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Pevonedistat and Docetaxel in Treating Patients with Stage IV or Recurrent Non-small Cell Lung Cancer

Trial Status: Active

This phase II trial studies how well pevonedistat and docetaxel work in treating patients with stage IV non-small cell lung cancer or non-small cell lung cancer that has come back. Pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, 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 pevonedistat and docetaxel may work better in treating patients with non-small cell lung cancer.

Inclusion Criteria

  • Histologically confirmed stage IV NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or not otherwise specified) or recurrent NSCLC not amenable to curative therapy
  • Patients must have demonstrated progression on or intolerance to platinum-based chemotherapy
  • Patients whose tumors harbor an EGFR sensitizing mutation must have demonstrated progression on or intolerance to an Food and Drug Administration (FDA)-approved first-line EGFR tyrosine kinase inhibitor (TKI); patients with the EGFR T790M mutation, must also have demonstrated progression on or intolerance to osimertinib
  • Patients whose tumors harbor a ROS1 rearrangement must have demonstrated progression on or intolerance to crizotinib
  • Patients whose tumors harbor an ALK rearrangement must have demonstrated progression on or intolerance to an FDA-approved first-line TKI; if the first-line TKI was crizotinib, then they also must have demonstrated progression on or intolerance to an FDA-approved second-line TKI; patients who received alectinib or ceritinib as first-line therapy and have demonstrated progression or intolerance will be eligible for this trial
  • Patients whose tumors harbor the BRAF V600E mutation, must have demonstrated progression on or intolerance to the combination of dabrafenib and trametinib
  • Patients whose tumors have PD-L1 expression in >= 50% of tumor cells must have demonstrated progression on or intolerance to pembrolizumab; otherwise, patients who are eligible to receive an FDA-approved anti-PD-1/anti-PD-L1 agent as second-line therapy must also have demonstrated progression on or intolerance to the drug
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count (ANC) >= 1,500/mm^3 (repeat if more than 3 days before the first dose)
  • Platelet count >= 100,000/mm^3 (repeat if more than 3 days before the first dose)
  • Albumin > 2.7 g/dL (repeat if more than 3 days before the first dose)
  • Total bilirubin =< upper limit of normal (ULN) except in patients with Gilbert’s syndrome; patients with Gilbert’s syndrome may enroll if direct bilirubin =< 1.5 x ULN (repeat if more than 3 days before the first dose)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (repeat if more than 3 days before the first dose)
  • Creatinine clearance >= 50 mL/min (repeat if more than 3 days before the first dose)
  • Hemoglobin >= 8 g/dL; patients may be transfused to achieve this value; elevated indirect bilirubin due to post-transfusion hemolysis is allowed (repeat if more than 3 days before the first dose)
  • Female patients who are of childbearing potential and all males must agree to practice true abstinence or use effective methods of contraception
  • Patients must be able to understand and sign the informed consent
  • Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria
  • It is preferable that patients have an adequate tissue sample available for correlative studies evaluating SAG expression, cullin neddylation, and KRAS^G12D mutation, but lack of availability of such a tissue sample is not a requirement for trial enrollment

Exclusion Criteria

  • Treatment with any investigational products within 4 weeks before the first dose of any study drug
  • Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of study procedures
  • Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia that require IV antibiotics within 2 weeks of starting study treatment
  • Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period
  • Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection
  • Life-threatening illness unrelated to cancer
  • Patients with uncontrolled coagulopathy or bleeding disorder
  • Known human immunodeficiency virus (HIV) seropositivity
  • Known hepatitis B surface antigen seropositivity or known or suspected active hepatitis C infection * Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load; patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
  • Known hepatic cirrhosis or severe pre-existing hepatic impairment
  • Known cardiopulmonary disease defined as: * Unstable angina * Congestive heart failure (New York Heart Association class III or IV) * Myocardial infarction (MI) within 6 months prior to first dose of pevonedistat (patients who had ischemic heart disease resulting in MI and/or revascularization greater than 6 months before treatment and who are without cardiac symptoms may enroll) * Cardiomyopathy * Left ventricular ejection fraction < 50% as assessed by echocardiogram or radionuclide angiography * Clinically significant arrhythmia: ** History of polymorphic ventricular fibrillation or torsade de pointes ** Permanent atrial fibrillation [a fib], defined as continuous a fib for >= 6 months ** Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening ** Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation and ** Patients with paroxysmal a fib or < grade (Gr) 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen * Implantable cardioverter defibrillator * Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing) * Pulmonary hypertension
  • Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg)
  • Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines
  • Interstitial lung disease or pulmonary fibrosis
  • Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug, except for hydroxyurea
  • Symptomatic or history of untreated brain or leptomeningeal metastases; treated patients should be neurologically stable for 4 weeks after completion of appropriate therapy; patients should be off steroids at least 3 days prior to start of therapy on clinical trial
  • Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug; clinically significant metabolic enzyme inducers are not permitted during this study
  • Female patients who are lactating, breastfeeding, or have a positive pregnancy test
  • Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
  • Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
  • Known hypersensitivity to docetaxel or other drugs formulated with polysorbate 80
  • Prior therapy with docetaxel
  • Peripheral neuropathy of Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade >= 2

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Gregory Peter Kalemkerian
Phone: 734-647-8921

PRIMARY OBJECTIVES:

I. To determine the response rate with the combination of pevonedistat plus docetaxel in patients with relapsed or refractory non-small lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To determine the median progression-free survival and overall survival of patients treated with pevonedistat plus docetaxel and compare to historical controls with docetaxel alone.

II. To determine the stable disease rate of patients treated with pevonedistat plus docetaxel.

III. To determine the toxicity of pevonedistat plus docetaxel in patients with relapsed NSCLC.

TERTIARY OJBECTIVES:

I. To correlate response with SAG over-expression, KRAS^G12D mutation status, and degree of cullin neddylation.

OUTLINE:

Patients receive docetaxel intravenously (IV) on day 1 and pevonedistat IV over 60 minutes on days 1, 3, 5. Courses repeat every 21 days in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Gregory Peter Kalemkerian

  • Primary ID UMCC 2017.063
  • Secondary IDs NCI-2018-00081
  • Clinicaltrials.gov ID NCT03228186