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 Identifier:
D7080C00001
CT.gov Identifier:
NCT06599502
EudraCT Identifier:
N/A
EU Trial (CTIS) Number:
2024-516699-14-00
Study Contact Information:
N/A
Terminated/Withdrawn

Considering participating in a START clinical trial?

Get Started

Study 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.

1. To investigate the safety and tolerability of AZD0022 monotherapy and combination therapy with other anticancer drugs in subjects with advanced tumors carrying KRASG12D mutations, and to determine its MTD and/or OBD 2. To evaluate the antitumor activity and PK characteristics of AZD0022 monotherapy and combination therapy with other anticancer drugs 3. To investigate the changes in biomarkers mediated by AZD0022 monotherapy and combination therapy with other anticancer drugs 4. To collect and store blood or tissue-derived samples for companion diagnostic development 5. To collect and store DNA for genomic exploratory studies in accordance with local and ethical procedures 6. To evaluate changes in blood-based tumor biomarkers at baseline and/or during treatment

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Bowel (Colorectal)
  • Non-Small Cell Lung Cancer
  • Pancreas
  • Solid Tumor
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I/II
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
    N/A
    Study Status
    Indicates the current recruitment status or the expanded access status
    Terminated/Withdrawn

    Requirements information
    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.
    • 1 Be able to sign the informed consent, including compliance with the requirements and restrictions outlined in the ICF and this protocol.
    • 2 When signing the ICF, the subject must be ≥18 years old or have reached the legal age for signing informed consent in the region where the study is located.
    • 3 Subjects must have histologically or cytologically confirmed metastatic or locally advanced tumors.
    • 4 Subjects must have received standard therapy for the specific tumor type or had disease progression during such standard therapy or be refractory or intolerant to such standard therapy, or meet module-specific criteria. Subjects with contraindications to SoC therapy or who refuse SoC therapy may be enrolled in the study, provided that there is documentation that the subject has been informed of all available treatment options.
    • 5 Documented KRASG12D mutation
    • 6 Provide FFPE tumor samples.
    • 7 Subjects must have at least one measurable target lesion according to RECIST v1.1 (Eisenhauer 2009). Target lesions in areas previously treated with radiation should not be selected unless there is clear evidence that such lesions have progressed since radiation therapy.
    • 8 ECOG PS score ≤ 1 and no deterioration within 2 weeks before the first dose.
    • 9 The researchers believe that the subjects' life expectancy is at least 12 weeks.
    • 10 Ability to swallow oral medications.
    • 11 Have adequate organ and bone marrow function
    • 12 Contraceptive measures taken by men or women should comply with local regulations on contraceptive methods that can be taken by clinical research subjects.
    • 13 Module 1: Subjects must have received standard therapy for the specific tumor type or had disease progression during such standard therapy or were refractory or intolerant to such standard therapy, or met module-specific criteria. Subjects with contraindications to SoC therapy or who refused SoC therapy were also eligible for the study, provided that there was a documented understanding of all treatment options. (a) NSCLC: Patients must have NSCLC that is not suitable for radical treatment and have had disease progression during at least one line of SoC therapy for metastatic NSCLC (including but not limited to platinum-based chemotherapy, immunotherapy, targeted therapy, or first-line SoC combination therapy); previous experimental therapy was allowed. (b) CRC: Patients must have CRC that is not suitable for radical treatment and have had disease progression during at least 2 lines of SoC therapy for metastatic CRC; previous experimental therapy was allowed. CRC patients with MSI-H or dMMR status should also receive immune checkpoint inhibitors as part of SoC (if available) and have no contraindications. Patients who have previously received anti-EGFR therapy (including but not limited to cetuximab or panitumumab) are eligible for the study (if applicable). (c) PDAC: Patients must have PDAC that is not amenable to radical treatment and have disease progression during at least one line of SoC therapy for metastatic PDAC (including but not limited to FOLFIRINOX, gemcitabine + abraxane, and gemcitabine monotherapy); prior experimental therapy is allowed. (d) Patients enrolled in Part C (NSCLC and PDAC): Prior treatment for metastatic disease must have been received at least 1 line but no more than 2 lines of therapy; prior experimental therapy is allowed.
