Evaluation of AZD0022 Monotherapy and Combination Therapy with Cetuximab in KRASG12D-Mutated Advanced Tumors: A Phase I/IIa Study
- Trial ID
- 2024-516699-14-00
- Protocol
- D7080C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to investigate the **safety** and tolerability of AZD0022, both as a monotherapy and in combination with other anti-cancer agents, in participants with advanced tumors harboring a KRASG12D mutation. This includes determining the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) of AZD0022. The clinical relevance of this objective lies in its potential to establish a safe and effective dosing regimen for AZD0022, which could lead to improved therapeutic strategies for patients with these specific genetic mutations.
Secondary objectives include:
- Assessing the preliminary anti-tumor activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents.
- Evaluating the molecular response rate via circulating tumor DNA (ctDNA) during treatment with AZD0022.
- Characterizing the pharmacokinetics (PK) of AZD0022.
- Further assessing the safety and tolerability of AZD0022 in Part C of the study.
Participants
The clinical trial involves a total of **304 participants** diagnosed with advanced tumors, specifically **Non-Small Cell Lung Cancer**, **Colorectal Cancer**, and **Pancreatic Ductal Adenocarcinoma**, all harboring a KRASG12D mutation. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent. Participants were selected based on their histologically or cytologically confirmed metastatic or locally advanced tumors, with a documented KRASG12D mutation. They must have progressed on, be refractory to, or intolerant of standard therapy for their specific tumor type. The trial includes individuals who have received prior experimental treatments. Participants are required to have adequate organ and marrow function and at least one measurable target lesion. The study also considers lifestyle factors such as the ability to consume a standard high-fat meal and fasting requirements for specific cohorts. The trial population includes vulnerable groups, ensuring comprehensive representation in the study.
Plans and Procedures
The clinical trial is designed as a **Phase I/IIa**, open-label, multi-center study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of **AZD0022** monotherapy and in combination with other anti-cancer agents in participants with tumors harboring a **KRASG12D** mutation. The trial will involve participants diagnosed with **Non-Small Cell Lung Cancer**, **Colorectal Cancer**, and **Pancreatic Ductal Adenocarcinoma**. The study is expected to commence recruitment on April 1, 2025, and conclude by January 20, 2028.
The trial will follow a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on histological or cytological confirmation of metastatic or locally advanced tumors and the presence of a **KRASG12D** mutation. Participants will undergo a series of follow-up visits to monitor safety, tolerability, and response to treatment. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment. The expected duration of participant involvement will vary depending on individual response and tolerance to the treatment regimen.
Participants may be subject to early termination from the study if they experience unacceptable toxicity, significant adverse events, or if they choose to withdraw consent. The primary endpoints include the incidence and severity of adverse events, dose-limiting toxicities, and clinically significant changes in vital signs and laboratory parameters. Secondary endpoints will evaluate radiological response, overall survival, and pharmacokinetic parameters.
The trial methodology involves a combination of monotherapy and combination therapy arms, with dose escalation and optimization phases to determine the maximum tolerated dose and optimal biological dose of **AZD0022**. The study will employ a rigorous monitoring protocol to ensure participant safety and data integrity throughout the trial duration.
Treatment
The clinical trial involves the administration of **Erbitux**, a 5 mg/mL **solution for infusion** containing the active substance **cetuximab**. Cetuximab is a chimeric (mouse/human) monoclonal antibody, classified under the ATC code L01FE01. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The frequency and specific dosing schedule are determined based on the study protocol, with careful monitoring of participant compliance. The product is manufactured by Merck Europe B.V. and holds the marketing authorization number EU/1/04/281/003.
Another investigational product in the trial is **AZD0022**, a **film-coated tablet** containing the active substance AZD0022, a synthetic or chemical drug. The tablets are administered orally, with the dosage and frequency tailored according to the study's design to assess safety, tolerability, and efficacy. AZD0022 is produced by AstraZeneca AB, and the product is identified by the sponsor product code AZD0022. The trial includes monitoring of participant adherence to the dosing regimen to ensure accurate assessment of the drug's effects.
