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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06599502

Registration number

NCT06599502

Ethics application status

Date submitted

19/08/2024

Date registered

19/09/2024

Date last updated

13/06/2025

Titles & IDs

Public title

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

Scientific title

A Phase I/IIa, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0022 Monotherapy and in Combination With Anti-cancer Agents in Participants With Tumours Harbouring a KRASG12D Mutation (ALAFOSS-01)

Secondary ID [1]

D7080C00001

Universal Trial Number (UTN)

Trial acronym

ALAFOSS-01

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Advanced Solid Tumours

Non-Small Cell Lung Cancer (NSCLC)

Pancreatic Ductal Adenocarcinoma (PDAC)

Colorectal Cancer (CRC)

Condition category

Condition code

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - AZD0022
Treatment: Drugs - Cetuximab

Experimental: Module 1 Part A. Dose Escalation - AZD0022 monotherapy

Experimental: Module 1 Part B. Dose Optimisation - AZD0022 monotherapy

Experimental: Module 1 Part C. Potential Efficacy Expansion - AZD0022 monotherapy

Experimental: Module 1 Part B. Food Effect Cohort - AZD0022 monotherapy

Experimental: Module 2 Part A. Dose Escalation - AZD0022 in combination with Cetuximab

Experimental: Module 2 Part B. Dose Optimisation - AZD0022 in combination with Cetuximab

Experimental: Module 2 Part C. Potential Efficacy Expansion - AZD0022 in combination with Cetuximab

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

Treatment: Drugs: Cetuximab
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

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

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

Assessment method [1]

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.

Timepoint [1]

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

Primary outcome [2]

Number of patients who discontinue AZD0022 due to toxicity

Assessment method [2]

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)

Timepoint [2]

From time of informed consent to 30 days post last dose

Primary outcome [3]

ORR (Objective Response Rate)

Assessment method [3]

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)

Timepoint [3]

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

Secondary outcome [1]

CR rate (Complete Response)

Assessment method [1]

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)

Timepoint [1]

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

Secondary outcome [2]

DoR (Duration of Response)

Assessment method [2]

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.

Timepoint [2]

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.

Secondary outcome [3]

DCR (Disease Control Rate)

Assessment method [3]

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.

Timepoint [3]

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

Secondary outcome [4]

DRR (Durable Response Rate)

Assessment method [4]

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.

Timepoint [4]

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

Secondary outcome [5]

TTR (Time to Response)

Assessment method [5]

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

Timepoint [5]

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.

Secondary outcome [6]

PFS (Progression Free Survival)

Assessment method [6]

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.

Timepoint [6]

'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

Secondary outcome [7]

Change in tumour size

Assessment method [7]

Timepoint [7]

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.

Secondary outcome [8]

OS (Overall Survival)

Assessment method [8]

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.

Timepoint [8]

From first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts) to death; approximate duration of 2 years.

Secondary outcome [9]

Complete Molecular Response (cMR).

Assessment method [9]

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).

Timepoint [9]

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.

Secondary outcome [10]

Pharmacokinetics of AZD0022: Maximum plasma concentration of the study drug (Cmax)

Assessment method [10]

Maximum observed plasma concentration of the study drug Part A (Dose Escalation) and Part B (Dose Optimisation)

Timepoint [10]

Secondary outcome [11]

Pharmacokinetics of AZD0022: Time to maximum plasma concentration of the study drug (T-max)

Assessment method [11]

Time to maximum observed plasma concentration of the study drug Part A (Dose Escalation) and Part B (Dose Optimisation)

Timepoint [11]

Secondary outcome [12]

Pharmacokinetics of AZD0022: AuClast (Area Under the Plasma Contentration-Time Curve to the Last Measurable Plasma Concentration)

Assessment method [12]

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)

Timepoint [12]

Secondary outcome [13]

Pharmacokinetics of AZD0022: Terminal elimination half-life (t 1/2)

Assessment method [13]

Terminal elimination half life. Part A (Dose Escalation) and Part B (Dose Optimisation)

Timepoint [13]

Secondary outcome [14]

Incidence of participants with Adverse events (AEs) and Serious Adverse Events (SAEs).

Assessment method [14]

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).

Timepoint [14]

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

Secondary outcome [15]

Number of patients who discontinue AZD0022 due to toxicity

Assessment method [15]

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).

Timepoint [15]

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

Secondary outcome [16]

TDT (Time to Discontinuation of Treatment)

Assessment method [16]

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.

Timepoint [16]

From first dose until discontinuation of treatment for any reason; approximate duration of 2 years.

Secondary outcome [17]

TFST (Time to First Subsequent Anti-Cancer)

Assessment method [17]

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.

Timepoint [17]

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.

Secondary outcome [18]

Change in phospho-ERK

Assessment method [18]

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.

Timepoint [18]

From baseline, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.

Secondary outcome [19]

Geometric mean and 90% CI for the ratio of fed:fasted in AUClast and Cmax for food-effect cohort.

