Clinical Trials /

Testing the Combination of MLN4924 (Pevonedistat), Carboplatin, and Paclitaxel for Non-small Cell Lung Cancer (NSCLC)

NCT03965689

Description:

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.

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

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of MLN4924 (Pevonedistat), Carboplatin, and Paclitaxel for Non-small Cell Lung Cancer (NSCLC)
  • Official Title: A Phase 2 Study of MLN4924 (Pevonedistat) in Combination With Carboplatin and Paclitaxel in Advanced NSCLC Previously Treated With Immunotherapy

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-03212
  • SECONDARY ID: NCI-2019-03212
  • SECONDARY ID: 10266
  • SECONDARY ID: 10266
  • SECONDARY ID: UM1CA186716
  • NCT ID: NCT03965689

Conditions

  • Metastatic Lung Non-Small Cell Squamous Carcinoma
  • Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8
  • Unresectable Lung Non-Small Cell Carcinoma
  • Unresectable Lung Non-Squamous Non-Small Cell Carcinoma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (paclitaxel, carboplatin, pevonedistat)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (paclitaxel, carboplatin, pevonedistat)
PevonedistatMLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924Treatment (paclitaxel, carboplatin, pevonedistat)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. 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:

      I. To estimate the progression-free survival (PFS) of patients with advanced NSCLC treated
      with MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel.

      II. To estimate the overall survival (OS) of patients with advanced NSCLC treated with
      MLN4924 (pevonedistat) in combination with carboplatin and paclitaxel.

      III. To evaluate the safety profile of MLN4924 (pevonedistat) in combination with carboplatin
      and paclitaxel.

      CORRELATIVE OBJECTIVES:

      I. 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).

      II. 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), beta 2 microglobulin (B2M),
      glutamate-cysteine ligase regulatory subunit (GCLM), glutathione-disulfide reductase (GSR),
      deoxyribonucleic acid (DNA)-3-methyladenine (MAG1), ribosomal protein lateral stalk subunit
      P0 (RPLPO), sulfiredoxin-1 (SRXN1), thioredoxin reductase 1 (TXNRD1), and
      ubiquitin-conjugating enzyme (UBC).

      III. To perform qualitative assessment of tumor NAE1 and ubiquitin-conjugating enzyme E2 M
      (UBC12) protein expression at baseline.

      IV. To assess circulating tumor cells (CTCs) for DNA damage repair pathway alterations (i.e.,
      gamma H2AX induction, RAD51).

      V. To evaluate pharmacokinetic (PK) parameters of MLN4924 (pevonedistat) when given in
      combination with paclitaxel and carboplatin.

      OUTLINE:

      Patients receive paclitaxel intravenously (IV) over 3 hours on day 1, carboplatin IV over
      15-60 minutes on day 1, and pevonedistat IV over 1 hour on days 1, 3, and 5. Treatment
      repeats every 21 days for at least 4 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, all patients without disease progression are followed up
      every 3 months for 1 year. and then every 6 months until 5 years from end of study treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (paclitaxel, carboplatin, pevonedistat)ExperimentalPatients receive paclitaxel IV over 3 hours on day 1, carboplatin IV over 15-60 minutes on day 1, and pevonedistat IV over 1 hour on days 1, 3, and 5. Treatment repeats every 21 days for at least 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Paclitaxel
  • Pevonedistat

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed stage IIIB or IV NSCLC (squamous or
             nonsquamous) that is metastatic or unresectable.

          -  Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors
             (RECIST) 1.1.

          -  Patients 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.

          -  Patients 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.

          -  Absolute neutrophil count >= 1,500/mcL.

          -  Platelet count >= 150,000/mcL.

          -  Total bilirubin =< 1 x institutional upper limit of normal (ULN). Patients with
             Gilbert's syndrome may enroll if direct bilirubin =< 1.5 x institutional ULN.

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             institutional ULN. Patients with metastatic liver disease may enroll if =< 5 x ULN.

          -  Hemoglobin >= 8 g/dL. If clinically indicated, patients may receive red blood cell
             transfusion on this study.

          -  Creatinine clearance =< institutional ULN. OR

          -  Glomerular filtration rate (GFR) > 30 mL/min/1.73 m^2 .

          -  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.

          -  Life expectancy >= 12 weeks.

          -  Patients 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.

