A Phase I/IIa Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD0022 as Monotherapy and in Combination With Anti-cancer Agents in Adult Participants With Tumours Harbouring a KRASG12D Mutation

NCT06599502 | Terminated Phase 1 FDA Drug

• 1 other identifier: D7080C00001
• Study Type: interventional
• Target: 17
• Locations: 4 countries
• Sites: 6

Brief Summary

This is a first-in-human, modular, Phase I/IIa, open-label, multi-centre study to assess the safety, tolerability, PK, and preliminary efficacy of AZD0022 monotherapy in combination with other anti-cancer agents in participants with tumours harbouring a KRASG12D mutation.

Conditions

Advanced Solid Tumours; Non-Small Cell Lung Cancer (NSCLC); Pancreatic Ductal Adenocarcinoma (PDAC); Colorectal Cancer (CRC)

Outcome Measures

Primary Outcomes (3)

• Incidence of participants with Dose-Limiting Toxicity (DLT), Adverse events (AEs) and Serious Adverse Events (SAEs).

  Determine if treatment with AZD0022 as a monotherapy and in combination with other anti-cancer agents is safe and tolerable through the assessment of DLTs, AEs, SAEs, and change from baseline in laboratory parameters, vital signs, and ECGs. Part A (Dose Escalation) and Part B (Dose Optimisation). DLTs only applicable for Part A.

  From time of informed consent, through study completion to 30 days post last dose; an average of 2 years

• Number of patients who discontinue AZD0022 due to toxicity

  To investigate the safety and tolerability of AZD0022 as a monotherapy and in combination with other anti-cancer agents in participants with advanced tumours harbouring a KRASG12D mutation Part A (Dose Escalation) and Part B (Dose Optimisation)

  From time of informed consent to 30 days post last dose

• ORR (Objective Response Rate)

  Evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part C (Potential Efficacy Expansion) Percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR)

  Time from first dose of AZD002 through study completion; approximate duration of 2 years

Secondary Outcomes (23)

• CR rate (Complete Response)

  From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years

• DoR (Duration of Response)

  From the date of first response until date of disease progression (RECIST 1.1) or death in the absence of disease progression; approximate duration of 2 years.

• DCR (Disease Control Rate)

  From first dose (non-randomised study parts) or from randomisation (randomised) until progression. For each patient, this is expected to be at 12 weeks

• DRR (Durable Response Rate)

  From first documented response up until progression, or the last evaluable assessment in the absence of progression; approximate duration of 2 years.

• TTR (Time to Response)

  From first dose (non-randomised study parts) or from randomisation (randomised study parts) until the date of documented objective response; approximate duration of 2 years.

Study Arms (7)

Module 1 Part A. Dose Escalation

EXPERIMENTAL

AZD0022 monotherapy

Drug: AZD0022

Module 1 Part B. Dose Optimisation

EXPERIMENTAL

AZD0022 monotherapy

Drug: AZD0022

Module 1 Part C. Potential Efficacy Expansion

EXPERIMENTAL

AZD0022 monotherapy

Drug: AZD0022

Module 1 Part B. Food Effect Cohort

EXPERIMENTAL

AZD0022 monotherapy

Drug: AZD0022

Module 2 Part A. Dose Escalation

EXPERIMENTAL

AZD0022 in combination with Cetuximab

Drug: AZD0022; Drug: Cetuximab

Module 2 Part B. Dose Optimisation

EXPERIMENTAL

AZD0022 in combination with Cetuximab

Drug: AZD0022; Drug: Cetuximab

Module 2 Part C. Potential Efficacy Expansion

EXPERIMENTAL

AZD0022 in combination with Cetuximab

Drug: AZD0022; Drug: Cetuximab

Interventions

AZD0022 DRUG

AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.

Module 1 Part A. Dose Escalation; Module 1 Part B. Dose Optimisation; Module 1 Part B. Food Effect Cohort; Module 1 Part C. Potential Efficacy Expansion; Module 2 Part A. Dose Escalation; Module 2 Part B. Dose Optimisation; Module 2 Part C. Potential Efficacy Expansion

Cetuximab DRUG

Cetuximab (Erbitux®) is a recombinant chimeric human/mouse Immunoglobulin G monoclonal antibody which binds to EGFR and competitively inhibits the binding of EGFR and other ligands

Module 2 Part A. Dose Escalation; Module 2 Part B. Dose Optimisation; Module 2 Part C. Potential Efficacy Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For whole study:
• 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 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 be considered, provided that it is documented and the participant has been informed about all available therapeutic options.
• Documented KRASG12D mutation in tissue or liquid biopsy.
• 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 defined in study protocol.
• Type of tumours with a KRASG12D mutation:
• 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.
• 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.
• For Part B food-effect cohort, participants must be able to eat a standard high-fat meal and must be able to fast for at least 10 hours.
• For Part A (M2A, dose escalation) participants must have pathologically documented locally advanced or metastatic CRC with a KRASG12D mutation.

You may not qualify if:

• For whole study:
• Any significant laboratory finding or any severe and uncontrolled medical condition.
• 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
• History of allogenic organ transplantation.
• Participants with any of the following cardiac criteria:
• Mean resting QTcF \> 470 milliseconds on screening
• Any factors that increase the risk of QT prolongation
• 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.
• 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.
• Prior exposure to any direct small molecule KRAS inhibitor.
• Herbal preparations/medications are not allowed during treatment with study drug.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (6)

Research Site

Duarte, California, 91010, United States

Location

Research Site

New York, New York, 10016, United States

Location

Research Site

Fairfax, Virginia, 22031, United States

Location

Research Site

Melbourne, 3000, Australia

Location

Research Site

Chūōku, 104-0045, Japan

Location

Research Site

Seoul, 03080, South Korea

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms

Interventions

Cetuximab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This protocol has a modular design, with the potential for future Modules or treatment to be added via protocol amendments. Participants will receive oral doses of AZD0022, either as monotherapy or in combination with other anti-cancer agents

Study Record Dates

• First Submitted: August 19, 2024
• First Posted: September 19, 2024
• Study Start: October 18, 2024
• Primary Completion: October 20, 2025
• Study Completion: January 29, 2026
• Last Updated: March 18, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Locations

US (3); KR (1); JP (1); AU (1)