    • 14 Disease progression or recurrence within 6 months after completion of neoadjuvant/adjuvant therapy (i.e., chemotherapy, immunotherapy, chemoradiotherapy, etc.) will be considered first-line treatment.
    • 15 Module II: Subjects must have received standard therapy for the specific tumor type or had disease progression during such standard therapy or were refractory or intolerant to such standard therapy, or meet module-specific criteria. Subjects with contraindications to SoC therapy or who refuse SoC therapy may also be included in the study, provided that there is a record that the subject has been informed of all available treatment options. (a) CRC: Patients must have CRC that is not suitable for radical treatment and have had disease progression during at least 2 lines of SoC therapy for metastatic CRC; previous experimental treatment is allowed. CRC patients with MSI-H or dMMR status should also receive immune checkpoint inhibitors as part of SoC (if available and without contraindications). Patients who have previously received anti-EGFR therapy (including but not limited to cetuximab or panitumumab) are eligible to participate in the study (if applicable). (b) PDAC: Patients must have PDAC that is not suitable for radical treatment and have disease progression during at least one line of SoC treatment for metastatic PDAC (including but not limited to FOLFIRINOX, gemcitabine + abraxane, and gemcitabine monotherapy); previous experimental treatment is allowed. (c) Patients enrolled in Part C (M2C): Have received at least 2 lines but no more than 3 lines of treatment for metastatic disease; previous experimental treatment is allowed.
    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
    • 1Any significant abnormal laboratory test results or any severe and uncontrolled medical condition, such as uncontrolled hypertension, active bleeding disorders, liver failure, unstable respiratory or cardiac disease, active bacterial, viral, fungal or other infection requiring systemic treatment, which the investigator believes makes the subject unsuitable for participation in the study or poses a safety risk to the subject.
    • 2Active gastrointestinal disease or other conditions that would significantly interfere with the absorption of oral therapy (including but not limited to uncontrolled ulcerative disease, uncontrolled nausea, vomiting, grade ≥ 2 diarrhea, malabsorption syndrome, and total small bowel resection).
    • 3Any clinically significant current or past evidence of ILD (e.g., requiring IV steroids or high supplemental oxygen), or new suspected ILD that could not be excluded by imaging at screening.
    • 4Spinal cord compression, leptomeningeal disease, or active brain metastases. Subjects with asymptomatic brain metastases are allowed to enroll if they meet the following criteria: 1. Have received treatment and have radiographically confirmed stable disease for ≥4 weeks. 2. Do not require continuous corticosteroid treatment (>10 mg prednisone/day or equivalent) for at least 2 weeks prior to the first dose.
    • 5History of allogeneic organ transplantation.
    • 6Serological status reflecting active hepatitis B or C infection: 1. Subjects with positive anti-HBc antibodies and negative surface antigen need to have a negative PCR result before enrollment. Subjects with positive hepatitis B surface antigen and positive hepatitis B PCR will be excluded. Subjects with serological results suggestive of HBV vaccination (anti-HBs positive as the only serological marker) and known previous HBV vaccination history do not need to be tested for HBV DNA by PCR. Note: In Japan, HBs antibody-positive patients will be screened, monitored, and treated for HBV DNA according to local guidelines. 2. Subjects with positive hepatitis C antibodies will need to obtain a negative PCR result before enrollment. Patients with positive hepatitis C PCR will be excluded.
    • 7HIV-infected subjects were considered eligible only if they were on effective antiretroviral therapy, had an undetectable viral load for 6 months, and had a CD4+ T-cell count of at least ≥350 cells/L.