        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 1 highly effective method and 1 additional effective (barrier)
             method of contraception, at the same time, from the time of signing the informed
             consent through 4 months after the last dose of study drug (female and male condoms
             should not be used together), or

          -  Agree to practice true abstinence, when this is in line with the preferred and usual
             lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
             symptothermal, postovulation methods] withdrawal, spermicides only, and lactational
             amenorrhea are not acceptable methods of contraception.) Male patients, even if
             surgically sterilized (i.e., status postvasectomy), who

          -  Agree to practice effective barrier contraception during the entire study treatment
             period and through 4 months after the last dose of study drug (female and male condoms
             should not be used together), OR

          -  Agree to practice true abstinence, when this is in line with the preferred and usual
             lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
             symptothermal, postovulation methods for the female partner] withdrawal, spermicides
             only, and lactational amenorrhea are not acceptable methods of contraception.)

               -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
                  viral load must be undetectable on suppressive therapy, if indicated.

               -  Patients with a history of hepatitis C virus (HCV) infection must have been
                  treated and cured. For patients with HCV infection who are currently on
                  treatment, they are eligible if they have an undetectable HCV viral load.

               -  Patients with a prior or concurrent malignancy whose natural history or treatment
                  does not have the potential to interfere with the safety or efficacy assessment
                  of the investigational regimen are eligible for this trial.

               -  Left ventricular ejection fraction (LVEF) >= 50% as assessed by echocardiogram or
                  radionuclide angiography.

               -  Ability to understand and the willingness to sign a written informed consent
                  document. Participants with impaired decision-making capacity (IDMC) who have a
                  legally authorized representative (LAR) or caregiver and/or family member
                  available will also be considered eligible.

               -  Patients with NSCLC harboring genomic aberrations (e.g. sensitizing EGFR, ALK,
                  ROS1, NTRK, BRAF V600E mutation positive) must have received prior treatment with
                  Food and Drug Administration (FDA) approved targeted therapy for patients for
                  which FDA approved targeted therapies is available.

        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 defined as:

               -  Unstable angina;

               -  Congestive heart failure (New York Heart Association [NYHA] class III or IV;);

               -  Myocardial infarction within 6 months prior to first dose (patients who had
                  ischemic heart disease such as acute coronary syndrome [ACS], myocardial
                  infarction, and/or revascularization greater than 6 months before screening and
                  who are without cardiac symptoms may enroll);

               -  Symptomatic cardiomyopathy;

               -  Clinically significant arrhythmia:

                    -  History of polymorphic ventricular fibrillation or torsade de pointes,

                    -  Permanent atrial fibrillation, defined as continuous atrial fibrillation for
                       >= 6 months,

                    -  Persistent atrial fibrillation, defined as sustained atrial fibrillation
                       lasting > 7 days and/or requiring cardioversion in the 4 weeks before
                       screening,

                    -  Grade 3 atrial fibrillation defined as symptomatic and incompletely
                       controlled medically, or controlled with device (e.g., pacemaker), or
                       ablation and

                    -  Patients with paroxysmal atrial fibrillation or grade < 3 atrial
                       fibrillation for period of at least 6 months are permitted to enroll
                       provided that their rate is controlled on a stable regimen.

               -  Clinically symptomatic pulmonary hypertension requiring pharmacologic therapy.

          -  Peripheral neuropathy that is grade >= 3, or grade 2 with pain on clinical examination
             during the screening period.

          -  Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mmHg, diastolic
             blood pressure > 95 mmHg).

          -  Prolonged rate corrected QT (QTc) interval >= 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description:Defined as the proportion of evaluable subjects with a response. Response will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Patients will be re-evaluated for response every 6 weeks. The number and frequencies of responses will be summarized in tabular format. The ORR will be calculated and reported along with the corresponding 95% confidence interval which will be constructed using the Wilson score method.

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From the start of treatment to time of progression or death, whichever occurs first, assessed for up to 5 years
Safety Issue:
Description:Will be analyzed using the Kaplan-Meier method. Median PFS will be calculated along with the corresponding 95% confidence interval which will be constructed using the non-parametric Brookmeyer-Crowley method.
Measure:Overall survival (OS)
Time Frame:From the start of treatment to time of death; assessed for up to 5 years
Safety Issue:
Description:Defined as the duration of time from start of treatment to time of death. Analyzed using the Kaplan-Meier method. Median OS will be calculated along with the corresponding 95% confidence interval which will be constructed using the non-parametric Brookmeyer-Crowley method.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Evaluated by type and severity using the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All toxicities observed will be summarized in terms of types and severity. Toxicities will be tabulated and summarized by organ systems. Incidence rates of toxicities will be analyzed descriptively.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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