Assessment method [19]

To characterise the effect of food on AZD0022 as monotherapy Module 1 Food-effect only

Timepoint [19]

From first dose, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.

Secondary outcome [20]

PFS (Progression Free Survival) by BICR

Assessment method [20]

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)

Timepoint [20]

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

Secondary outcome [21]

ORR (Objective Response Rate) by BICR

Assessment method [21]

Timepoint [21]

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

Secondary outcome [22]

DoR (Duration of Rate) by BICR

Assessment method [22]

Timepoint [22]

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.

Secondary outcome [23]

ORR (Objective Response Rate) by Investigator

Assessment method [23]

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)

Timepoint [23]

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

Eligibility

Key inclusion criteria

Key

For whole study:

1. 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.
2. 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.
3. 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.
4. Documented KRASG12D mutation in tissue or liquid biopsy.
5. Provision of a FFPE tumour sample.
6. Participants must have at least one measurable target lesion per RECIST v1.1.
7. Adequate organ and marrow function as defined in study protocol.

Module 1 Key Inclusion Criteria

1. Type of tumours with a KRASG12D mutation:

1. 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.
2. 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.
3. 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.
4. 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.
2. 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.
3. 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.

Module 2 Inclusion Criteria

1. For Part A (M2A, dose escalation) participants must have pathologically documented locally advanced or metastatic CRC with a KRASG12D mutation.
2. For Part B (M2B, dose optimisation) participants must have pathologically documented locally advanced or metastatic, PDAC or CRC with a KRASG12D mutation.
3. For Part C (M2C, potential efficacy expansion) participants must have pathologically documented locally advanced or metastatic CRC with a KRASG12D mutation.

4(a) 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.

(b) 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.

(c) 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.

5. 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.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

For whole study:

1. Any significant laboratory finding or any severe and uncontrolled medical condition.
2. 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.
3. Spinal cord compression, leptomeningeal disease, or active brain metastases. Asymptomatic brain metastases are allowed
4. History of allogenic organ transplantation.
5. 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.
6. Prior exposure to any direct small molecule KRAS inhibitor.
7. Herbal preparations/medications are not allowed during treatment with study drug.
8. 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. This also applies to moderate inhibitors and moderate inducers of CYP3A4/5 during Parts A and B of Modules 1 and 2.
9. 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.
10. 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

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Other

Other design features

Phase

Phase 1

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Recruiting

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

18/10/2024

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

20/01/2028

Actual

Sample size

Target

430

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Research Site - Melbourne

Recruitment postcode(s) [1]

3000 - Melbourne

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

California

Country [2]

United States of America

State/province [2]

Colorado

Country [3]

United States of America

State/province [3]

Missouri

Country [4]

United States of America

State/province [4]

New York

Country [5]

United States of America

State/province [5]

Pennsylvania

Country [6]

United States of America

State/province [6]

Texas

Country [7]

United States of America

State/province [7]

Virginia

Country [8]

Belgium

State/province [8]

Edegem

Country [9]

Belgium

State/province [9]

Leuven

Country [10]

Canada

State/province [10]

Alberta

Country [11]

Canada

State/province [11]

Ontario

Country [12]

Canada

State/province [12]

Quebec

Country [13]

China

State/province [13]

Beijing

Country [14]

China

State/province [14]

Chengdu

Country [15]

China

State/province [15]

Zhengzhou

Country [16]

Hong Kong

State/province [16]

Hong Kong

Country [17]

Italy

State/province [17]

Milano

Country [18]

Italy

State/province [18]

Napoli

Country [19]

Italy

State/province [19]

Verona

Country [20]

Japan

State/province [20]

Kashiwa

Country [21]

Japan

State/province [21]

Tokyo

Country [22]

Korea, Republic of

State/province [22]

Seoul

Country [23]

Netherlands

State/province [23]

Amsterdam

Country [24]

Poland

State/province [24]

Gdansk

Country [25]

Poland

State/province [25]

Lódz

Country [26]

Spain

State/province [26]

Barcelona

Country [27]

Spain

State/province [27]

L'Hospitalet de Llobregat

Country [28]

Spain

State/province [28]

Madrid

Country [29]

Spain

State/province [29]

Valencia

Country [30]

Thailand

State/province [30]

Bangkok

Country [31]

Turkey

State/province [31]

Ankara

Country [32]

Turkey

State/province [32]

Istanbul

Country [33]

United Kingdom

State/province [33]

Cambridge

Country [34]

United Kingdom

State/province [34]

Manchester

Country [35]

United Kingdom

State/province [35]

Newcastle-Upon-Tyne

Funding & Sponsors

Primary sponsor type

Commercial sector/industry

Name

AstraZeneca

Country

Ethics approval

Ethics application status

Summary

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.

Trial website

https://clinicaltrials.gov/study/NCT06599502

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Contact person for public queries

Name

AstraZeneca Clinical Study Information Center

Address

Country

Phone

1-877-240-9479

information.center@astrazeneca.com

Contact person for scientific queries

Data sharing statement

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT06599502

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06599502