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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

PHASE1PHASE2RECRUITING

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.

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Study details:

This first time in human, open-label, multi-centre study will administer AZD0022 orally to participants with tumours harbouring a KRASG12D mutation. This study will have initially 2 modules. * Module 1: AZD0022 monotherapy.

* Module 2: AZD0022 in combination with other anti-cancer agents (Cetuximab). Each Module has 3 parts. Dose Escalation (Part A), Dose Optimisation (Part B) and Potential Efficacy Expansion (Part C).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

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. 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.

For Module 1 Key Inclusion Criteria: Type of tumours with a KRASG12D mutation including NSCLC, CRC, and PDAC.

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.

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.

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 treatment 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 treatment 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 treatment are allowed.

Exclusion criteria

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, bradycardia defined as a heart rate less than 60 beats per minute and/or hypotension, baseline LVEF below the institutional lower limit of normal or < 50%, symptomatic heart failure (as defined by New York Heart Association class ≥ 2), acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, or coronary intervention procedure 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.

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.

Receipt of a cytotoxic or non-cytotoxic drug: 21 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.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-10-18

Primary completion: 2028-01-20

Study completion finish: 2028-02-03

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT06599502

Intervention or treatment

DRUG: AZD0022

DRUG: Cetuximab

Conditions

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

Condition: Advanced Solid Tumours, Pancreatic Ductal Adenocarcinoma (PDAC) and more
DRUG: AZD0022 and other drugs
Melbourne, Not Specified, Australia
Sponsor: AstraZeneca

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Closest Location:

