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

NCT03704688 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 17-297
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Non Small Cell Lung Cancer; KRAS Gene Mutation

Keywords

trametinib; Ponatinib; KRAS Mutant Advanced Non-Small Cell Lung Cancer; 17-297; Memorial Sloan Kettering Cancer Center

Outcome Measures

Primary Outcomes (2)

• 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

• 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

Study Arms (6)

Phase I: Dose Level -3

EXPERIMENTAL

Trametinib 0.5mg PO q daily Ponatinib 15mg PO q daily

Drug: Trametinib 0.5 mg; Drug: Ponatinib 15 MG

Phase I: Dose Level -2

EXPERIMENTAL

Trametinib 1.0 mg PO q daily Ponatinib 15mg PO q daily

Drug: Trametinib 1 MG; Drug: Ponatinib 15 MG

Phase I: Dose Level -1

EXPERIMENTAL

Trametinib 1.5 mg PO q daily 15mg PO q daily

Drug: Trametinib 1.5 MG; Drug: Ponatinib 15 MG

Phase I: Dose Level 1

EXPERIMENTAL

Trametinib 2 mg PO q daily Ponatinib 15mg PO q daily

Drug: Trametinib 2 mg; Drug: Ponatinib 15 MG

Phase I: Dose Level 2

EXPERIMENTAL

Trametinib 2 mg PO q daily Ponatinib 30mg PO q daily

Drug: Trametinib 2 mg; Drug: Ponatinib 30 MG

Phase II

EXPERIMENTAL

Maximum tolerated dose as established in Phase I portion

Drug: Trametinib 2 mg; Drug: Ponatinib 15 MG

Interventions

Trametinib 0.5 mg DRUG

0.5mg PO q daily

Phase I: Dose Level -3

Trametinib 1 MG DRUG

1.0 mg PO q daily

Phase I: Dose Level -2

Trametinib 1.5 MG DRUG

1.5mg PO q daily

Phase I: Dose Level -1

Trametinib 2 mg DRUG

2 mg PO q daily

Phase I: Dose Level 1; Phase I: Dose Level 2; Phase II

Ponatinib 15 MG DRUG

15mg PO q daily

Phase I: Dose Level -1; Phase I: Dose Level -2; Phase I: Dose Level -3; Phase I: Dose Level 1; Phase II

Ponatinib 30 MG DRUG

30mg PO q daily

Phase I: Dose Level 2

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead

Study Sites (7)

Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)

Basking Ridge, New Jersey, 07920, United States

Location

Memorial Sloan Kettering Monmouth (Limited Protocol Activities)

Middletown, New Jersey, 07748, United States

Location

Memorial Sloan Kettering Bergen (Limited Protocol Activities)

Montvale, New Jersey, 07645, United States

Location

Memorial Sloan Kettering Cancer Center @ Suffolk (Limited protocol activity)

Commack, New York, 11725, United States

Location

Memorial Sloan Kettering Westchester (Limited Protocol Activities)

Harrison, New York, 10604, United States

Location

Memorial Sloan - Kettering Cancer Center

New York, New York, 10021, United States

Location

Memorial Sloan Kettering Nassau (Limited protocol activity)

Uniondale, New York, 11553, United States

Location

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

trametinib; ponatinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Dr. Kathryn Arbour
• Organization: Memorial Sloan Kettering Cancer Center

arbourk@mskcc.org

646-608-3792

Study Officials

• Kathryn Arbour, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2018
• First Posted: October 15, 2018
• Study Start: October 9, 2018
• Primary Completion: February 4, 2022
• Study Completion: February 4, 2022
• Last Updated: May 16, 2025
• Results First Posted: September 21, 2023

Record last verified: 2022-02

Locations

US (7)