Abstract B207: Nivolumab +/- Ipilimumab in patients with hypermutated cancers detected in blood: NIMBLE
Authors: Rizvi Naiyer , Tang Patricia , Bhardwaj Nina , Chan Timothy A. , Weber Jeffrey S. , Vickers Michael , Pintova Sofya , Hirte Holger , Segal Neil H. , Dhani Neesha , Cho Daniel , Chia Stephen , Burns Caitlin , Tu Donsheng , Pearce Laura , Urton Alison , Smoragiewicz Martin , Dancey Janet 
Published: February 2019

Abstract
Background: During DNA replication, there is an increased risk for base substitution due to replicative errors caused by DNA polymerases, which have error rates of approximately 10-5 per base pair per cell division. One of the mechanisms to counteract these errors involves real-time proofreading via exonuclease activity present in both DNA polymerase ε, which synthesizes the leading strand and is encoded by POLE, and DNA polymerase δ, which is involved in lagging strand synthesis and encoded by POLD1. Mutations in POLE or POLD1 are associated with an increase in DNA replication error rates and high tumor mutational burden (TMB). High TMB may confer sensitivity to immunotherapy with checkpoint inhibitors. The prevalence of POLE/POLD1 mutations is 5-10% across a wide assortment of tumor types, and POLE/POLD1 mutations can be identified through plasma circulating free DNA (cfDNA) testing. Therefore, POLE/POLD1 mutated tumors present an attractive target for treatment with the immune checkpoint inhibitors nivolumab and ipilimumab. Methods: This is an international multicenter, open-label, randomized phase II noncomparative trial of nivolumab alone or in combination with ipilimumab for the treatment of patients with advanced hypermutated solid tumors detected by a blood-based assay. While the intent is to expand this study into a platform to test additional liquid biomarker assays, the biomarker selection of eligible patients will initially be based on detection of either POLE or POLD1 mutations by cfDNA. Patients with POLE or POLD1 mutations identified on previous tumor tissue testing via the CLIA certified testing platform are also eligible. Patients will be randomized 1:1 to receive either nivolumab monotherapy (240mg IV every 2 weeks) or in combination with ipilimumab (1mg/kg IV every 6 weeks) until progression. Stratification factors are ECOG performance status (0,1) and number of prior treatments (0, 1-2,3 or more). Other key eligibility criteria include: histologically confirmed metastatic or unresectable solid tumors (except primary CNS tumors), tissue block (or minimum 20 slides) available from primary or metastatic tumor, measurable disease per RECIST 1.1, ≥ 18 years of age, received at least 1 standard cancer therapy (unless patient refused) for their tumor type and progressed on most recent regimen, and received no prior immunotherapy. A sample size of 50 evaluable patients in each arm will achieve 90% power to show a clinically meaningful objective response rate (ORR). These calculations assume nivolumab monotherapy p0 &lt; 13%, p1 &gt; 30%, and in combination with ipilimumab therapy p0 &lt; 30%, p1 &gt;50%. Objectives: The primary objective is to evaluate the ORR of nivolumab monotherapy and of nivolumab + ipilimumab in randomized patients with detectable POLE or POLD1 mutations as determined by plasma cfDNA. Secondary objectives are to evaluate efficacy by ORR and duration of response in all treated patients with detectable POLE or POLD1 mutations in either plasma cfDNA or tumor tissue as well as to assess correlation between POLE/D1 mutations in tumor and POLE/D1 mutations in blood. Exploratory endpoints include determining progression-free survival and overall survival, correlation between POLE/POLD1 mutations occurring within or outside of the exonuclease domain and TMB as determined by whole exome and RNA sequencing, and correlation between TMB assessed in plasma cfDNA and assessed directly in tumor tissue. NCT03461952.
Citation Format: Naiyer Rizvi, Patricia Tang, Nina Bhardwaj, Timothy A. Chan, Jeffrey S. Weber, Michael Vickers, Sofya Pintova, Holger Hirte, Neil H. Segal, Neesha Dhani, Daniel Cho, Stephen Chia, Caitlin Burns, Donsheng Tu, Laura Pearce, Alison Urton, Martin Smoragiewicz, Janet Dancey. Nivolumab +/- Ipilimumab in patients with hypermutated cancers detected in blood: NIMBLE [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B207.