Portland, Oregon 97239


Purpose:

This randomized phase I trial is studying the side effects and the best dose of selumetinib when given together with paclitaxel as a second line therapy in treating patients with stage IIIB-IV non-small cell lung cancer (NSCLC). Selumetinib may stop or slow the growth of tumor cells by blocking a protein called mitogen-activated protein kinase (MEK) that is needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving selumetinib together with paclitaxel may kill more tumor cells.


Study summary:

PRIMARY OBJECTIVES: I. To determine the safety and tolerability of three pre-planned arms of continuous, intermittent, and pulsatile selumetinib with paclitaxel as second-line treatment in patients with stage IIIB or IV NSCLC. SECONDARY OBJECTIVES: I. To determine the preliminary clinical response of continuous, intermittent, and pulsatile selumetinib with paclitaxel as second-line treatment in patients with stage IIIB or IV NSCLC. TERTIARY OBJECTIVES: I. To characterize the pharmacokinetics (PK) of selumetinib in this patient population. II. To determine progression-free survival (PFS) and overall survival (OS) in patients treated with selumetinib/paclitaxel. III. To assess correlations between cell-free DNA (cfDNA) molecular features from blood and molecular features and pathways from the biopsy samples, and use this as a surrogate measure of tumor response and duration of response as evaluated in the primary and secondary objectives. OUTLINE: This is a dose-finding study of selumetinib. The goal is to find out what dose and dosing schedule is the most effective in this population. Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive selumetinib orally (PO) twice daily (BID) on days 1-21 and paclitaxel intravenously (IV) over 30 minutes on days 1 and 8. ARM II: Patients receive selumetinib PO BID on days 1-5, 8-12, and 15-19 and paclitaxel as in Arm I. ARM III: Patients receive selumetinib PO BID on days 1-3, 8-10, and 15-17 and paclitaxel as in Arm I. In all three arms, treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing clinical benefit from study treatment may continue treatment based on the principal investigator (PI) approval on a patient-by-patient basis. After completion of study treatment, patients are followed up at 30 days, every 8 weeks for 12 months, and then every 3 months thereafter.


Criteria:

