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

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase: Completed; Phase 2; Phase 1

Conditions: KRAS Gene Mutation; Non Small Cell Lung Cancer

Treatments: Drug: Trametinib 0.5 mg; Drug: Ponatinib 30 MG; Drug: Trametinib 1 MG; Drug: Ponatinib 15 MG; Drug: Trametinib 2 mg; Drug: Trametinib 1.5 MG

Study type: Interventional

Funder types: Other

Identifiers

NCT03704688

17-297

Details and patient eligibility

About

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.

Enrollment: 12 patients

Sex: All

Ages: 19+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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12 participants in 6 patient groups

Phase I: Dose Level -3

Experimental group

Description:

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

Treatment:

Drug: Ponatinib 15 MG

Drug: Trametinib 0.5 mg

Phase I: Dose Level -2

Experimental group

Description:

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

Treatment:

Drug: Ponatinib 15 MG

Drug: Trametinib 1 MG

Phase I: Dose Level -1

Experimental group

Description:

Trametinib 1.5 mg PO q daily 15mg PO q daily

Treatment:

Drug: Trametinib 1.5 MG

Drug: Ponatinib 15 MG

Phase I: Dose Level 1

Experimental group

Description:

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

Treatment:

Drug: Trametinib 2 mg

Drug: Ponatinib 15 MG

Phase I: Dose Level 2

Experimental group

Description:

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

Treatment:

Drug: Trametinib 2 mg

Drug: Ponatinib 30 MG

Phase II

Experimental group

Description:

Maximum tolerated dose as established in Phase I portion

Treatment:

Drug: Trametinib 2 mg

Drug: Ponatinib 15 MG