First in Human Study of AZD9592 in Solid Tumors

Study Overview
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Brief Summary
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This is a first-in-human (FIH) Phase I, multi-center, open-label, study of AZD9592, in patients with advanced solid tumors. The study consists of several study modules, each evaluating the safety, tolerability, preliminary efficacy, pharmacokinetics (PK), pharmacodynamics, anti-tumor activity, and immunogenicity of AZD9592, as monotherapy or in combination with anti-cancer agents.

Official Title
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A Phase I, Multicenter, Open-label, First-in-Human, Dose Escalation and Expansion Study of AZD9592 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumours, Carcinoma Non-small Cell Lung, Head and Neck Neoplasms, Colorectal Neoplasms

Intervention / Treatment
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* Drug: AZD9592
* Drug: Osimertinib
* Drug: 5-Fluorouracil (5-FU)
* Drug: Leucovorin
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-1 Life expectancy ≥ 12 weeks Measurable disease per RECIST v1.1 Adequate organ and marrow function as defined in the protocol Additional Inclusion Criteria for Module 1: • Histologically or cytologically confirmed metastatic or locally advanced EGFRmut., NSCLC; metastatic EGFRwt. NSCLC; recurrent or metastatic HNSCC of the oral cavity; metastatic CRC. Additional Inclusion Criteria for Module 2: • Histologically or cytologically confirmed metastatic NSCLC EGFRmut. Additional Inclusion Criteria for Module 3: • Histologically or cytologically confirmed metastatic CRC. Key Exclusion Criteria: History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Spinal cord compression or a history of leptomeningeal carcinomatosis. Active infection including tuberculosis and HBV, HCV or HIV Brain metastases unless treated (prior treatment required only for Module 1), asymptomatic, stable, and not requiring continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study treatment. Participants with cardiac comorbidities as defined in the study protocol

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1 AZD9592 Monotherapy<br>Module 1 has two parts: Part A aims to determine the safety, tolerability, maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of AZD9592. Part B aims to determine the safety, tolerability and evaluate anti-tumor activity of AZD9592 as monotherapy in select solid tumors | Drug: AZD9592<br>* Varying doses of AZD9592<br>|
| Experimental: Module 2 AZD9592 Combination with Osimertinib<br>Module 2 has two parts: Part A aims to determine the safety, tolerability, maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of AZD9592 in combination with Osimertinib. Part B aims to determine the safety, tolerability and evaluate anti-tumor activity of AZD9592 in combination with Osimertinib in NSCLC EGFRm | Drug: AZD9592<br>* Varying doses of AZD9592<br>Drug: Osimertinib<br>* tablets administered orally<br>|
| Experimental: Module 3 AZD9592 Combination 5-FU, Bevacizumab, Leucovorin<br>Module 3 has two parts: Part A aims to determine the safety, tolerability and/or recommended phase 2 dose (RP2D) of AZD9592 in combination with 5-FU, Bevacizumab, Leucovorin in Colorectal Cancer (CRC) Part B aims to determine the safety, tolerability and evaluate anti-tumor activity of AZD9592 in combination with 5-FU, Bevacizumab, Leucovorin in Colorectal Cancer (CRC) | Drug: AZD9592<br>* Varying doses of AZD9592<br>Drug: 5-Fluorouracil (5-FU)<br>* IV infusion<br>Drug: Leucovorin<br>* IV infusion<br>Drug: Bevacizumab<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) | Number of patients with adverse events by system organ class and preferred term | From time of Informed Consent to 30 days post last dose of AZD9592 | 
| Incidence of Serious Adverse Events (SAEs) | Number of patients with serious adverse events by system organ class and preferred term | From time of Informed Consent to 30 days post last dose of AZD9592 | 
| Incidence of dose-limiting toxicities (DLT) as defined in the protocol | Number of patients with at least 1 dose-limiting toxicity (DLT), which is any toxicity defined as a DLT in the Clinical Study Protocol | From time of first dose of AZD9592 to end of DLT period (approximately 21 days) | 
| Incidence of baseline laboratory finding, ECG and vital signs changes | measured by laboratory and vital sign variables over time including change from baseline | From time of Informed Consent to 30 days post last dose of AZD9592 | 
| Proportion of patients with radiological response (ORR) | Assessed by overall response rate (ORR) defined as the proportion of patients who have a confirmed complete or partial radiological response by the Investigator according to RECIST v1.1 (for patients in the dose expansion cohorts, only) | From date of first dose of AZD9592 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The percentage or number of patients with a confirmed investigator assessed complete or partial response according to response criteria in solid tumours (RECIST v1.1) | From date of first dose of AZD9592 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years) | 
| Duration of Response (DoR) | The time from date of first response until date of disease progression or last evaluable assessment (RECIST v1.1) in the absence of progression | From date of first dose of AZD9592 up until progression, or the last evaluable assessment in the absence of progression (approximately 2 years) | 
| Disease Control Rate (DCR) at 12 weeks | The percentage of patients with confirmed CR or PR or having SD maintained (RECIST v1.1) for >=11 weeks from first dose | From date of first dose of AZD9592 up until progression, or the last evaluable assessment in the absence of progression (for each patient this is expected to be measured at 12 weeks) | 
| Progression free Survival (PFS) | The time from first dose until RECIST 1.1 defined disease progression or death due to any cause | From date of first dose of AZD9592 up until date of progression or death due to any cause (approximately 2 years) | 
| Overall Survival (OS) | The time from the date of the first dose of study treatment until death due to any cause. | From date of first dose of AZD9592 up until the date of death due to any cause (approximately 2 years) | 
| Pharmacokinetics of AZD9592: Plasma PK concentrations | Measurement of plasma concentrations of AZD9592, total antibody and total unconjugated warhead | From date of first dose of AZD9592 up until 30 days post last dose | 
| Pharmacokinetics of AZD9592: Area under the concentration time curve (AUC) | Measurement of PK parameters: Area under the concentration time curve (AUC) | From date of first dose of AZD9592 up until 30 days post last dose | 
| Pharmacokinetics of AZD9592: Maximum plasma concentration of the study drug (C-max) | Measurement of PK parameters: Maximum observed plasma concentration of the study drug (C-max) | From date of first dose of AZD9592 up until 30 days post last dose | 
| Pharmacokinetics of AZD9592: Time to maximum plasma concentration of the study drug (T-max) | Measurement of PK parameters: Time to maximum observed plasma concentration of the study drug (T-max) | From date of first dose of AZD9592 up until 30 days post last dose | 
| Pharmacokinetics of AZD9592: Clearance | Measurement of PK parameters: the volume of plasma from which the study drug is completely removed per unit time (Clearance) | From date of first dose of AZD9592 up until 30 days post last dose | 
| Pharmacokinetics of AZD9592: Half-life | Measurement of PK parameters: Terminal elimination half-life (t 1/2) | From date of first dose of AZD9592 up until 30 days post last dose | 
| Immunogenicity of AZD9592: Anti-Drug Antibodies (ADA) | Evaluating the number and percentage of patients who develop Anti-drug antibody (ADA) during treatment | From date of first dose of AZD9592 up until 30 days post last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, First in Human, Antibody Drug Conjugate, Solid Tumour, Phase I