A Phase I/II Study of ABSK141 in Patients With Advanced Solid Tumors ( ABSK141-101 )

The study will start with a dose escalation of oral ABSK141 in patients with advanced solid tumors harboring KRAS G12D mutation to evaluate safety, tolerability, and PK. The expansion part will investigate oral ABSK141 at the recommended doses for expansion (RDEs) to evaluate safety and efficacy among selected tumor types harboring KRAS G12D mutation and optimize the dosage.

The phase II study will further investigate oral ABSK141 at the recommended phase 2 doses (RP2Ds) to evaluate safety and efficacy among selected tumor types harboring KRAS G12D mutation.

• ABSK141-400mg (Drug), also known as ABSK141, investigational drug: In the escalation part#patients will first orally receive a single dose of ABSK141 on D-3, followed by a three-day run-in period to assess the PK profile of singledose ABSK141 400mg administration. Thereafter, patients will continuously receive ABSK141 400mg once daily (QD).
• ABSK141-Recommended Dose for Expansion (RDE) (Drug), also known as ABSK141, investigational drug: In the expansion part# patients will orally receive ABSK141 at the recommended dose for expansion (RDE).patients will continuously receive ABSK141 Recommended Dose for Expansion (RDE) once daily (QD).
• ABSK141-800mg (Drug), also known as ABSK141, investigational drug: In the escalation part#patients will first orally receive a single dose of ABSK141 on D-3, followed by a three-day run-in period to assess the PK profile of singledose ABSK141 800mg administration. Thereafter, patients will continuously receive ABSK141 800mg once daily (QD).
• ABSK141-1200mg (Drug), also known as ABSK141, investigational drug: In the escalation part#patients will first orally receive a single dose of ABSK141 on D-3, followed by a three-day run-in period to assess the PK profile of singledose ABSK141 1200mg administration. Thereafter, patients will continuously receive ABSK141 1200mg once daily (QD).
• ABSK141-Recommended Phase 2 dose (RP2D) (Drug), also known as ABSK141, investigational drug: Phase II #patients will orally receive ABSK141 at the Recommended Phase 2 Dose (RP2D).

Primary outcomes

• Incidence of DLTs [from Run-in to Day28]: dose-limiting toxicities
• Incidence and severity of AEs [from the time that the patient provides informed consent through and including 30 days after the last administration of ABSK141.]: Adverse events
• Incidence and severity of SAEs [from the time that the patient provides informed consent through and including 30 days after the last administration of ABSK141.]: serious adverse events

Secondary outcomes

• Cmax [From pre-dose to up to 72 hours post-dose]: maximum observed concentration
• AUC [From pre-dose to up to 72 hours post-dose]: area under the concentration-time curve
• t1/2 [From pre-dose to up to 72 hours post-dose]: elimination half-life
• CL/F [From pre-dose to up to 72 hours post-dose]: apparent oral clearance
• tmax [From pre-dose to up to 72 hours post-dose]: time to maximum observed concentration
• ORR [From the first dose date to the date of first confirmed response (CR/PR), assessed up to 24 months.]: Objective response rate
• DOR [From date of first confirmed response (CR/PR) to date of first documented progression (PD) or death from any cause, whichever comes first, assessed up to 24 months.]: Duration of response
• PFS [From the first dose date to the date of first documented progressive disease (PD) or death from any cause, whichever occurs first, assessed up to 24 months.]: Progression-free survival
• DCR [From the first dose date to the date of first documented disease status assessment (CR/PR/SD/PD), assessed up to 24 months.]: Disease control rate
• OS [From the first dose date to the date of death from any cause, assessed up to24 months]: Overall survival

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patients should understand, sign, and date the written informed consent form prior to screening
2. Male or female age 18 years or older
3. Patients with histologically confirmed locally-advanced or metastatic solid tumors .

