Clinical Trials /

Selumetinib and Paclitaxel as Second-Line Treatment in Treating Patients With Stage IIIB-IV Non-small Cell Lung Cancer

NCT02503358

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selumetinib and Paclitaxel as Second-Line Treatment in Treating Patients With Stage IIIB-IV Non-small Cell Lung Cancer
  • Official Title: A Randomized, Open-Label, Phase I Trial of Continuous, Intermittent, and Pulsatile Selumetinib (AZD6244) Plus Paclitaxel as Second-Line Treatment for Stage IIIB or IV Non-small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: IRB00011462
  • SECONDARY ID: NCI-2015-01018
  • SECONDARY ID: 11,462
  • SECONDARY ID: SOL-15008-L
  • SECONDARY ID: IRB00011462
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT02503358

Conditions

  • Stage IIIB Non-Small Cell Lung Cancer AJCC v7
  • Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (continuous selumetinib and paclitaxel)
SelumetinibARRY-142886, AZD6244, MEK Inhibitor AZD6244Arm I (continuous selumetinib and paclitaxel)

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.

Detailed Description

      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 deoxyribonucleic acid (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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (continuous selumetinib and paclitaxel)ExperimentalPatients receive selumetinib PO BID on days 1-21 and paclitaxel IV over 30 minutes on days 1 and 8.
  • Paclitaxel
  • Selumetinib
Arm II (intermittent selumetinib and paclitaxel)ExperimentalPatients receive selumetinib PO BID on days 1-5, 8-12, and 15-19 and paclitaxel as in Arm I.
  • Paclitaxel
  • Selumetinib
Arm III (pulsatile selumetinib and paclitaxel)ExperimentalPatients receive selumetinib PO BID on days 1-3, 8-10, and 15-17 and paclitaxel as in Arm I.
  • Paclitaxel
  • Selumetinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically and/or cytologically confirmed, non-small cell lung cancer (NSCLC) of
             adenocarcinoma histology at the time of initial diagnosis.

               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.

               -  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 available
             treatment. Patients who progressed on such treatment, i.e., have developed acquired
             resistance and are no longer reasonably expected to derive therapeutic benefit are
             eligible for the trial.

          -  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 chemotherapy or immunotherapy within 14 days prior to enrollment.
             Subjects receiving palliative radiation to CNS disease within 7 days may be eligible
             with PI approval. If the most recent treatment line is an EGFR-TKI, the washout period
             is a minimum of 3 days before the start of paclitaxel/selumetinib (i.e. treatment with
             the EGFR-TKI may continue until 3 days before start of study treatment). For other
             targeted therapy agents, the washout period will be 5 half-lives, prior to start of
             treatment on study.

          -  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. Based on the in vitro data and SimCYP
             simulations, selumetinib is considered unlikely to perpetrate clinically significant
             drug-drug interaction via inhibition or induction of CYP enzymes

          -  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

          -  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 with protocol treatment/research
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of grade 3 or higher treatment-related adverse event (AE) using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Treatment arms will be summarized reporting the number of patients treated; the number who experience grade 3 or higher treatment-related AE. In addition, number of treatment cycles received will be summarized using descriptive statistics (median and range) by treatment arm. Comprehensive safety data on all toxicities will be tabulated by type, grade, duration, attribution to treatment, and treatment arm. A patient level summary by worst grade toxicity will be included. Laboratory data and concomitant medications associated with episodes of toxicity will be summarized as needed.

Secondary Outcome Measures

Measure:Best response complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame:Up to 4 years
Safety Issue:
Description:
Measure:Disease control rate (DCR)
Time Frame:Up to 4 years
Safety Issue:
Description:DCR will be calculated as the proportion/percentage of patients with best overall response of CR, PR, or SD. Corresponding 95% confidence intervals, calculated by the binomial method, will be reported. In addition, patients in each response category (CR, PR, SD) will be summarized by descriptive statistics (median and range) with respect to time to onset of response and duration of response.
Measure:Median overall survival (OS)
Time Frame:From randomization to death or date of censoring, assessed at 6 months
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate OS per treatment arm.
Measure:Median overall survival (OS)
Time Frame:From randomization to death or date of censoring, assessed at 12 months
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate OS per treatment arm.
Measure:Median progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame:From randomization until documented disease progression or death (by any cause, in the absence of progression), assessed at 6 months
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate PFS per treatment arm.
Measure:Median progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame:From randomization until documented disease progression or death (by any cause, in the absence of progression), assessed at 12 months
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate PFS per treatment arm.
Measure:Objective response rate (ORR)
Time Frame:Up to 4 years
Safety Issue:
Description:ORR will be estimated for the three pre-planned arms of selumetinib/paclitaxel. ORR will be calculated as the proportion/percentage of patients with best overall response of CR or PR.
Measure:Overall survival (OS)
Time Frame:From randomization to death or date of censoring, assessed up to 4 years post-treatment
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate OS per treatment arm.
Measure:Progression free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame:From randomization until documented disease progression or death (by any cause, in the absence of progression), assessed up to 4 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate PFS per treatment arm.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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