Testing the Combination of MLN4924 (Pevonedistat), Carboplatin, and Paclitaxel in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) Who Have Previously Been Treated With Immunotherapy

Description

PRIMARY OBJECTIVE:

I. To determine the overall response rate (ORR) of patients with advanced non-small cell lung cancer (NSCLC) treated with pevonedistat (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 30-60 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 at 30 days, every 3 months for 1 year and then every 6 months until 5 years from end of study treatment.