Both investigational products are used in the study to evaluate their safety, tolerability, and preliminary efficacy in participants with tumors harboring a KRASG12D mutation. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study is designed to explore the potential benefits of these investigational drugs, either as monotherapy or in combination with other anti-cancer agents, in a controlled clinical setting.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. For Parts A and B, the primary endpoints include the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), the incidence of dose-limiting toxicities (DLTs) during dose escalation, and clinically significant changes in vital signs, laboratory parameters, and ECG results. Additionally, the discontinuation of AZD0022 due to toxicity will be monitored. For Part C, the primary endpoint is the overall response rate (ORR) evaluated according to RECIST v1.1.
Secondary endpoints for Parts A and B include radiological response evaluated according to RECIST v1.1, which encompasses ORR, complete response (CR) rate, duration of response (DoR), disease control rate (DCR), disease response rate (DRR), time to response (TTR), progression-free survival (PFS), and changes in tumour size. Overall survival (OS) will also be assessed. Pharmacokinetic parameters such as Cmax, tmax, AUClast, and t1/2λz will be determined from plasma, urine, and whole blood concentrations after oral administration of AZD0022. For Part C, secondary endpoints include the incidence of AEs/SAEs, clinically significant changes in vital signs, laboratory parameters, and ECG results, AZD0022 discontinuation due to toxicity, and radiological response evaluated according to RECIST v1.1. Additional measures include OS, the proportion of participants demonstrating a complete molecular response, time to deterioration (TDT), and time to first subsequent therapy (TFST).
Inclusion and Exclusion Criteria
Inclusion Criteria
- For all Modules: Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol. Participant must be ≥ 18 years or the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the ICF. Participants must have a histologically or cytologically confirmed metastatic or locally advanced tumour. Further details on tumour types are specified in Module-specific inclusion criteria. Participants must have received and progressed on, are refractory or are intolerant to standard therapy for the specific tumour type, or as per Module-specific criteria. Documented KRASG12D mutation. For Parts A and B: KRASG12D mutation can be identified by a pre-existing local test result or by central testing with a next generation sequencing assay at an accredited laboratory. Local KRASG12D testing must be performed using a verified and well-validated test in line with local regulations, performed at a Clinical Laboratory Improvement Amendments certified laboratory (for the US sites) or an accredited laboratory (for sites outside the US). Local results can be obtained from a tumour or ctDNA sample. If such a pre-existing local result is not available, a tissue sample must be submitted for central testing. For Part C: KRASG12D mutation will be identified by an approved or qualified central diagnostic test in an accredited laboratory per local regulations. Provision of a FFPE tumour sample. Participants must have at least one measurable target lesion per RECIST v1.1. Adequate organ and marrow function as shown in Table 5 in the protocol.
- Plus for Module 1: Participants must have received and progressed on, are refractory or are intolerant to standard therapy for the specific tumour type, or as per Module-specific criteria. For NSCLC: Patients must have NSCLC that is not amenable to curative treatment and should have progressed on at least one prior line of SoC treatment for metastatic NSCLC (including but not limited to platinum-based chemotherapy, immunotherapy, targeted therapy or first line SoC combinations); prior experimental treatments are allowed. For CRC: Patients must have CRC that is not amenable to curative treatment and should have progressed on at least 2 prior lines of SoC treatment for metastatic CRC; prior experimental treatments are allowed. CRC patients with MSI-H or dMMR status should have also received immune checkpoint inhibitors as part of SoC if available and no contraindications. Patients who received prior anti-EGFR (including, but not limited to cetuximab or panitumumab), are eligible, if applicable. For PDAC: Patients must have PDAC that is not amenable to curative treatment and should have progressed at least one prior line of SoC treatment for metastatic PDAC (including but not limited to FOLFIRINOX, gemcitabine plus abraxane and gemcitabine monotherapy); prior experimental treatments are allowed. For patients enrolled in Part C (NSCLC and PDAC): at least one but no more than 2 lines of prior treatment in metastatic settings; prior experimental treatments are allowed. Progression or recurrence of the disease within 6 months of completing neo/adjuvant treatment (ie, chemotherapy, immunotherapy, chemoradiotherapy, etc) will be considered as a first line of treatment. M1A backfill cohorts for participants with NSCLC and PDAC undergoing mandatory paired biopsy: For M1A backfill cohorts, participants must provide written informed consent to provide baseline and on treatment tumour biopsies and tumour must be suitable for biopsy defined as having an accessible tumour by whichever modality the site uses and, ideally, confirmed by the person who will perform the procedure; and a stable clinical condition that will allow the participant to tolerate the procedure. M1FE Cohort and Food-effect Assessments: For Part B food-effect cohort, during the cross-over design on C0D1 and C1D1, participants must be able to eat a standard high-fat meal and must be able to fast for at least 10 hours. The core fasting restrictions apply to this cohort from dosing on C1D2 onwards.
