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

NCT ID: NCT05180422

Last Updated: 2023-10-18

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-15
• Study Completion Date: 2023-01-31

Brief Summary

This is a multicenter, non-randomized, open-label, phase I/II study to evaluate the safety and tolerability of AMG 510 plus MVASI in subjects with advanced KRAS p.G12C mutant non-small cell lung cancer (NSCLC) with small, untreated brain metastases.

Detailed Description

Each patient is scheduled to receive AMG 510 (KRASG12C inhibitor) in combination with MVASI (vascular endothelial growth factor [VEGF] inhibitor; bevacizumab biosimilar); both drugs will be provided by the study:

AMG 510:

Continuous once daily (QD) oral dosing (Days 1-21 each cycle) with or without food.

MVASI:

Intravenous (i.v.) infusion every 21 days (i.e. Day 1 of each 21-day cycle).

The study will be conducted in 2 parts. The dose expansion part of the study (Part 2) can open once the maximum tolerated dose (MTD) and/or a biologically active dose (e.g. recommended phase 2 dose [RP2D]) using a 3+3 study design has been determined in Part 1.

CNS response will be assessed using RANO-BM criteria, and non-CNS objective response will be based on Solid Tumor Response Criteria [RECIST v1.1] assessment of overall tumor burden at baseline versus that detected on subsequent CT/MRI re-scans. This includes a brain MRI on C2D1 (21 days) and a CT chest/abdomen/pelvis (C/A/P) at 6 weeks, then brain MRI at 15 weeks and CT C/A/P imaging at 12-16 weeks, and then every 4 cycles (every 12 weeks) while on study. It is intended that patients will be treated until disease progression or intolerable toxicity. Patients will be followed for survival for up to 18 months after ending study treatment.

Conditions

Non Small Cell Lung Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Expansion

AMG 510/MVASI

Group Type: EXPERIMENTAL

AMG 510

Intervention Type: DRUG

Continuous once daily (QD) oral dosing (Days 1-21 each cycle) with or without food.

MVASI

Intervention Type: DRUG

Intravenous (i.v.) infusion every 21 days (i.e. Day 1 of each 21-day cycle).

Interventions

AMG 510

Continuous once daily (QD) oral dosing (Days 1-21 each cycle) with or without food.

Intervention Type: DRUG

MVASI

Intravenous (i.v.) infusion every 21 days (i.e. Day 1 of each 21-day cycle).

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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.

Exclusion Criteria

Patients meeting any of the following criteria will not be permitted to enter the trial:

1. Other coexisting malignancies or malignancies diagnosed within the previous 2 years are not eligible.

• Exceptions to this include non-melanoma skin cancer, cervical cancer in-situ, well-differentiated thyroid cancer or prostate cancer.
• Other cancers that per assessment of the principal investigator are not prognosis-limiting can be allowed after review by the principal investigator. If there is no evidence of disease for at least 3 years prior to initiating treatment in this study, patients may be eligible.

2. Prior receipt of AMG-510, other KRAS G12C inhibitors, or VEGF inhibitors for the treatment of non-small cell lung cancer.

3. Myocardial infarction within 6 months of study Day 1, symptomatic congestive heart failure equivalent to New York Heart Association > Class II (see Appendix 2) or unstable (requiring hospitalization or heart catheterization) angina currently.

4. Patient on full dose, therapeutic anticoagulation for thromboembolic event, arrhythmia, or prothesis with coumadin.

5. Evidence of clinically significant hemorrhage (per study physician) in untreated CNS lesion(s) on screening MRI.

6. Major surgery within 28 days of enrollment or presence of a non-healing wound.

7. Proteinuria of greater than 1 gram per 24 hours.

8. Recent history of moderate or severe hemoptysis within 7 days (greater than 20mL of pure blood within 24 hours).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: collaborator

Criterium, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Wade Iams, MD, MSCI

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

02AT21-KRAS

Identifier Type: -

Identifier Source: org_study_id