A Phase I/II Study of AMG 510 in Combination With MVASI in Patients With Advanced, Unresectable or Metastatic KRAS G12C Mutant NSCLC With Asymptomatic Brain Metastasis

1. Signed and dated written informed consent.

2. Male or female ≥ 18 years of age at the time of informed consent.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

4. As estimated by study physician, life expectancy ≥ 12 weeks.

5. Histologically proven, locally advanced, recurrent or metastatic KRAS G12C mutant non-small cell lung cancer (NSCLC), with pathological documentation of KRAS p.G12C mutation identified through DNA sequencing either in tumor tissue or blood circulating tumor DNA.

6. At least one untreated brain metastasis ≥ 5mm in diameter in any line of treatment:

* Subjects with largest measurable intracranial lesion ≥5 mm but \<10 mm may be allowed to enroll upon agreement with investigator (for patients with target lesions of ≥ 5mm but \<10 mm, 1.5 mm slice thickness brain MRI is required).

* "Untreated" refers to the lesion not being previously treated with stereotactic radiosurgery (SRS).

* Prior treatment with whole brain radiation therapy or local surgery is permissible provided unequivocal progression in the lesion has since occurred and completion 14 days prior to study enrollment.

7. For at least 7 days prior to first dose of AMG 510 and MVASI in this study: Patient must be asymptomatic from CNS metastases and on a stable dose of corticosteroids.

8. Able to take oral medications and willing to record daily adherence to investigational product.

9. As assessed by electrocardiogram (ECG) completed ≤ 14 days before initiation of protocol treatment, the corrected QT interval (QTc) will be calculated by Fridericia's method (QTcF) - see Section 7.12. Eligible candidates (male or female) must have the following QTcF value on baseline ECG:

• QTcF ≤ 470 ms.

The average QTcF value from three (3) separate ECG tracings, each performed on the same day (ideally at least 5 minutes apart), will serve as the baseline QTcF value used to meet eligibility.

10. Adequate organ and bone marrow function resulted ≤ 14 days prior to first dose of protocol-indicated treatment:

1. Prothrombin time (PT) and partial thromboplastin time (PTT) \< 1.5x institutional upper limit of normal (ULN).

2. Absolute neutrophil count (ANC) \> 1500/µL.

3. Hemoglobin ≥ 9 g/dL.

4. Platelets ≥ 75,000/µL.

5. Total bilirubin ≤ 1.5x ULN; or

* \< 2x ULN in subjects with documented Gilbert's syndrome; or

* \< 3x ULN in subjects for whom the indirect bilirubin level suggests an extrahepatic source of total bilirubin elevation).

6. AST (SGOT) and ALT (SGPT) ≤ 2.5x ULN; or

• ≤ 5x ULN if liver metastases are present.

7. Serum creatinine ≤ 1.5mg/dL.

11. Women must not be breastfeeding and further agree to not breastfeed during study treatment; and for at least 1 week (7 days) after patient's final dose of AMG 510, and for at least 6 months (183 days) after patient's final dose of MVASI.

12. A woman of childbearing potential (WOCBP) - see Appendix 3 for definition of WOCBP - must have a negative serum or urine β-hCG pregnancy test (or in cases of β-hCG tumor production, may be confirmed not pregnant by uterine ultrasound during screening) within 14 days prior to receiving first dose of protocol-indicated treatment to be eligible, and must agree to follow instructions for using acceptable contraception (Appendix 3) from the time of signing consent, and until at least 6 months (183 days) after her final dose of AMG 510 and MVASI.

13. A man able to father children (see Appendix 3 for definition) who is sexually active with a WOCBP must agree to follow instructions for using acceptable contraception (Appendix 3), from the time of signing consent, and until at least 6 months (183 days) after his final dose of AMG 510 and MVASI.

What this study is about