- Plus for Module 2: For Part A (M2A, dose escalation) participants must have pathologically documented locally advanced or metastatic CRC with a KRASG12D mutation. For Part B (M2B, dose optimisation) participants must have pathologically documented locally advanced or metastatic, PDAC or CRC with a KRASG12D mutation. For Part C (M2C, potential efficacy expansion) participants must have pathologically documented locally advanced or metastatic CRC with a KRASG12D mutation. Participants must have received and progressed on, are refractory or are intolerant to standard therapy for the specific tumour type, or as per Module-specific criteria. Participants with contraindications to or who refuse SoC therapy may also be considered provided that it is documented, and the participant has been informed about all available therapeutic options. For CRC: Patients must have CRC that is not amenable to curative treatment and should have progressed on at least 2 prior lines of SoC treatment for metastatic CRC; prior experimental treatments are allowed. CRC patients with MSI-H or dMMR status should have also received immune checkpoint inhibitors as part of SoC if available and no contraindications. Patients who received prior anti-EGFR (including, but not limited to cetuximab or panitumumab), are eligible, if applicable. For PDAC: Patients must have PDAC that is not amenable to curative treatment and should have progressed at least one prior line of SoC treatment for metastatic PDAC (including but not limited to FOLFIRINOX, gemcitabine plus abraxane and gemcitabine monotherapy); prior experimental treatments are allowed. For patients enrolled in Part C (M2C), at least 2 but no more than 3 lines of prior treatment in metastatic setting; prior experimental treatments are allowed. Progression or recurrence of the disease within 6 months of completing neo/adjuvant treatment (ie, chemotherapy, immunotherapy, and chemoradiotherapy) will be considered as a first line of treatment. Module 2 Part A Backfill: Participants must provide written informed consent to provide baseline and on treatment tumour biopsies and tumour must be suitable for biopsy defined as having an accessible tumour; by whichever modality the site uses and, ideally, confirmed by the person who will perform the procedure; and a stable clinical condition that will allow the participant to tolerate the procedure.
Exclusion Criteria
- For all Modules: Any significant laboratory finding or any severe and uncontrolled medical condition eg, uncontrolled hypertension, active bleeding diseases, hepatic failure, unstable respiratory or cardiac conditions, active bacterial, viral, fungal, or other infection requiring systemic treatment, which in the Investigator's opinion makes it undesirable or pose a safety risk for the participant to participate in the study. Active gastrointestinal diseases or other conditions that will interfere significantly with the absorption of oral therapy (included but not limited to uncontrolled ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥ 2, malabsorption syndrome, and total small bowel resection). Any evidence of clinically significant current or prior ILD (eg, required IV steroids or high supplemental oxygen) or where a new suspected ILD cannot be ruled out by imaging at screening. Spinal cord compression, leptomeningeal disease, or active brain metastases. Asymptomatic brain metastases are allowed if they meet the following criteria: Have been treated and have been stable for greater than or equal to 4 weeks as documented by radiologic imaging; Have not required continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for a minimum 2 weeks prior first dose.
