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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

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] 0 0
D7080C00001
Universal Trial Number (UTN)
Trial acronym
ALAFOSS-01
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Solid Tumours 0 0
Non-Small Cell Lung Cancer (NSCLC) 0 0
Pancreatic Ductal Adenocarcinoma (PDAC) 0 0
Colorectal Cancer (CRC) 0 0
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] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of participants with Dose-Limiting Toxicity (DLT), Adverse events (AEs) and Serious Adverse Events (SAEs).
Timepoint [1] 0 0
From time of informed consent, through study completion to 30 days post last dose; an average of 2 years
Primary outcome [2] 0 0
Number of patients who discontinue AZD0022 due to toxicity
Timepoint [2] 0 0
From time of informed consent to 30 days post last dose
Primary outcome [3] 0 0
ORR (Objective Response Rate)
Timepoint [3] 0 0
Time from first dose of AZD002 through study completion; approximate duration of 2 years
Secondary outcome [1] 0 0
CR rate (Complete Response)
Timepoint [1] 0 0
From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years
Secondary outcome [2] 0 0
DoR (Duration of Response)
Timepoint [2] 0 0
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] 0 0
DCR (Disease Control Rate)
Timepoint [3] 0 0
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] 0 0
DRR (Durable Response Rate)
Timepoint [4] 0 0
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] 0 0
TTR (Time to Response)
Timepoint [5] 0 0
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] 0 0
PFS (Progression Free Survival)
Timepoint [6] 0 0
'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] 0 0
Change in tumour size
Timepoint [7] 0 0
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] 0 0
OS (Overall Survival)
Timepoint [8] 0 0
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] 0 0
Complete Molecular Response (cMR).
Timepoint [9] 0 0
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] 0 0
Pharmacokinetics of AZD0022: Maximum plasma concentration of the study drug (Cmax)
Timepoint [10] 0 0
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 [11] 0 0
Pharmacokinetics of AZD0022: Time to maximum plasma concentration of the study drug (T-max)
Timepoint [11] 0 0
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 [12] 0 0
Pharmacokinetics of AZD0022: AuClast (Area Under the Plasma Contentration-Time Curve to the Last Measurable Plasma Concentration)
Timepoint [12] 0 0
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.
Secondary outcome [13] 0 0
Pharmacokinetics of AZD0022: Terminal elimination half-life (t 1/2)
Timepoint [13] 0 0
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.
Secondary outcome [14] 0 0
Incidence of participants with Adverse events (AEs) and Serious Adverse Events (SAEs).
Timepoint [14] 0 0
From time of informed consent, through study completion to 30 days post last dose; an average of 2 years
Secondary outcome [15] 0 0
Number of patients who discontinue AZD0022 due to toxicity
Timepoint [15] 0 0
From time of informed consent, through study completion to 30 days post last dose; an average of 2 years
Secondary outcome [16] 0 0
TDT (Time to Discontinuation of Treatment)
Timepoint [16] 0 0
From first dose until discontinuation of treatment for any reason; approximate duration of 2 years.
Secondary outcome [17] 0 0
TFST (Time to First Subsequent Anti-Cancer)
Timepoint [17] 0 0
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] 0 0
Change in phospho-ERK
Timepoint [18] 0 0
From baseline, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
Secondary outcome [19] 0 0
Geometric mean and 90% CI for the ratio of fed:fasted in AUClast and Cmax for food-effect cohort.
Timepoint [19] 0 0
From first dose, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
Secondary outcome [20] 0 0
PFS (Progression Free Survival) by BICR
Timepoint [20] 0 0
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] 0 0
ORR (Objective Response Rate) by BICR
Timepoint [21] 0 0
From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years
Secondary outcome [22] 0 0
DoR (Duration of Rate) by BICR
Timepoint [22] 0 0
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] 0 0
ORR (Objective Response Rate) by Investigator
Timepoint [23] 0 0
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?
No
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
3/02/2028
Actual
Sample size
Target
430
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Missouri
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
United States of America
State/province [4] 0 0
Virginia
Country [5] 0 0
Belgium
State/province [5] 0 0
Edegem
Country [6] 0 0
Belgium
State/province [6] 0 0
Leuven
Country [7] 0 0
Canada
State/province [7] 0 0
Alberta
Country [8] 0 0
Canada
State/province [8] 0 0
Ontario
Country [9] 0 0
Canada
State/province [9] 0 0
Quebec
Country [10] 0 0
Italy
State/province [10] 0 0
Milano
Country [11] 0 0
Italy
State/province [11] 0 0
Napoli
Country [12] 0 0
Italy
State/province [12] 0 0
Verona
Country [13] 0 0
Netherlands
State/province [13] 0 0
Amsterdam
Country [14] 0 0
Poland
State/province [14] 0 0
Gdansk
Country [15] 0 0
Poland
State/province [15] 0 0
Lódz
Country [16] 0 0
Spain
State/province [16] 0 0
Barcelona
Country [17] 0 0
Spain
State/province [17] 0 0
L'Hospitalet de Llobregat
Country [18] 0 0
Spain
State/province [18] 0 0
Madrid
Country [19] 0 0
Spain
State/province [19] 0 0
Valencia
Country [20] 0 0
Turkey
State/province [20] 0 0
Ankara
Country [21] 0 0
Turkey
State/province [21] 0 0
Istanbul

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
AstraZeneca Clinical Study Information Center
Address 0 0
Country 0 0
Phone 0 0
1-877-240-9479
Fax 0 0
Email 0 0
information.center@astrazeneca.com
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
When will data be available (start and end dates)?
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
Available to whom?
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.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://vivli.org/


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