Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer

Non Small Cell Lung Cancer Clinical Trial

Official title:

A Phase 1 Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03704688
• Other study ID #: 17-297
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: October 9, 2018
• Est. completion date: February 4, 2022

Study information

• Verified date: February 2022
• Source: Memorial Sloan Kettering Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety of the combination of ponatinib and trametinib as well as the most appropriate dosages of the combination.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: February 4, 2022
• Est. primary completion date: February 4, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically proven diagnosis of advanced lung adenocarcinoma

• KRAS mutation

• Radiographic progression following prior treatment with platinum doublet chemotherapy and prior treatment with a PD-1/L1 inhibitor. Patients who are deemed not eligible for therapy with a PD-1/L1 inhibitor by their treating physician will also be eligible.

• Able to take oral medications

• Measurable disease as per RECIST 1.1. Previously irradiated sites of tumor may be considered measurable if there is radiographic progression at the site subsequent to the time of completing radiation.

• Karnofsky performance status (KPS) = 70%

• Age >18 years old

• Adequate organ function:

• AST, ALT = 2.5 x ULN - Total bilirubin = 1.5 x ULN -Albumin = 2.5g/dL

• Creatinine < 1.5 x ULN OR calculated creatinine clearance = 50mL/min

• Absolute neutrophil count (ANC) = 1,200 cells/mm^3

• Hemoglobin = 9.0 g/dL

• Platelets = 100,000/mm^3

• Amylase and lipase within normal limits (amylase = 100, lipase = 78)

• Female patients who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse

• Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, or

• Agree to completely abstain from heterosexual intercourse

Exclusion Criteria:

• Patients with symptomatic brain metastasis requiring escalating doses of steroids

• Patients with grade 2 or greater diarrhea prior to study initiation despite maximal medical management

• History of acute pancreatitis within 1 year of study entry or history of chronic pancreatitis

• History of or ongoing alcohol abuse that, in the opinion of the Investigator, would compromise compliance or impart excess risks associated with study participation.

• Pregnant or lactating women

• Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of starting treatment on protocol

• Patients who have received prior treatment with MEK inhibitor

• A history of clinically significant interstitial lung disease or pneumonitis

• Significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to: History of clinically significant (as determined by the treating physician) atrial arrhythmia; or any ventricular arrhythmia, History of congenital long QT syndrome., Abnormal QTc (= 450 msec in males and = 470 msec in females), Ejection fraction = 50% as assessed by echocardiogram.

• History of arterial thrombotic disease, specifically including, but not restricted to:

Myocardial infarction or unstable angina, cerebrovascular event (CVA) or transient ischemic attack (TIA), Peripheral vascular disease or claudication.

• Uncontrolled hypertension (Diastolic blood pressure > 100 mmHg; Systolic blood pressure > 150 mmHg).

• History of venous thromboembolism (e.g. deep venous thrombosis or pulmonary embolism) within 6 months of study entry. Note: Participants enrolled after this window must be on appropriate therapeutic anticoagulation.

• History of central serous retinopathy or retinal vein occlusion

• Patients with baseline risk factors for central serous retinopathy or retinal vein occlusion such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure >21 mmHg are excluded from the trial

• History of prior malignancy within 2 years that requires treatment. Patients who are considered NED from a malignancy may be considered on a case by case basis.

• Any other condition that, in the opinion of the investigator, may compromise the safety, compliance of the patient, or would preclude the patient from successful completion of the study

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• KRAS Gene Mutation
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• Trametinib 0.5 mg
0.5mg PO q daily
• Trametinib 1 MG
1.0 mg PO q daily
• Trametinib 1.5 MG
1.5mg PO q daily
• Trametinib 2 mg
2 mg PO q daily
• Ponatinib 15 MG
15mg PO q daily
• Ponatinib 30 MG
30mg PO q daily

Locations

Country	Name	City	State
United States	Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)	Basking Ridge	New Jersey
United States	Memorial Sloan Kettering Cancer Center @ Suffolk (Limited protocol activity)	Commack	New York
United States	Memorial Sloan Kettering Westchester (Limited Protocol Activities)	Harrison	New York
United States	Memorial Sloan Kettering Monmouth (Limited Protocol Activities)	Middletown	New Jersey
United States	Memorial Sloan Kettering Bergen (Limited Protocol Activities)	Montvale	New Jersey
United States	Memorial Sloan - Kettering Cancer Center	New York	New York
United States	Memorial Sloan Kettering Nassau (Limited protocol activity)	Uniondale	New York

Sponsors (1)

Lead Sponsor	Collaborator
Memorial Sloan Kettering Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose of Ponatinib, Phase I	In the Phase I portion of the study, a standard 3+3 design will be used to find the maximum tolerated dose.	maximum of 18 months
Primary	Overall Response Rate	In the Phase II portion of the study, RECIST criteria 1.1 will evaluate the overall response rate. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	1 year

External Links

•   Memorial Sloan Kettering Cancer Center