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

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT03704688

Collaborator

(none)

Enrollment

Locations

Arms

39.9

Actual Duration (Months)

1.7

Patients Per Site

Patients Per Site Per Month

Study Details

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

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 :

Oct 9, 2018

Actual Primary Completion Date :

Feb 4, 2022

Actual Study Completion Date :

Feb 4, 2022

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

Maximum Tolerated Dose of Ponatinib and Trametinib [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.
Overall Response Rate [1 year]
In the Phase II portion of the study, RECIST criteria 1.1 will evaluate the overall response rate.

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memoral Sloan Kettering Basking Ridge (Limited Protocol Activities)	Basking Ridge	New Jersey	United States	07920
2	Memoral Sloan Kettering Monmouth (Limited Protocol Activities)	Middletown	New Jersey	United States	07748
3	Memorial Sloan Kettering Bergen (Limited Protocol Activities)	Montvale	New Jersey	United States	07645
4	Memorial Sloan Kettering Cancer Center @ Suffolk (Limited protocol activity)	Commack	New York	United States	11725
5	Memoral Sloan Kettering Westchester (Limited Protocol Activities)	Harrison	New York	United States	10604
6	Memorial Sloan - Kettering Cancer Center	New York	New York	United States	10021
7	Memorial Sloan Kettering Nassau (Limited protocol activity)	Uniondale	New York	United States	11553