    • 8Subjects who meet any of the following cardiac criteria: 1. Mean resting QTcF > 470 ms (averaged over 5 minutes) obtained by triplicate ECG at screening. 2. Any factors that increase the risk of QTc interval prolongation, such as congenital long QT syndrome or family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative, or any concomitant medication known to prolong the QTc interval, and factors that increase the risk of arrhythmic events, such as uncorrected serum electrolyte abnormalities (i.e., sodium, potassium, calcium, magnesium). 3. Any clinically significant resting ECG rhythm, conduction, or morphology abnormality (e.g., complete left bundle branch block, second or third degree atrioventricular block) and clinically significant sinus node dysfunction not treated with a pacemaker. 4. Bradycardia, defined as a heart rate less than 60 beats/minute and/or hypotension, defined as a blood pressure reading less than 90 mmHg (systolic) or 60 mmHg (diastolic).
    • 9Baseline LVEF is less than the lower limit of institutional normal value or <50% (whichever is lower).
    • 10Subjects with other cardiovascular diseases defined by any of the following: 1. Symptomatic heart failure (defined as New York Heart Association grade ≥ 2). 2. Acute coronary syndrome/acute myocardial infarction, unstable angina, or coronary artery intervention, percutaneous coronary intervention, or coronary artery bypass grafting within 6 months before C1D1. 3. The presence of clinically significant valvular heart disease. 4. A history of atrial or ventricular arrhythmias requiring treatment; however, subjects with extrasystoles and atrial fibrillation with optimally controlled ventricular rate are allowed to be included in the study. 5. Transient ischemic attack or stroke within 6 months before the first dose.
    • 11History of other primary malignant diseases, except for the following: 1. Malignant tumors that have received radical treatment and have no known active disease for at least 2 years before the first dose of the study intervention drug, with a low potential risk of recurrence. 2. Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease. 3. Adequately treated carcinoma in situ with no evidence of disease. 4. Local non-invasive primary diseases that are under surveillance.
    • 12Prior exposure to any direct small molecule KRAS inhibitors.
    • 13The use of herbal preparations/drugs was not permitted during the study drug treatment period (including the screening period but excluding the follow-up period).
    • 14Any drug that is known to be a strong inhibitor or inducer of CYP3A4/5 or a sensitive CYP3A4/5 substrate or a CYP3A4/5 substrate with a narrow therapeutic range (e.g., aprepitant) should not be discontinued or replaced with a safe alternative. This also applies to moderate inhibitors and moderate inducers of CYP3A4/5 during Parts A and B of Module 1 and Module 2.
    • 15Prior treatment with cytotoxic or non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter) before the first dose of the study intervention drug. Prior treatment with biologics, including immuno-oncology drugs and monoclonal antibody therapy, within 28 days or 5 half-lives (whichever is shorter) before the first dose of the study intervention drug.
    • 16Prior to the first dose of study treatment, patients had received definitive radiotherapy ≤ 4 weeks, or limited-field radiotherapy for palliative purposes ≤ 2 weeks.
    • 17Patients who have undergone major surgery (defined by the investigator) within ≤ 4 weeks before the first dose of study treatment or have not recovered from surgery.
    • 18Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up phase of an interventional study.
    • 19The patient has known hypersensitivity to the study intervention drug or any excipient of the product.
    • 20Participate in the planning and/or conduct of the study (applicable to sponsor staff and/or site staff).
    • twenty oneThe presence of any serious, acute or chronic medical condition, psychiatric disorder, alcohol or drug abuse or dependence, or abnormal laboratory test results that, in the judgment of the investigator, may increase the risks associated with participation in the study or administration of study treatment, or may interfere with the interpretation of study results, and may render the patient unsuitable for participation in the study
    • twenty twoFor women only: Currently pregnant (confirmed by a positive pregnancy test result) or breastfeeding or planning to become pregnant.

    Clinical Study Information for Healthcare Providers

    By clicking the button below you will find in-depth information about this clinical trial, including study design, primary and secondary endpoints, and more. This information is intended for healthcare professionals seeking to review the scientific and operational aspects of the study.

    View Study Information

    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START San Antonio
    San Antonio, TX, United States, 78229
    Investigator
    Drew Rasco
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Bowel (Colorectal)
    Non-Small Cell Lung Cancer
    Pancreas
    Solid Tumor