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Clinical Trial 20576

Cancer Type: Thoracic
Study Type: Treatment
NCT#: NCT03965689

Phase: Phase II
Prinicipal Investigator:

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Overview

Study Title

A Phase 2 Study of MLN4924 (Pevonedistat) in Combination with Carboplatin and Paclitaxel in Advanced NSCLC Previously Treated with Immunotherapy

Summary

This phase II trial studies how well MLN4924 (pevonedistat), carboplatin, and paclitaxel work in treating patients with stage IIIB or IV non-small cell lung cancer. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pevonedistat together with carboplatin and paclitaxel may work better in treating patients with non-small cell lung cancer when compared with other standard chemotherapy drugs.

Objective

Primary Objective: To determine the overall response rate (ORR) of patients with advanced non-small cell lung cancer (NSCLC) treated with MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel. Secondary Objectives: To estimate the progression-free survival (PFS) of patients with advanced NSCLC treated with MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel. To estimate the overall survival (OS) of patients with advanced NSCLC treated with MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel. To evaluate the safety profile of MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel. Correlative Objectives: To evaluate expression of nuclear factor-erythroid 2 p45-related factor 2 (NRF2) target genes NAD(P)H: quinone oxidoreductase1 (NQO1) and the cysteine/glutamate antiporter solute carrier family 7 member 11 (SCL7A11). To determine expression of pharmacodynamic markers induced by neural precursor cell expressed developmentally downregulated protein 8 (NEDD-8) activating enzyme (NAE) inhibition: cyclic AMP-dependent transcription factor (ATF3), β2 microglobulin (B2M), glutamate-cysteine ligase regulatory subunit (GCLM), glutathione-disulfide reductase (GSR), DNA-3-methyladenine (MAG1), ribosomal protein lateral stalk subunit P0 (RPLPO), sulfiredoxin-1 (SRXN1), thioredoxin reductase 1 (TXNRD1), and ubiquitinconjugating enzyme (UBC). To perform qualitative assessment of tumor NAE1 and ubiquitin-conjugating enzyme E2 M (UBC12) protein expression at baseline. To assess circulating tumor cells (CTCs) for DNA damage repair pathway alterations (i.e., γH2AX induction, RAD51). To evaluate pharmacokinetic (PK) parameters of MLN4924 (pevonedistat) when given in combination with paclitaxel and carboplatin.

Treatments

Therapies

Medications

MLN4924 (Pevonedistat); Paraplatin (carboplatin); Pevonedistat (); Taxol (paclitaxel); carboplatin (); paclitaxel ()

Inclusion Criteria

  • 18 years of age or older
  • Histologically confirmed stage IIIB or IV NSCLC (squamous or nonsquamous) that is metastatic or unresectable.
  • Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
  • Must have progressed on prior treatment with checkpoint inhibitor (PD-1/PD-L1 inhibitors) either as a single-agent therapy or in combination, as below. Patients will be eligible if there is a contra-indication to checkpoint inhibitor therapy. Patients who have progressed after receiving a checkpoint inhibitor in combination with a platinum-based doublet, as first-line treatment for NSCLC. Patients who have progressed on checkpoint inhibitor as second-line therapy, after receiving a platinum-based doublet as first-line therapy. Patients who have progressed on platinum-based doublet as second-line therapy, after receiving a checkpoint inhibitor as first-line therapy.
  • Must have disease progression on or after platinum-based chemotherapy for metastatic disease or within 6 months of completion of platinum-based chemotherapy administration as adjuvant/neoadjuvant chemotherapy or concurrent chemoradiation.
  • Adequate organ function as defined per protocol
  • Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible: CD4 count > 350 cells/mm^3. Undetectable viral load within the last six months. HIV positive patients must be stable on highly active antiretroviral therapy (HAART). Clinically significant metabolic enzyme inducers are not permitted during this study(e.g., ritonavir, efavirenz, nevirapine). No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
  • Participants are eligible if central nervous system (CNS) metastases are adequately treated and neurological symptoms have returned to baseline or are controlled for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids, or on stable or decreasing dose of steroids.
  • The effects of MLN4924 (pevonedistat) on the developing human fetus are unknown. For this reason and because agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study or within 4 months of completion, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MLN4924 (pevonedistat) administration.
  • Other criteria apply

  • Exclusion Criteria

  • Patients who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy.
  • Patients who are receiving any other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN4924 (pevonedistat), carboplatin, or paclitaxel.
  • Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
  • Patients receiving any 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 the study.
  • Patients with uncontrolled intercurrent illness.
  • Patients with psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because MLN4924 (pevonedistat), carboplatin, and paclitaxel have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN4924 (pevonedistat), breastfeeding must be discontinued if the mother is treated with MLN4924 (pevonedistat). These potential risks may also apply to other agents used in this study.
  • 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 cardiopulmonary disease as defined per protocol.
  • Peripheral neuropathy that is grade 3 or greater, or grade 2 with pain on clinical examination during the screening period.
  • Uncontrolled high blood pressure
  • Prolonged rate corrected QT (QTc) interval greater than or equal to 500 msec, calculated according to institutional guidelines.
  • Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis.
  • Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period.
  • Life-threatening illness unrelated to cancer.
  • Patients with uncontrolled coagulopathy or bleeding disorder.
  • Known hepatic cirrhosis or severe pre-existing hepatic impairment.

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