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AZD0022

AZD0022 is an innovative oral drug being studied in a first-in-human clinical trial for patients with advanced cancers that have a specific genetic mutation called KRAS G12D. This Phase I/IIa study, known as ALAFOSS-01, is investigating how safe and effective AZD0022 is when used alone or in combination with other cancer treatments, particularly in non-small cell lung cancer, pancreatic ductal adenocarcinoma, and colorectal cancer. The trial follows a modular design to systematically evaluate different dosing strategies and potential combinations, with a focus on understanding how the drug works in the body and whether it can effectively shrink tumors in patients with this specific mutation.

Table of Contents

What is AZD0022?

AZD0022 is a new medication that is currently being studied for cancer treatment. It is taken orally (by mouth) and is specifically designed to target cancers that have a particular genetic mutation called KRAS G12D[1]. This is what scientists call a “first-in-human” drug, meaning it is in the early stages of testing in people after showing promise in laboratory studies.

AZD0022 belongs to a class of medications known as KRAS inhibitors, which are designed to block the function of the mutated KRAS protein. KRAS mutations are common in several types of cancer and have been difficult to target with medications until recently[1].

How AZD0022 Works

AZD0022 specifically targets the KRAS G12D mutation, which is a specific alteration in the KRAS gene. When this mutation is present, it leads to abnormal activation of cellular pathways that promote cancer growth[1].

The medication works by blocking or inhibiting the function of the mutated KRAS G12D protein. By doing so, it aims to interrupt the signals that tell cancer cells to grow and divide uncontrollably. One way researchers are measuring if the drug is working as intended is by checking the levels of a substance called phospho-ERK, which is part of the KRAS signaling pathway[1].

Which Cancers Can AZD0022 Treat?

AZD0022 is being studied for several types of cancer that commonly carry the KRAS G12D mutation. The current clinical trials are focusing on[1]:

  • Non-Small Cell Lung Cancer (NSCLC) – A type of lung cancer that accounts for about 85% of all lung cancers
  • Pancreatic Ductal Adenocarcinoma (PDAC) – The most common form of pancreatic cancer
  • Colorectal Cancer (CRC) – Cancer that starts in the colon or rectum
  • Other advanced solid tumors that have the KRAS G12D mutation

What makes AZD0022 special is that it targets a specific genetic change (KRAS G12D) rather than a specific cancer type. This approach is part of what’s called “precision medicine,” where treatments are matched to the genetic profile of a patient’s cancer[1].

Current Clinical Trials

AZD0022 is currently being studied in a Phase I/IIa clinical trial called ALAFOSS-01. This means it’s in the early stages of human testing. The study is designed to answer important questions about the drug[1]:

  • Is it safe for patients?
  • What side effects might occur?
  • How does the body process the drug?
  • Does it show signs of being effective against cancer?
  • What is the best dose to give patients?

The trial has a modular design with initially two main modules[1]:

  1. Module 1: Testing AZD0022 alone (monotherapy)
  2. Module 2: Testing AZD0022 in combination with another cancer drug called Cetuximab (Erbitux®)

Each module is further divided into three parts[1]:

  • Part A (Dose Escalation): Finding the right dose by starting with a low dose and gradually increasing it
  • Part B (Dose Optimization): Fine-tuning the dose and understanding more about how the drug works
  • Part C (Potential Efficacy Expansion): Gathering more information about how effective the drug is at the chosen dose

There is also a special group in Module 1 Part B called the “Food Effect Cohort” that is studying how taking the medication with food might affect how the body processes it[1].

Treatment Approaches with AZD0022

The clinical trial is exploring two main approaches to using AZD0022[1]:

AZD0022 Alone (Monotherapy)

In Module 1 of the trial, patients receive only AZD0022. This helps researchers understand the effects of the drug on its own. This approach allows them to determine the drug’s safety profile and see if it can shrink tumors without combining it with other treatments[1].

AZD0022 Combined with Cetuximab

In Module 2, AZD0022 is being combined with a drug called Cetuximab (brand name Erbitux®). Cetuximab is an antibody (a type of protein) that targets a receptor called EGFR (Epidermal Growth Factor Receptor) on cancer cells. This receptor is involved in cell growth and division[1].

By combining AZD0022 with Cetuximab, researchers hope to attack cancer cells through two different pathways simultaneously, potentially making the treatment more effective than either drug alone[1].

