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

• ClinicalTrials.gov Identifier: NCT03704688
• Recruitment Status: Active, not recruiting
• First Posted: October 15, 2018
• Last Update Posted: April 30, 2020
• Sponsor: Memorial Sloan Kettering Cancer Center
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer; KRAS Gene Mutation	Drug: Trametinib 0.5 mg; Drug: Trametinib 1 MG; Drug: Trametinib 1.5 MG; Drug: Trametinib 2 mg; Drug: Ponatinib 15 MG; Drug: Ponatinib 30 MG	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer
• Actual Study Start Date: October 9, 2018
• Estimated Primary Completion Date: April 2021
• Estimated Study Completion Date: April 2021

Arms and Interventions

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: Trametinib 1 MG; 1.0 mg PO q daily; Drug: Ponatinib 15 MG; 15mg PO q daily
Experimental: Phase I: Dose Level -1; Trametinib 1.5 mg PO q daily 15mg PO q daily	Drug: Trametinib 1.5 MG; 1.5mg PO q daily; Drug: Ponatinib 15 MG; 15mg PO q daily
Experimental: Phase I: Dose Level 1; Trametinib 2 mg PO q daily Ponatinib 15mg PO q daily	Drug: Trametinib 2 mg; 2 mg PO q daily; Drug: Ponatinib 15 MG; 15mg 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: Trametinib 2 mg; 2 mg PO q daily; Drug: Ponatinib 15 MG; 15mg PO q daily

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose of Ponatinib and Trametinib [ Time Frame: maximum of 18 months ]
   In the Phase I portion of the study, a standard 3+3 design will be used to find the maximum tolerated dose.
2. Overall Response Rate [ Time Frame: 1 year ]
   In the Phase II portion of the study, RECIST criteria 1.1 will evaluate the overall response rate.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, New Jersey

Memoral Sloan Kettering Basking Ridge (Limited Protocol Activities)

Basking Ridge, New Jersey, United States, 07920

Memoral Sloan Kettering Monmouth (Limited Protocol Activities)

Middletown, New Jersey, United States, 07748

Memorial Sloan Kettering Bergen (Limited Protocol Activities)

Montvale, New Jersey, United States, 07645

United States, New York

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

Commack, New York, United States, 11725

Memoral Sloan Kettering Westchester (Limited Protocol Activities)

Harrison, New York, United States, 10604

Memorial Sloan - Kettering Cancer Center

New York, New York, United States, 10021

Memorial Sloan Kettering Nassau (Limited protocol activity)

Uniondale, New York, United States, 11553

Sponsors and Collaborators

Memorial Sloan Kettering Cancer Center

Investigators

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

More Information

Additional Information:

Memorial Sloan Kettering Cancer Center 

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT03704688
• Other Study ID Numbers: 17-297
• First Posted: October 15, 2018
• Last Update Posted: April 30, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Memorial Sloan Kettering Cancer Center:

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

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Trametinib; Ponatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action