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

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.

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.

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.

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.

What this study is about