How Effectiveness is Being Measured

Researchers are using several methods to determine if AZD0022 is working against cancer[1]:

  • Objective Response Rate (ORR): The percentage of patients whose tumors shrink by a significant amount
  • Complete Response (CR): When all signs of cancer disappear
  • Partial Response (PR): When the tumor shrinks by at least 30%
  • Duration of Response (DoR): How long the cancer remains controlled after it responds to treatment
  • Disease Control Rate (DCR): The percentage of patients whose cancer either shrinks or stops growing for at least 11 weeks
  • Progression-Free Survival (PFS): How long patients live without their cancer getting worse
  • Overall Survival (OS): How long patients live after starting treatment
  • Complete Molecular Response (cMR): Measuring cancer DNA in the blood to see if it decreases or disappears with treatment
  • Change in tumor size: Measuring whether tumors are shrinking and by how much

These measurements are being assessed both by the doctors treating the patients and by independent reviewers who look at imaging scans (called BICR or Blinded Independent Central Review)[1].

Safety Monitoring

Patient safety is a primary concern in the clinical trial. The researchers are carefully monitoring for any side effects or problems that might be caused by AZD0022. This includes[1]:

  • Dose-Limiting Toxicities (DLTs): Side effects that are severe enough that the dose cannot be increased further
  • Adverse Events (AEs): Any unwanted medical occurrence in a patient receiving the drug
  • Serious Adverse Events (SAEs): AEs that result in hospitalization, disability, or are life-threatening
  • Regular laboratory tests to check blood counts, liver function, and other important health indicators
  • Monitoring of vital signs like blood pressure and heart rate
  • ECGs (electrocardiograms) to check heart function

The researchers are also tracking how many patients need to stop treatment because of side effects, which helps them understand if the treatment is tolerable for most patients[1].

Study Aspect Details
Study Name ALAFOSS-01 (NCT06599502)
Drug AZD0022 – an oral KRAS G12D inhibitor
Study Phase Phase I/IIa
Study Design Open-label, multi-center study with modular design
Target Population Adults with tumors harboring KRAS G12D mutations, including Non-Small Cell Lung Cancer (NSCLC), Pancreatic Ductal Adenocarcinoma (PDAC), and Colorectal Cancer (CRC)
Study Modules Module 1: AZD0022 monotherapy
Module 2: AZD0022 + Cetuximab
Module Parts Part A: Dose Escalation
Part B: Dose Optimization (including Food Effect Cohort)
Part C: Potential Efficacy Expansion
Primary Outcomes • Safety and tolerability (DLTs, AEs, SAEs)
• Number of patients discontinuing due to toxicity
• Objective Response Rate (ORR)
Key Secondary Outcomes • Complete Response rate
• Duration of Response
• Disease Control Rate
• Progression-Free Survival
• Overall Survival
• Pharmacokinetic parameters
• Molecular response via ctDNA
Approximate Study Duration 2 years

FAQ

  • What is AZD0022 and how does it work? AZD0022 is an oral medication that specifically targets and inhibits KRAS G12D mutations in cancer cells. KRAS is a protein that, when mutated, can drive uncontrolled cell growth leading to cancer. AZD0022 works by blocking the function of the mutated KRAS G12D protein, potentially stopping or slowing cancer growth in patients whose tumors have this specific genetic alteration.
  • What types of cancer is AZD0022 being tested for? AZD0022 is being tested in patients with advanced solid tumors that have a KRAS G12D mutation. The trial specifically focuses on three types of cancer: Non-Small Cell Lung Cancer (NSCLC), Pancreatic Ductal Adenocarcinoma (PDAC), and Colorectal Cancer (CRC). These cancer types are known to frequently harbor KRAS mutations.
  • How is the clinical trial for AZD0022 structured? The ALAFOSS-01 trial has a modular design with initially two modules: Module 1 testing AZD0022 as a single agent (monotherapy) and Module 2 testing AZD0022 in combination with cetuximab (a cancer drug that targets EGFR). Each module is divided into three parts: Part A (Dose Escalation) to find a safe dose, Part B (Dose Optimization) to refine the dosing, and Part C (Potential Efficacy Expansion) to further evaluate effectiveness. There's also a Food Effect Cohort to understand how food affects the drug.
  • What are researchers measuring to determine if AZD0022 is effective? Researchers are measuring several outcomes to determine effectiveness, including: Objective Response Rate (ORR) – the percentage of patients whose tumors shrink; Duration of Response (DoR) – how long the response lasts; Disease Control Rate (DCR) – the percentage of patients with stable disease or better; Progression-Free Survival (PFS) – time until the cancer progresses; and Overall Survival (OS) – how long patients live. They're also analyzing blood and tumor samples to see if the drug is hitting its target by measuring changes in certain biomarkers.
  • What safety measures are being monitored during the AZD0022 clinical trial? Safety is being closely monitored throughout the trial. Researchers are tracking Dose-Limiting Toxicities (DLTs), Adverse Events (AEs), and Serious Adverse Events (SAEs). They're also monitoring laboratory values, vital signs, and ECGs (heart rhythm tests) to detect any changes from baseline. Additionally, they're tracking how many patients need to discontinue treatment due to side effects. All participants are followed for safety for 30 days after their last dose of the study drug.

