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

Phase 2Active Not RecruitingNCT04999969

AstraZeneca126 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

126

Conditions

Locally Advanced or Metastatic Solid Tumours

Interventions

AZD0171DRUG

AZD0171

DurvalumabDRUG

Durvalumab

GemcitabineDRUG

Chemotherapy (Standard-of-Care)

Nab-paclitaxel

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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)

Locations (34)

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs), Immune Mediated AEs (imAEs) and Serious AEs (SAEs)

The safety and tolerability of study intervention (AZD0171, durvalumab, and standard-of-care chemotherapy) was assessed. The grading scales found in the revised National Cancer Institute CTCAE latest version was utilized for all events with an assigned CTCAE grading. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (ADL); Grade 4: Life-threatening, urgent intervention required; Grade 5: Death related to AE.

Time frame: From Cycle 1 Day 1 (each cycle was 28 days in length) until Day 90 (post last dose of study intervention), up to 34 months

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.

Time frame: At 12 months

Secondary Outcomes

Objective Response Rate (ORR)

The ORR is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) that occurred prior to the initiation of subsequent anti-cancer treatment and prior to progression. The ORR was assessed per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Time frame: From Cycle 1 Day 1 (each cycle was 28 days in length) until initiation of subsequent anti-cancer treatment and prior to progression (up to 35 months).

Disease Control Rate (DCR)

The DCR is defined as the percentage of participants with a best overall response of confirmed CR or PR, or who had stable disease (SD) maintained for 16 weeks from first dose. DCR was assessed per RECIST v1.1 criteria.

Data from ClinicalTrials.gov

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Chemotherapy (Standard-of-Care)

Research Site

La Jolla, California, United States

Research Site

Los Angeles, California, United States

Research Site

Orange, California, United States

Research Site

Ventura, California, United States

Research Site

Atlanta, Georgia, United States

Research Site

Coeur d'Alene, Idaho, United States

Research Site

Boston, Massachusetts, United States

Research Site

Ann Arbor, Michigan, United States

Research Site

Grand Rapids, Michigan, United States

Research Site

Buffalo, New York, United States

...and 24 more locations

Time frame: Up to 16 weeks

Duration of Response (DoR)

The DoR is defined as the time from first documented objective response (confirmed CR or confirmed PR) until date of first documented disease progression or death (by any cause in the absence of disease progression). The DoR was assessed per RECIST v1.1 criteria.

Time frame: From screening until disease progression or last evaluable assessment in the absence of progression, whichever came first (up to 35 months)

Median Progression Free Survival (PFS)

The PFS is defined as the time from first dose of study intervention until the date of objective disease progression or death (by any cause in the absence of progression), whichever was earlier. The PFS was analyzed using the Kaplan-Meier method.

Time frame: From first dose of study intervention until disease progression or last evaluable assessment in the absence of progression, whichever came first (up to 35 months)

Progression Free Survival at 4 Months (PFS-4)

The percentage of participants alive and free of progression at 4 months per Kaplan-Meier estimate.

Time frame: At 4 months

Median Overall Survival (OS)

The OS is defined as the time from the start of study intervention to the date of death due to any cause.

Time frame: From first dose of study intervention until death (Up to 35 months) or from first dose of study intervention until last evaluable assessment (Up to 35 months)

Change From Baseline in Serum Levels of Carbohydrate Antigen 19-9 (CA19-9)

Mean change from baseline was assessed for serum CA19-9

Time frame: Day 1 of each Cycle through Cycle 27 (each cycle was 28 days in length), at end of treatment and at Day 28 follow up (post last dose); up to 35 months

Number of Participants With Positive Anti-drug Antibodies (ADAs) Against AZD0171 in Serum

Number and percentage of participants in the below categories are provided:(i)ADA positive (+ve) at baseline and/or post-baseline visits. The percentage of these participants in a population is known as ADA prevalence(ii)ADA +ve post-baseline and not detected at baseline (treatment-induced ADA positive)(iii)Treatment-boosted ADA +ve:Baseline +ve ADA titre-boosted to a 4-fold or higher level following drug administration(iv)Treatment-emergent ADA +ve:The sum of treatment-induced ADA +ve and treatment-boosted ADA +ve. The percentage of these participants in a population is known as ADA incidence(v)Persistent +ve:ADA negative (-ve) at baseline and having at least 2 post-baseline ADA +ve measurements with ≥ 16 weeks between first and last positive, or an ADA +ve result at the last available post-baseline assessment(vi)Transient +ve:ADA -ve at baseline and at least 1 post-baseline ADA +ve measurement and not fulfilling the conditions for persistently +ve.

