Summary

This is a Phase 1a/1b study of aurora kinase A inhibitor VIC-1911 administered as
monotherapy and in combination with sotorasib for the treatment of locally advanced or
metastatic KRAS G12C-mutant non-small cell lung cancer(NSCLC).

Objectives

Selected subjects will include males and females age =18 years; histologically confirmed
locally advanced or metastatic KRAS G12C-mutated NSCLC; received at least 1 prior line of
cancer therapy with a PD-1 or PD-L1 inhibitor with or without platinum-based
chemotherapy; recovered from all acute toxicities (= Grade 1) due to prior therapy;
adequate renal and hepatic function; and no known history of significant cardiac, hepatic
or ocular disease.

Dose Escalation Phase:

Following screening, a total of up to 36 subjects are anticipated to establish the dose
limiting toxicity (DLT) and maximum tolerated doses (MTDs) of VIC-1911 monotherapy and
VIC-1911 in combination with sotorasib therapy.

Cohort 1a: Subjects who are refractory to or relapsed on prior KRAS G12C inhibitor
therapy will receive VIC-1911 monotherapy. Up to 24 subjects are anticipated in this
cohort.

Cohort 1b: Subjects who are refractory to or relapsed on prior KRAS G12C inhibitor
therapy or are naïve to KRASG12C inhibitor therapy will receive VIC-1911 plus sotorasib
combination therapy. Up to 12 subjects are anticipated in this cohort.

A 3+3 dose escalation schema will be followed to establish the dose limiting toxicity
(DLT) and maximum tolerated dose (MTD) of VIC-1911 and VIC-1911 plus sotorasib
combination. A total of at least 6 subjects will be treated at the MTD in each group
before initiating the Expansion Phase.

Expansion Phase:

Following screening, a total of 104 subjects with KRAS G12C-mutated locally advanced or
metastatic NSCLC are anticipated to expand the disease treatment settings of VIC-1911 as
monotherapy or in combination with sotorasib. VIC-1911 monotherapy and VIC-1911 plus
sotorasib combination therapy will be administered orally at the MTDs established during
the Dose Escalation Phase.

Cohort 2a: Subjects who are refractory to or relapsed on prior KRAS G12C inhibitor
therapy will receive VIC-1911 monotherapy. (n=29)

Cohort 2b: Subjects who are refractory to or relapsed on prior KRAS G12C inhibitor
therapy will receive VIC-1911 plus sotorasib combination therapy.(n=29)

Cohort 2c: Subjects who are naïve to KRAS G12C inhibitor therapy will receive VIC-1911
plus sotorasib combination therapy. (n=46)

VIC-1911 and sotorasib will be taken in the fasted state, 1 hour before or 2 hours after
a meal.

Subjects who demonstrate clinical benefit (CR, PR or SD) will be allowed to continue
therapy with VIC-1911 and sotorasib until progression of disease, observation of
unacceptable adverse events, intercurrent illness or changes in the subject's condition
that prevents further study participation.

Disease response will be assessed according to Response Evaluation Criteria in Solid
Tumors (RECIST v.1.1).

Blood for hematology, coagulation parameters and serum chemistry determinations and urine
will be collected, ECGs will be taken and ophthalmologic exams will be conducted during
the study.

Blood will be taken for PK assessment of VIC-1911 and PD assessment of circulating tumor
DNA biomarker determinations.

Tumor biopsies will be taken from consenting subjects at Screening and on-study for
correlative biomarker determinations. Results will be correlated with clinical outcome.

Eligibility

1. Males and females = 18 years of age
2. Have locally advanced or metastatic histologically or cytologically confirmed NSCLC, KRAS G12C-mutated
3. The presence of a KRAS G12C mutation should be established prior to entry as assessed in a CLIA qualified laboratory. Testing may be done on tumor tissue (archival or fresh) or on ctDNA from blood.
4. Have received at least 1 prior line of cancer therapy with a PD-1 or PD-L1 inhibitor with or without platinum-based chemotherapy (unless subject is not eligible or refuses chemotherapy or PD-1/PD-L1 therapy and have documented progression on all prior cancer therapies
5. Dose Escalation Phase:
6. Cohort 1a: (VIC-1911 monotherapy): Locally advanced or metastatic NSCLC refractory to or relapsed on at least 1 prior cancer therapy as noted above, and relapsed/refractory on KRAS G12C inhibitor therapy as the most recent cancer therapy prior to study
7. Cohort 1b: (VIC-1911 plus sotorasib): Locally advanced or metastatic NSCLC:
8. Refractory to or relapsed on at least 1 prior cancer therapy as noted above, and relapsed/refractory on KRAS G12C inhibitor therapy as the most recent cancer therapy prior to study, or
9. Refractory to or relapsed on at least 1 prior cancer therapy as noted above, and Naïve to KRAS G12C inhibitor therapy
10. Expansion Phase 1b:
11. Cohort 2a: (VIC-1911 monotherapy): Locally advanced or metastatic NSCLC refractory to or relapsed on at least 1 prior cancer therapy as noted above, and relapsed/refractory on KRAS G12C inhibitor therapy as the most recent cancer therapy prior to study
12. Cohort 2b: (VIC-1911 plus sotorasib): Locally advanced or metastatic NSCLC refractory to or relapsed on at least 1 prior cancer therapy as noted above, and relapsed/refractory on KRAS G12C inhibitor therapy as the most recent cancer therapy prior to study
13. Cohort 2c: (VIC-1911 plus sotorasib): Locally advanced or metastatic NSCLC refractory to or relapsed on at least 1 prior cancer therapy as noted above, and naïve to KRAS G12C inhibitor therapy
14. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
15. Have discontinued previous treatments for cancer, except for sotorasib for subjects to receive VIC-1911 plus sotorasib combination treatment, and have resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior cancer treatment, surgery, or radiotherapy to Grade = 1
16. Adequate performance status: Eastern Cooperative Oncology Group (ECOG) = 2
17. Life expectancy of = 3 months
18. Subjects with brain metastases: 11.1 KRAS G12C inhibitor naïve: Subjects with clinically stable (i.e., no increase in corticosteroid requirement) asymptomatic brain metastases are allowed without prior local therapy, as long as all lesions are each = 1 cm. Prior local therapy is required (e.g., stereotactic radiosurgery [SRS], stereotactic body radiation therapy [SBRT], or surgery) for any lesion > 1 cm or any lesion that is symptomatic. Subjects must be clinically stable and asymptomatic following local therapy. 11.2 KRAS G12C inhibitor pretreated: Subjects with clinically stable (i.e., no increase in corticosteroid requirement) asymptomatic brain metastases following prior local therapy (e.g., SRS, SBRT or surgery) are allowed.
19. Adequate hematologic without ongoing transfusion support:
20. Hemoglobin (Hb) = 8 g/dL
21. Absolute neutrophil count (ANC) = 1.0 x 10^9 cells/L
22. Platelets = 75 x 10^9 cells/L
23. Adequate renal and hepatic function:
24. Calculated creatinine clearance = 50 mL/minute x 1.73 m2 per the Cockcroft-Gault formula
25. Total bilirubin = 1.5 times the ULN, unless due to Gilbert's disease, or < 3 times the ULN for subjects with liver metastases
26. ALT/AST = 2 times the ULN, or < 3 times the ULN for subjects with liver metastases
27. Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects must agree to use adequate methods to avoid pregnancy throughout the study and for 28 days after the completion of study treatment.
28. Ability to proved written informed consent

Treatment Sites in Georgia