Inclusion Criteria: - Histologically and/or cytologically confirmed, non-small cell lung cancer (NSCLC) of adenocarcinoma histology. 1. Mixed tumors will be categorized by the predominant cell type; (Note: If small cell elements are present the patient is ineligible). 2. Known mutational status of KRAS and BRAF oncogenes. 3. For patients in whom mutational testing result is unknown or unavailable from a prior test, KRAS and BRAF testing will be performed (at a CLIA-certified laboratory) using an archived or fresh biopsy as per Standard of Care, prior to enrollment. - Stage IIIB-IV, locally advanced or metastatic disease according to the 7 th edition of the AJCC lung cancer TNM classification system - Measurable disease as defined by RECIST v1.1 criteria. Baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to Enrollment. - Failure of at least one line of systemic anti-cancer therapy for advanced NSCLC defined as either of the following: 1. Radiological documentation of disease progression (or failure to achieve a response) or 2. Discontinuation due to toxicity - ECOG Performance Status of 0 or 1 - Estimated life expectancy, in the judgment of the Investigator, which will permit receipt of treatment of 12 weeks or more - Adequate bone marrow function as defined below: - Absolute neutrophil count ≥ 1.5x109 /L (1500 per mm3 ) - Platelets ≥ 100x109 /L (100,000 per mm3 ) - Hemoglobin > 9.0 g/dL - Adequate liver function as defined below: - Serum Bilirubin < 1.5 x upper limit of normal (ULN) for institution [Exception: Patients who have elevated serum bilirubin due to underlying Gilbert's Syndrome or familial benign unconjugated hyperbilirubinemia are allowed.] - AST (SGOT) < 2.5 x upper limit of normal (ULN) for institution (or < 5.0 x ULN in presence of liver metastases) - ALT (SGPT) < 2.5 x upper limit of normal (ULN) for institution (or < 5.0 x ULN in presence of liver metastases) - Adequate renal function as defined by one of the following: - Serum Creatinine ≤1.5 mg/dl OR - Serum Creatinine clearance > 50ml/min (calculated by Cockcroft-Gault formula) - 18 years and older - Females of child bearing potential that are sexually active must agree to either practice 2 medically accepted highly effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 30 days after the last dose of study drug. See Appendix C for a list of protocolapproved highly effective methods of contraceptive combinations. 26 - Negative test for pregnancy is required for females of child-bearing potential; A female of child bearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1. has not undergone a hysterectomy or bilateral oophorectomy; or 2. has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months or 730 days). - Conception while on treatment must be avoided - Males of child bearing potential must agree to practice effective barrier contraception during the entire study treatment period and through 6 months) after the last dose of study drug, (includes males surgically sterilized - i.e. status post vasectomy). - Ability to understand and the willingness to sign a written Informed Consent and HIPAA document/s Exclusion Criteria: - Known actionable mutations, (e.g. EGFR, ALK, ROS1), against which there is an established effective targeted therapy. For patients with unknown/unavailable mutation status, a biopsy will be attempted in order to profile the genetic make-up of the tumor. If this has not been successful due to inadequate tissue sample, poor yield or the procedure deemed high-risk, genetic profiling of cf-DNA could be substituted for a repeat biopsy. - Any prior treatment with either a MEK, Ras, or Raf inhibitor for advanced or metastatic NSCLC. - A history of hypersensitivity to selumetinib, or any excipient agents (e.g. Captisol or TPGS- a water soluble form of Vitamin E) - Any unresolved toxicity > CTCAE grade 2 despite optimal care/support, from previous anti-cancer therapy, except for alopecia, within 7 days prior to Cycle 1, day 1 - Cardiac conditions as follows: - Uncontrolled hypertension (BP ≥ 150/95 mmHg, despite medical therapy) - Left ventricular ejection fraction (LVEF) < 55%, measured by echocardiography - Atrial fibrillation with a ventricular rate > 100 bpm on ECG at rest - Symptomatic heart failure (NYHA grade II-IV) - Prior or current cardiomyopathy - Severe valvular heart disease - Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy) - Acute coronary syndrome within 6 months prior to starting treatment - Ophthalmological conditions as follows: - Intra-ocular pressure > 21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure) - Current or past history of central serous retinopathy or retinal vein occlusion - Prior treatment with any other chemotherapy, immunotherapy, or anticancer drug, agent or biologic within 14 days prior to enrollment [Exception: Radiotherapy] - Major surgical procedure within 21 days prior to enrollment - Brain metastases or spinal cord compression unless asymptomatic, treated and stable off steroids and anti-convulsants for at least 30 days - Received an investigational drug within 30 days of starting treatment, or have not recovered from side effects of an investigational drug - Concomitant (or receipt of) treatment with medications that may affect the metabolism of selumetinib (e.g. CYP1A2, CYP2C19 or 2A4 inhibitors/ inducers) within 14 days prior to Cycle 1, day 1. [Exception: Patients actively receiving a safe substitute in the judgment of the Principal Investigator are eligible and may continue to receive the safe substitute during protocol treatment.] - Concomitant (or receipt of) treatment with medications that may affect the metabolism of paclitaxel (e.g. CYP2C8 or CYP3A4 inhibitors/ inducers) within 14 days prior to Cycle 1, day 1. [Exception: Patients actively receiving a safe substitute in the judgment of the Principal Investigator are eligible and may continue to receive the safe substitute during protocol treatment.] In the absence of formal clinical drug interaction studies, caution should be exercised when administering paclitaxel (Taxol) concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) OR induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz and nevirapine) either CYP2C8 or CYP3A4. - Female patients who are pregnant or breast-feeding (confirmation that the patient is not pregnant must be by a negative pregnancy test result obtained during screening; pregnancy testing is required of women of childbearing potential but not required for post-menopausal or surgically, sterilized women) - Any evidence of severe or uncontrolled systemic disease, including, but not limited to, ongoing or active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) - Serious medical or psychiatric illness/condition likely in the judgment of the Investigator to interfere with compliance to protocol treatment/research


NCT ID:

NCT02503358


Primary Contact:

Principal Investigator
Khaled Tolba
OHSU Knight Cancer Institute


Backup Contact:

N/A


Location Contact:

Portland, Oregon 97239
United States

Khaled A. Tolba
Phone: 503-494-8666
Email: tolba@ohsu.edu

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: November 23, 2017

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