For backfill cohorts in the escalation part:

1. Patients must have the following solid tumor harboring KRAS G12D mutation:

   1. Colorectal cancer (CRC);
   2. Non-small cell lung cancer (NSCLC);
   3. Pancreatic ductal adenocarcinoma (PDAC);
2. Patients must have at least one measurable target lesion according to RECIST 1.1

For expansion Part:

1. Patients must have the following solid tumor harboring KRAS G12D mutation:

   1. Colorectal cancer (CRC);
   2. Non-small cell lung cancer (NSCLC);
   3. Pancreatic ductal adenocarcinoma (PDAC);
   4. Other solid tumors;
2. Patients must have at least one measurable target lesion according to RECIST 1.1

For phase II:

1. Patients with locally advanced or metastatic solid tumors confirmed by histological examination, whose disease has progressed after standard treatment or who are intolerant to standard treatment, or for whom there is currently no standard treatment.
2. Patients must have the following solid tumor harboring KRAS G12D mutation:

   1. Colorectal cancer (CRC);
   2. Non-small cell lung cancer (NSCLC);
   3. Pancreatic ductal adenocarcinoma (PDAC);
   4. Other solid tumors;
3. Patients must have at least one measurable target lesion according to RECIST 1.1 4. ECOG performance status 0 or 1 5. Adequate organ function and bone marrow function as indicated by the following screening assessments performed within 14 days prior to the first dose of study drug 6. For patients participating exploration of food effect:

(1) be able to eat a standardized high-fat, high caloric meal within 30 minutes (2) be able to fast for 10 hours

Exclusion Criteria:

1. Known allergy or hypersensitivity to any component of the investigational product
2. (For backfill cohorts and expansion part) Patients who were previously treated with an investigational KRAS G12D inhibitor, pan- or multi-RAS inhibitor, or had prior therapy with any direct RAS-targeted therapy
3. Has a known additional malignancy that is progressing or has required active treatment
4. Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly affecting GI function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. If any of these conditions exist, the site should discuss with the sponsor to determine patient eligibility
5. Previous anti-tumor therapy, including chemotherapy, endocrine therapy, molecular targeted therapy or other investigational drugs received ≤2 weeks or ≤5-half life (whichever is shorter), radiotherapy and antibody therapy received ≤4 weeks prior to initiation of study treatment
6. Major surgery within 4 weeks of the first dose of study drug. Note that all surgical wounds must be healed and free of infection or dehiscence
7. Prior toxicities from chemotherapy, radiotherapy, and other anti-cancer therapies, including immunotherapy, that have not regressed to Grade ≤1 severity (CTCAE v5.0)
8. Patients should not use proton pump inhibitors for at least 7 days prior to the first dose of ABSK141 and during treatment with ABSK141.
9. P-gp inhibitor and strong CYP3A inhibitors to 7 days or 5 half-lives whichever is longer and for CYP3A inducers to 2 weeks or 5 half-lives
10. Active central nervous system (CNS) metastases
11. History of interstitial lung disease requiring systemic steroid treatment.
12. Impaired cardiac function or clinically significant cardiac disease
13. NSCLC cohorts: Patient previously identified as having a driver mutation (according to local standard of care or guidelines) and have not received any targeted therapy, for example: EGFR mutation, ALK rearrangement, KRAS G12C mutation, NTRK1/2/3 gene fusion, RET fusion, MET exon14 skipping mutation, BRAF V600E mutation, ROS1 rearrangement, etc
14. Known acquired immunodeficiency syndrome (AIDS)-related illness, or positive test for HIV 1/2 antibody
15. Exclusion of hepatitis infection
16. Patients with refractory/uncontrolled ascites or pleural effusion
17. Pregnant or nursing (lactating) women
18. refuse to use highly effective methods of birth control during the study and for up to 6 months after the last dose of study drug.
19. Sexually active males who refuse to use a condom during intercourse while taking drug and for 5 consecutive compound half-lives plus 60 days after stopping study drug.
20. Vaccination with a live, attenuated vaccine within 4 weeks prior to the first dose of study treatment except for administration of inactivate vaccines
21. Planned major surgery during study treatment
22. Any other clinically significant comorbidities

• Xianjun Yu, Doctor, Principal investigator, Fudan University