Ongoing Clinical Trials on AZD0022

  • Study on the Safety and Effectiveness of AZD0022 Alone and with Other Cancer Drugs for Adults with KRAS-G12D Mutated Tumors in Lung, Colorectal, and Pancreatic Cancer

    Not recruiting

    2 1 1 1
    Investigated diseases:
    Investigated drugs:
    Belgium Italy The Netherlands Poland Spain

Glossary

  • KRAS G12D mutation: A specific genetic change in the KRAS gene, where at position 12 of the protein, the amino acid glycine (G) is replaced by aspartic acid (D). This mutation can drive cancer growth and is found in various cancer types.
  • Phase I/IIa trial: An early stage clinical trial that combines elements of both Phase I (testing safety and dosing) and Phase II (preliminary testing of effectiveness) studies. Phase I/IIa trials help researchers establish safe doses while also beginning to assess whether the drug shows promise against the disease.
  • Monotherapy: Treatment with a single drug rather than a combination of drugs.
  • Cetuximab (Erbitux®): A monoclonal antibody drug that targets EGFR (Epidermal Growth Factor Receptor), a protein that helps cancer cells grow. By blocking EGFR, cetuximab can slow or stop cancer growth.
  • Dose-Limiting Toxicity (DLT): Side effects that are severe enough to prevent increasing the dose of a drug during a clinical trial. Identifying DLTs helps determine the maximum safe dose.
  • Adverse Event (AE): Any unfavorable medical occurrence in a participant receiving a drug, whether or not considered related to the treatment. This can range from mild symptoms to serious conditions.
  • Serious Adverse Event (SAE): An adverse event that results in death, is life-threatening, requires hospitalization, causes significant disability, or leads to birth defects.
  • Objective Response Rate (ORR): The percentage of patients whose cancer shrinks or disappears after treatment. It includes both complete responses (CR) and partial responses (PR).
  • Complete Response (CR): The disappearance of all detectable cancer in response to treatment.
  • Partial Response (PR): A decrease in tumor size by at least 30% in response to treatment.
  • Stable Disease (SD): Cancer that is neither growing nor shrinking significantly in response to treatment.
  • Duration of Response (DoR): The length of time from when a tumor starts responding to treatment until it begins growing again.
  • Disease Control Rate (DCR): The percentage of patients who achieve complete response, partial response, or stable disease for at least a specified period (in this trial, 11 weeks).
  • Progression-Free Survival (PFS): The length of time during and after treatment that a patient lives without the cancer getting worse.
  • Overall Survival (OS): The length of time from the start of treatment that patients are still alive.
  • RECIST v1.1: Response Evaluation Criteria in Solid Tumors Version 1.1 – a standardized set of rules used to determine if tumors are responding to treatment by measuring changes in tumor size.
  • ctDNA: Circulating tumor DNA – fragments of DNA released by tumor cells into the bloodstream. Analyzing ctDNA can provide information about genetic changes in the tumor without needing a tissue biopsy.
  • Pharmacokinetics (PK): The study of how drugs move through the body, including how they are absorbed, distributed, metabolized, and excreted.
  • Cmax: The maximum concentration of a drug in the blood after administration.
  • Tmax: The time it takes for a drug to reach its maximum concentration in the blood after administration.
  • AUClast: Area Under the Plasma Concentration-Time Curve to the last measurable concentration – a measure of the total exposure to a drug over time.
  • Terminal elimination half-life (t½): The time it takes for the concentration of a drug in the body to decrease by half during the elimination phase.
  • BICR: Blinded Independent Central Review – a process where medical images are reviewed by experts who don't know which treatment the patient received, to reduce bias in evaluating response to treatment.
  • phospho-ERK: A phosphorylated (activated) form of ERK, which is a protein in the KRAS signaling pathway. Measuring changes in phospho-ERK can indicate whether AZD0022 is effectively blocking KRAS signaling.
  • Food effect cohort: A group of participants in a clinical trial who receive the drug both with and without food to determine if food affects how the drug is absorbed and processed by the body.
  • Non-Small Cell Lung Cancer (NSCLC): The most common type of lung cancer, accounting for about 85% of all lung cancers. It grows and spreads more slowly than small cell lung cancer.
  • Pancreatic Ductal Adenocarcinoma (PDAC): The most common type of pancreatic cancer, arising from the cells lining the ducts that carry digestive enzymes from the pancreas to the small intestine.
  • Colorectal Cancer (CRC): Cancer that starts in the colon (large intestine) or rectum, which are parts of the digestive system.

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