Clinical trial NCT06599502: 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
Official 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumours
Non-Small Cell Lung Cancer (NSCLC)
Pancreatic Ductal Adenocarcinoma (PDAC)
Colorectal Cancer (CRC)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2024-09-19
Enrollment: 430
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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
Primary purpose: TREATMENT

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).

Eligibility criteria: Key Inclusion Criteria:

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.

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

Primary outcomes:
measure: Incidence of participants with Dose-Limiting Toxicity (DLT), Adverse events (AEs) and Serious Adverse Events (SAEs).
timeFrame: From time of informed consent, through study completion to 30 days post last dose; an average of 2 years
measure: Number of patients who discontinue AZD0022 due to toxicity
timeFrame: From time of informed consent to 30 days post last dose
measure: ORR (Objective Response Rate)
timeFrame: Time from first dose of AZD002 through study completion; approximate duration of 2 years
Secondary outcomes:
measure: CR rate (Complete Response)
timeFrame: From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years
measure: DoR (Duration of Response)
timeFrame: 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.
measure: DCR (Disease Control Rate)
timeFrame: From first dose (non-randomised study parts) or from randomisation (randomised) until progression. For each patient, this is expected to be at 12 weeks
measure: DRR (Durable Response Rate)
timeFrame: From first documented response up until progression, or the last evaluable assessment in the absence of progression; approximate duration of 2 years.
measure: TTR (Time to Response)
timeFrame: 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.
measure: PFS (Progression Free Survival)
timeFrame: '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
measure: Change in tumour size
timeFrame: 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.
measure: OS (Overall Survival)
timeFrame: From first dose of study intervention (non-randomised study parts) or from randomisation (randomised study parts) to death; approximate duration of 2 years.
measure: Complete Molecular Response (cMR).
timeFrame: 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.
measure: Pharmacokinetics of AZD0022: Maximum plasma concentration of the study drug (Cmax)
timeFrame: 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.
measure: Pharmacokinetics of AZD0022: Time to maximum plasma concentration of the study drug (T-max)
timeFrame: 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.
measure: Pharmacokinetics of AZD0022: AuClast (Area Under the Plasma Contentration-Time Curve to the Last Measurable Plasma Concentration)
timeFrame: 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.
measure: Pharmacokinetics of AZD0022: Terminal elimination half-life (t 1/2)
timeFrame: 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.
measure: Incidence of participants with Adverse events (AEs) and Serious Adverse Events (SAEs).
timeFrame: From time of informed consent, through study completion to 30 days post last dose; an average of 2 years
measure: Number of patients who discontinue AZD0022 due to toxicity
timeFrame: From time of informed consent, through study completion to 30 days post last dose; an average of 2 years
measure: TDT (Time to Discontinuation of Treatment)
timeFrame: From first dose until discontinuation of treatment for any reason; approximate duration of 2 years.
measure: TFST (Time to First Subsequent Anti-Cancer)
timeFrame: 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.
measure: Change in phospho-ERK
timeFrame: From baseline, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
measure: Geometric mean and 90% CI for the ratio of fed:fasted in AUClast and Cmax for food-effect cohort.
timeFrame: From first dose, at predefined intervals throughout the administration of AZD0022; approximate duration of 2 years.
measure: PFS (Progression Free Survival) by BICR
timeFrame: 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
measure: ORR (Objective Response Rate) by BICR
timeFrame: From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years
measure: DoR (Duration of Rate) by BICR
timeFrame: 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.
measure: ORR (Objective Response Rate) by Investigator
timeFrame: From first dose (non-randomised study parts) or from randomisation (randomised) through study completion; approximate duration of 2 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Stanford
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Kansas City
country: United States
facility: Research Site
state: Missouri
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Melbourne
country: Australia
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Beijing
country: China
facility: Research Site
city: Chengdu
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
city: Hong Kong
country: Hong Kong
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Verona
country: Italy
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: L'Hospitalet de Llobregat
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Research Site
Study officials:
References: