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)

AstraZeneca6 sites in 4 countries17 target enrollmentOctober 18, 2024

InterventionsAZD0022 Cetuximab

DrugsAZD0022

Overview

Phase: Phase 1
Intervention: AZD0022
Conditions: Not specified
Sponsor: AstraZeneca
Enrollment: 17
Locations: 6
Primary Endpoint: Incidence of participants with Dose-Limiting Toxicity (DLT), Adverse events (AEs) and Serious Adverse Events (SAEs).
Status: Terminated
Last Updated: last month

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials Related News

Overview

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.

Detailed Description

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).

Registry

euclinicaltrials.eu

Start Date

October 18, 2024

End Date

January 29, 2026

Last Updated

last month

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

AstraZeneca

Responsible Party

Sponsor

Principal Investigator

AstraZeneca Clinical Study Information Center

Scientific

AstraZeneca AB

Eligibility Criteria

Inclusion Criteria

•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 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.
•Adequate organ and marrow function as defined in study protocol.
•Module 1 Key Inclusion Criteria
•Type of tumours with a KRASG12D mutation:

Exclusion Criteria

•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).

Intervention: Cetuximab

Outcomes

Primary Outcomes

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

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

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.

Number of patients who discontinue AZD0022 due to toxicity

Time Frame: From time of informed consent to 30 days post last dose

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)

ORR (Objective Response Rate)

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

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)

Secondary Outcomes

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.)
PFS (Progression Free Survival)('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(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)(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).(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)(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)(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)(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)(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).(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(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)(From first dose until discontinuation of treatment for any reason; approximate duration of 2 years.)
TFST (Time to First Subsequent Anti-Cancer)(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(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.(From first dose, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.)
PFS (Progression Free Survival) by BICR(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(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(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(From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years)