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

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

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.

Study Overview

• Status: Completed
• Conditions: Non Small Cell Lung Cancer; KRAS Gene Mutation
• Intervention / Treatment: Drug: Trametinib 0.5 mg; Drug: Ponatinib 15 MG; Drug: Trametinib 1 MG; Drug: Trametinib 1.5 MG; Drug: Trametinib 2 mg; Drug: Ponatinib 30 MG

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
    • Montvale, New Jersey, United States, 07645
      • Memorial Sloan Kettering Bergen (Limited Protocol Activities)
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Cancer Center @ Suffolk (Limited protocol activity)
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Westchester (Limited Protocol Activities)
    • New York, New York, United States, 10021
      • Memorial Sloan - Kettering Cancer Center
    • Uniondale, New York, United States, 11553
      • Memorial Sloan Kettering Nassau (Limited Protocol Activity)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I: Dose Level -3; Trametinib 0.5mg PO q daily Ponatinib 15mg PO q daily	Drug: Trametinib 0.5 mg; 0.5mg PO q daily; Drug: Ponatinib 15 MG; 15mg PO q daily
Experimental: Phase I: Dose Level -2; Trametinib 1.0 mg PO q daily Ponatinib 15mg PO q daily	Drug: Ponatinib 15 MG; 15mg PO q daily; Drug: Trametinib 1 MG; 1.0 mg PO q daily
Experimental: Phase I: Dose Level -1; Trametinib 1.5 mg PO q daily 15mg PO q daily	Drug: Ponatinib 15 MG; 15mg PO q daily; Drug: Trametinib 1.5 MG; 1.5mg PO q daily
Experimental: Phase I: Dose Level 1; Trametinib 2 mg PO q daily Ponatinib 15mg PO q daily	Drug: Ponatinib 15 MG; 15mg PO q daily; Drug: Trametinib 2 mg; 2 mg PO q daily
Experimental: Phase I: Dose Level 2; Trametinib 2 mg PO q daily Ponatinib 30mg PO q daily	Drug: Trametinib 2 mg; 2 mg PO q daily; Drug: Ponatinib 30 MG; 30mg PO q daily
Experimental: Phase II; Maximum tolerated dose as established in Phase I portion	Drug: Ponatinib 15 MG; 15mg PO q daily; Drug: Trametinib 2 mg; 2 mg PO q daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Investigators: Principal Investigator: Kathryn Arbour, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2018
• Primary Completion (Actual): February 4, 2022
• Study Completion (Actual): February 4, 2022

Study Registration Dates

• First Submitted: October 10, 2018
• First Submitted That Met QC Criteria: October 10, 2018
• First Posted (Actual): October 15, 2018

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Memorial Sloan Kettering Cancer Center; trametinib; Ponatinib; KRAS Mutant Advanced Non-Small Cell Lung Cancer; 17-297
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ponatinib; Trametinib
• Other Study ID Numbers: 17-297

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No