic Solid Tumours

Intervention / Treatment
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* Drug: AZD0171
* Drug: Durvalumab
* Drug: Gemcitabine
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group performance status of 0 or 1 at screening/enrolment Must have a Gustave Roussy Immune Score of 0 or 1 Participants diagnosed with histologically confirmed metastatic pancreatic adenocarcinoma Participants must have at least 1 measurable lesion to be called a target lesion according to RECIST v1.1 All participants must consent to providing sufficient archival specimen taken during metastatic stage or fresh tumour specimens for tumoural CD8+ T cell testing for enrolment Presence of tumoural CD8+ T cells based on a predetermined benchmarked PDAC external sample Normal organ and bone marrow function measured within 28 days prior to first dose of study intervention Body weight ≥ 35 kg Exclusion Criteria: Symptomatic central nervous system metastasis or any history of leptomeningeal disease or cord compression A participant with an already known sensitising mutation or tumour characteristic for pancreatic cancer for which there is a preferred local standard-of-care treatment History of thromboembolic event within the past 3 months prior to the scheduled first dose of study intervention Any unresolved toxicities ≥ Grade 2 per Common Terminology Criteria for Adverse Events v5.0 from prior therapy (excluding vitiligo, alopecia, controlled diabetes) History of solid organ transplantation History of active primary immunodeficiency Ongoing or an active infection, including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus. A negative COVID-19 PCR test taken within 28 days of the start of the study treatment is required. Uncontrolled intercurrent illness Participants with prior history of myocardial infarction, transient ischemic attack, coronary bypass, or stroke within the past 3 months prior to the first dose of study intervention Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 electrocardiograms Active or prior documented autoimmune or inflammatory disorders History of another primary malignancy Receipt of any conventional or investigational anticancer therapy prior to the scheduled first dose of study intervention Prior receipt of any immune-mediated therapy Use of immunosuppressive medication within 14 days prior to the first dose of study intervention Receipt of live, attenuated vaccine within 28 days prior to the first dose of study intervention (Participants can receive non-live COVID-19 vaccines, at the discretion of the Investigator)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD0171 + Durvalumab + chemotherapy<br>Participants will receive AZD0171 (intravenous [IV]) along with durvalumab (IV) in combination with standard-of-care chemotherapy IV (gemcitabine and nab-paclitaxel). | Drug: AZD0171<br>* AZD0171<br>* Other names: MSC-1;Drug: Durvalumab<br>* Durvalumab<br>* Other names: MEDI4736;Drug: Gemcitabine<br>* Chemotherapy (Standard-of-Care)<br>Drug: Nab-paclitaxel<br>* Chemotherapy (Standard-of-Care)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs), immune mediated AEs (imAEs) and serious AEs (SAEs) | Assessment of safety and tolerability of study intervention (AZD0171, durvalumab, and standard-of-care chemotherapy). | Until Day 90 (post last dose of study intervention on Day 15) | 
| Overall survival at 12 months (OS-12) | Percentage of participants alive at 12 months after initiation of study intervention per Kaplan- Meier estimate of OS at 12 months. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Assessment of efficacy of study intervention according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) using investigator assessment of disease response. The percentage of response evaluable participants with a confirmed response of complete response (CR) or partial response (PR). | Up to 24 months | 
| Disease control rate (DCR) | Assessment of the efficacy of study intervention according to RECIST v1.1. The DCR is defined as the percentage of participants according to RECIST v1.1 with a confirmed response or stable disease maintained for 16 weeks. | Up to 24 months | 
| Duration of response (DoR) | Assessment of the efficacy of study intervention according to RECIST 1.1. The DoR is defined as the time from first documented response until date of documented disease progression or death. | Up to 24 months | 
| Median progression free survival (PFS) | PFS is defined as the time from first dose of study intervention until the date of objective disease progression or death. | Up to 24 months | 
| PFS at 4 months (PFS-4) | Percentage of participants free of progression at 4 months per Kaplan-Meier estimate. | 4 months | 
| Median overall survival (OS) | OS is defined as the time from the start of study intervention to the date of death due to any causes. | Up to 24 months | 
| Number of participants with change from Baseline in serum levels of carbohydrate antigen 19-9 (CA19-9) | Percentage change in local laboratory assessed serum CA19-9 from baseline. | From Screening (Day -28 to Day -1) until Day 28 post last dose of study intervention on Day 15 | 
| Number of participants developing detectable anti-drug antibodies (ADAs) against AZD0171 and/or durvalumab in serum | Immunogenicity of AZD0171 and/or durvalumab will be assessed. | Up to Day 90 post last dose of study intervention on Day 15 | 
| The PK profile of AZD0171, durvalumab and chemotherapy- Maximum observed plasma concentration (Cmax) | The PK profile of AZD0171, durvalumab and chemotherapies and/or their metabolites will be determined. | At predefined intervals from first dose of study intervention up to Day 90 post last dose of study intervention on Day 15 | 
| The PK profile of AZD0171, durvalumab and chemotherapy - Area under the concentration-time curve (AUC) | The PK profile of AZD0171, durvalumab and chemotherapies and/or their metabolites will be determined. | At predefined intervals from first dose of study intervention up to Day 90 post last dose of study intervention on Day 15 | 
| The PK profile of AZD0171, durvalumab and chemotherapy - Clearance (CL) | The PK profile of AZD0171, durvalumab and chemotherapies and/or their metabolites will be determined. | At predefined intervals from first dose of study intervention up to Day 90 post last dose of study intervention on Day 15 | 
| The PK profile of AZD0171, durvalumab and chemotherapy - Terminal elimination half-life (t1/2) | The PK profile of AZD0171, durvalumab and chemotherapies and/or their metabolites will be determined. | At predefined intervals from first dose of study intervention up to Day 90 post last dose of study intervention on Day 15 | 
| Participants with changes from Baseline in cluster of differentiation 8 (CD8+) T cell tumour infiltration in tumour samples | The changes in CD8+ T cell tumour infiltration associated with AZD0171 treatment in combination with durvalumab and chemotherapy will be assessed in participants with 1L mPDAC. | Up to 24 months | 
| Change from baseline in leukaemia inhibitory factor (LIF) bound to AZD0171 (total LIF) | The absolute values and the change from baseline in LIF bound to AZD0171 (total LIF) will be assessed. | At predefined intervals from first dose of study intervention up to Cycle 11 (each cycle is 28 days in length) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD0171, Durvalumab, Gemcitabine, Nab-paclitaxel, Leukaemia inhibitory factor, Pancreatic ductal adenocarcinoma, Immunotherapy