- History of allogenic organ transplantation. Serologic status reflecting active hepatitis B or C infection. Participants with HIV-infection are only considered eligible if on effective anti-retroviral therapy with undetectable viral load within 6 months and with at least CD4+ T-cell counts ≥ 350 cells/μL. Participants with any of the following cardiac criteria: Mean resting QTcF > 470 milliseconds on screening obtained from triplicate ECGs and averaged, recorded within 5 minutes; Any factors that increase the risk of QTc prolongation such as the congenital long QT syndrome or family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QTc interval as well as factors that increase the risk of arrhythmic events such as uncorrected abnormalities in serum electrolytes (ie, sodium, potassium, calcium and magnesium); Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, second- or third-degree atrioventricular block), and clinically significant sinus node dysfunction not treated with pacemaker; Bradycardia defined as a heart rate less than 60 beats per minute and/or hypotension defined as a blood pressure reading lower than 90 mm Hg for the top number (systolic) or 60 mm Hg for the bottom number (diastolic). Baseline LVEF below the institutional lower limit of normal or < 50%, whichever is lower. Participants with other cardiovascular diseases as defined by any of the following: Symptomatic heart failure (as defined by New York Heart Association class ≥ 2); Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months before C1D1; Presence of clinically significant valvular heart disease; History of atrial or ventricular arrhythmia requiring treatment; participants with extrasystoles and atrial fibrillation and optimally controlled ventricular rate are permitted; Transient ischaemic attack, or stroke within 6 months prior to first dose. History of other primary malignancy except for: Malignancy treated with curative intent and with no known active disease for at least 2 years before the first dose of study intervention and with low potential risk for recurrence; Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease; Adequately treated carcinoma in situ without evidence of disease; Localised non-invasive primary disease under surveillance. Prior exposure to any direct small molecule KRAS inhibitor. Herbal preparations/medications are not allowed during treatment with study drug, including the screening period, but excluding follow-up period. Any concomitant medications that are known strong inhibitors or inducers of CYP3A4/5, or sensitive CYP3A4/5 substrates or CYP3A4/5 substrates with a narrow therapeutic range (eg, aprepitant) that cannot be discontinued or replaced by safe alternative medication (eg, within 5 half-lives or 7-days, whichever is shorter, prior to starting study). This also applies to moderate inhibitors and moderate inducers of CYP3A4/5 during Parts A and B of Modules 1 and 2.
- Receipt of a cytotoxic or non-cytotoxic drug: 21 days or 5 half-lives, whichever is shorter, before the first dose of study intervention. Biological therapy including immune-oncology and monoclonal antibodies 28 days or 5 half-lives, whichever is shorter, before the first dose of study intervention. Less than or equal to 4 weeks for radiation therapy given with curative intent or ≤ 2 weeks for limited field radiation for palliation prior to the first dose of study treatment. Patients who have undergone major surgery (as defined by the Investigator) ≤ 4 weeks prior to first dose of study treatment or who have not recovered from the surgical procedure. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. Patients with a known hypersensitivity to study intervention or any of the excipients of the product. Involvement in the planning and/or conduct of the study (applies to both the Sponsor staff and/or staff at the study site). Any severe, acute or chronic medical, psychiatric condition, alcohol or drug abuse or dependence or laboratory abnormality that in the judgement of the Investigator, may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and would make the patient inappropriate for the study. For females only – currently pregnant (confirmed with positive pregnancy test) or breast-feeding or planning to become pregnant.
- Plus for Module 1: For Part B food-effect cohort, participants with insulin-dependent diabetes must be excluded. Any condition at the discretion of Investigator makes the patient not desirable for food-effect cohort. Plus for Module 2: History of allergic reactions attributed to compounds of similar chemical or biological composition to cetuximab. Patients with allergies to red meat and/or a medical history of alpha gal allergy must be excluded. Patients with increase or decrease of Grade per CTCAE v5.0 for the following parameters (treatment may be given during screening to correct values): (a) Potassium (b) Magnesium (c) Total calcium (corrected for low serum albumin).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Apr 2025 | 18 |
 Italy | Not Recruiting | 01 Apr 2025 | 27 |
 The Netherlands | Not Recruiting | 01 Apr 2025 | — |
 Poland | Not Recruiting | 01 Apr 2025 | 18 |
 Spain | Not Recruiting | 01 Apr 2025 | 45 |
| Netherlands | — | — | 18 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AZD0022 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11579724 |
AZD0022 | Test | FILM-COATED TABLET | ORAL | — | — | PRD11579725 |
Erbitux 5 mg/mL solution for infusion | Test | SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | — | — | PRD327539 |