Time frame: Cycle 1 (Days 1 and 15), Cycle 2 (Days 1 and 15), until Day 90 post last dose of study intervention (each cycle is 28 days in length), assessed up to 35 months

Number of Participants With Positive Anti-drug Antibodies (ADAs) Against Durvalumab in Serum

Time frame: Cycle 1 (Days 1 and 15), Cycle 2 (Days 1 and 15), until Day 90 post last dose of study intervention (each cycle is 28 days in length), assessed up to 35 months

Maximum Observed Plasma Concentration (Cmax) of AZD0171

The maximum concentration of AZD0171 was determined.

Time frame: Cycle 1 Day 1 and Cycle 4 Day 1 (each cycle is 28 days in length)

Maximum Observed Plasma Concentration (Cmax) of Nab-paclitaxel

The Cmax of Nab-paclitaxel was determined.

Time frame: Cycle 1 Day 15 and Cycle 4 Day 15 (each cycle is 28 days in length)

Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf) of AZD0171

The AUCinf of AZD0171 was determined.

Time frame: Cycle 1 Day 1 (each cycle is 28 days in length)

Area Under the Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUClast) of AZD0171

The AUClast of AZD0171 was determined.

Time frame: Cycle 1 Day 1 and Cycle 4 Day 1 (each cycle is 28 days in length)

Area Under the Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUClast) of Nab-paclitaxel

The AUClast of Nab-paclitaxel was determined.

Time frame: Cycle 1 Day 15 and Cycle 4 Day 15 (each cycle is 28 days in length)

Area Under the Concentration-time Curve in the Dose Interval (AUCtau) of AZD0171

The AUCtau of AZD0171 was determined.

Time frame: Cycle 1 Day 1 and Cycle 4 Day 1 (each cycle is 28 days in length)

Area Under the Concentration-time Curve in the Dose Interval (AUCtau) of Nab-paclitaxel

The AUCtau of Nab-paclitaxel was determined.

Time frame: Cycle 1 Day 15 and Cycle 4 Day 15 (each cycle is 28 days in length)

Clearance (CL) of AZD0171

The CL of AZD0171 was determined.

Time frame: Cycle 1 Day 1 and Cycle 4 and Day 1 (each cycle is 28 days in length)

Clearance (CL) of Nab-paclitaxel

The CL of Nab-paclitaxel was determined.

Time frame: Cycle 1 Day 15 and Cycle 4 Day 15 (each cycle is 28 days in length)

Terminal Elimination Half-life (t1/2λz) of AZD0171

The t1/2λz of AZD0171 was determined.

Time frame: Cycle 1 Day 1 and Cycle 4 Day 1 (each cycle is 28 days in length)

Terminal Elimination Half-life (t1/2λz) of Nab-paclitaxel

The t1/2λz of Nab-paclitaxel was determined.

Time frame: Cycle 1 Day 15 and Cycle 4 Day 15 (each cycle is 28 days in length)

Change From Screening in Cluster of Differentiation 8 (CD8+) T Cell Tumour Infiltration in Central Tumour Region

The changes in CD8+ T cell tumour infiltration (on-treatment during cycle 3 minus baseline) associated with AZD0171 treatment in combination with durvalumab and chemotherapy was assessed in participants with 1L metastatic pancreatic ductal adenocarcinoma.

Time frame: In cycle 3 (each cycle was 28 days in length), subsequent to the first disease assessment scan conducted at roughly 8 weeks.

Serum Concentration of Total Leukaemia Inhibitory Factor (LIF) Over Time

Serum concentration of LIF bound to AZD0171 (total LIF) was assessed.

Time frame: Cycle 1 Day 1 and Day 15, Cycle 2 Day 1 and Day 15, Cycle 3 Day 1 and Day 15, Cycle 4 Day 1 and Day 15, Cycle 5Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1 and Cycle 11 Day 1 (each cycle is 28 days in length)