Research Site

Research sites nearby

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Research Site
Melbourne, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Module 1 Part A. Dose Escalation AZD0022 monotherapy	DRUG: AZD0022 AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.
EXPERIMENTAL: Module 1 Part B. Dose Optimisation AZD0022 monotherapy	DRUG: AZD0022 AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.
EXPERIMENTAL: Module 1 Part C. Potential Efficacy Expansion AZD0022 monotherapy	DRUG: AZD0022 AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.
EXPERIMENTAL: Module 1 Part B. Food Effect Cohort AZD0022 monotherapy	DRUG: AZD0022 AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.
EXPERIMENTAL: Module 2 Part A. Dose Escalation AZD0022 in combination with Cetuximab	DRUG: AZD0022 AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.
EXPERIMENTAL: Module 2 Part B. Dose Optimisation AZD0022 in combination with Cetuximab	DRUG: AZD0022 AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.
EXPERIMENTAL: Module 2 Part C. Potential Efficacy Expansion AZD0022 in combination with Cetuximab	DRUG: AZD0022 AZD0022 is an oral KRASG12D inhibitor that blocks KRASG12D function in patients with this type of mutation.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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 outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
CR rate (Complete Response)	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion) Percentage of participants with a confirmed Complete Response (CR)	From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years
DoR (Duration of Response)	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion). Time from the date of first documented evidence of CR or PR until date of first documented disease progression or death.	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)	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion). Percentage of participants who have a confirmed CR, PR, or Stable Disease (SD) for at least 11 weeks after start of treatment.	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)	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion). Percentage of participants who have a confirmed response (CR/PR) with a duration of at least 3 months.	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)	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion) Time from first dose/randomisation date until date of first documented evidence of CR or PR per RECIST v1.1	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.
PFS (Progression Free Survival)	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion). Time from first dose/randomisation date until date of first documented disease progression or death.	'From first dose (non-randomised study parts) or from randomisation (randomised study parts) to progressive disease or death in the absence of disease progression; approximate duration of 2 years
Change in tumour size	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion) Percentage change in tumor size from baseline per RECIST v1.1	From the first dose of study intervention (non-randomised study parts) or from randomisation (randomised), at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
OS (Overall Survival)	To assess the preliminary anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion). Time from first dose/randomisation date until death due to any case.	From first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts) to death; approximate duration of 2 years.
Complete Molecular Response (cMR).	To assess the molecular response rate via ctDNA on treatment with AZD0022 as a monotherapy and in combination with other anti-cancer agents Part A (Dose Escalation), Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion).	From the first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts), at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
Pharmacokinetics of AZD0022: Maximum plasma concentration of the study drug (Cmax)	Maximum observed plasma concentration of the study drug Part A (Dose Escalation) and Part B (Dose Optimisation)	From the first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts), at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
Pharmacokinetics of AZD0022: Time to maximum plasma concentration of the study drug (T-max)	Time to maximum observed plasma concentration of the study drug Part A (Dose Escalation) and Part B (Dose Optimisation)	From the first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts), at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
Pharmacokinetics of AZD0022: AuClast (Area Under the Plasma Contentration-Time Curve to the Last Measurable Plasma Concentration)	A pharmacokinetic measurement of the volume of plasma from which the study drug is completely removed per unit time. Part A (Dose Escalation) and Part B (Dose Optimisation)	From the first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts), at predefined intervals throughout the administration of AZD0022 until Cycle 3 Day 1.
Pharmacokinetics of AZD0022: Terminal elimination half-life (t 1/2)	Terminal elimination half life. Part A (Dose Escalation) and Part B (Dose Optimisation)	From the first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts), at predefined intervals throughout the administration of AZD0022 until Cycle 3 Day 1.
Incidence of participants with Adverse events (AEs) and Serious Adverse Events (SAEs).	Determine if treatment with AZD0022 as a monotherapy and in combination with other anticancer agents is safe and tolerable through the assessment of AEs, SAEs, and change from baseline in laboratory parameters, vital signs, and ECGs. Part C (Potential Efficacy Expansion).	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 further assess the safety and tolerability of AZD0022 as a monotherapy and in combination with other anti-cancer agents Part C (Potential Efficacy Expansion).	From time of informed consent, through study completion to 30 days post last dose; an average of 2 years
TDT (Time to Discontinuation of Treatment)	To estimate the anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents. Part C (Potential Efficacy Expansion) Time from first dose/randomisation date until discontinuation of treatment or death due to any case.	From first dose until discontinuation of treatment for any reason; approximate duration of 2 years.
TFST (Time to First Subsequent Anti-Cancer)	To estimate the anti-tumour activity of AZD0022 as a monotherapy and in combination with other anti-cancer agents. Part C (Potential Efficacy Expansion). Time from first dose/randomisation date until start of first subsequent anti-cancer therapy after discontinuation of study treatment, or death due to any cause.	From date of first dose until start date of the first subsequent anti-cancer therapy after discontinuation of study treatment, or death; approximate duration of 2 years.
Change in phospho-ERK	To assess KRAS pathway inhibition on treatment with AZD0022 as monotherapy Module 1 Part A (Dose Escalation), Module 1 Part B (Dose Optimisation) and Module 1 Part C (Potential Efficacy Expansion)\* Module 2 Part A (Dose Escalation), Module 2 Part B (Dose Optimisation) and Module 2 Part C (Potential efficacy expansion)\* \*Potential Efficacy Expansion at Sponsor discretion based on emerging data.	From baseline, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
Geometric mean and 90% CI for the ratio of fed:fasted in AUClast and Cmax for food-effect cohort.	To characterise the effect of food on AZD0022 as monotherapy Module 1 Food-effect only	From first dose, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
PFS (Progression Free Survival) by BICR	To assess anti-tumour activity of AZD0022 as monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Module 1 Part B (Dose Optimisation) and Module 1 Part C (Potential Efficacy Expansion) Module 2 Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion)	From first dose (non-randomised study parts) or from randomisation (randomised study parts) to progressive disease or death in the absence of disease progression; approximate duration of 2 years
ORR (Objective Response Rate) by BICR	To assess anti-tumour activity of AZD0022 as monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Module 1 Part B (Dose Optimisation) and Module 1 Part C (Potential Efficacy Expansion) Module 2 Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion)	From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years
DoR (Duration of Rate) by BICR	To assess anti-tumour activity of AZD0022 as monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Module 1 Part B (Dose Optimisation) and Module 1 Part C (Potential Efficacy Expansion) Module 2 Part B (Dose Optimisation) and Part C (Potential Efficacy Expansion)	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.
ORR (Objective Response Rate) by Investigator	To assess anti-tumour activity of AZD0022 as monotherapy and in combination with other anti-cancer agents Radiological response evaluated according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) Module 1 Part A (Dose Escalation) and Module 1 Part B (Dose Optimisation) Module 2 Part A (Dose Escalation) and Module 2 Part B (Dose Optimisation)	From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years

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References

Clinical Trials Gov: 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