Clinical trial NCT03704688: Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer
Official title: A Phase 1 Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
First posted: 2018-10-15
Enrollment: 12
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Maximum Tolerated Dose of Ponatinib, Phase I
timeFrame: maximum of 18 months
measure: Overall Response Rate
timeFrame: 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen (Limited Protocol Activities)
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center @ Suffolk (Limited protocol activity)
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester (Limited Protocol Activities)
state: New York
city: New York
country: United States
facility: Memorial Sloan - Kettering Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau (Limited protocol activity)
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Kathryn Arbour, MD
role: PRINCIPAL_INVESTIGATOR
References: