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The MAPK/ERK pathway is activated by upstream genomic events and/or activation of multiple signaling events where information coalesces at this important nodal pathway point. This pathway is tightly regulated under normal conditions by phosphatases and bidirectional communication with other pathways, such as the AKT/m-TOR pathway. Recent evidence indicates that the MAPK/ERK signaling node can function as a tumor suppressor as well as the more common pro-oncogenic signal. The effect that predominates depends on the intensity of the signal and the context or tissue in which the signal is aberrantly activated. Genomic profiling of tumors has revealed common mutations in MAPK/ERK pathway components, such as BRAF. Currently approved for the treatment of melanoma, inhibitors of B-RAF kinase (BRAFi) are being studied alone and in combination with inhibitors of the MAPK and other pathways to optimize treatment of many tumor types. Therapies targeted toward MAPK/ERK components have variable response rates when used in different solid tumors, such as colorectal cancer and ovarian cancer. Understanding the differential nature of activation of the MAPK/ERK pathway in each tumor type is critical in developing single and combination regimens, as different tumors have unique mechanisms of primary and secondary signaling and subsequent sensitivity to drugs.

Purpose Our preclinical studies showed that the PARP inhibitor, olaparib prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic (PK/PD) effects, safety and activity of the combination. Patients and Methods Eligible patients had metastatic or recurrent women’s cancer. Olaparib tablets were introduced (100 or 200mg bid, days 1-7) in a 3+3 dose escalation with carboplatin AUC4 or 5 q21 days, up to eight cycles, followed by olaparib 300mg bid maintenance. Patients were randomized to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib PK, platinum-DNA adducts, comet assay and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib PK and platinum-DNA adducts. Results 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200mg bid+carboplatin AUC4 as the MTD. Olaparib clearance was increased ~50% when carboplatin was given 24hr before olaparib. In vitro experiments demonstrated carboplatin pre-exposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CR and 31 PR (46%) with a higher RR in BRCA mutation carriers compared to non-mutation carriers (68% v.19%). Conclusions Tablet olaparib with carboplatin is a safe and active combination. Carboplatin pre-exposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib.

PURPOSETo investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ≤ 8 cycles, with olaparib 400mg bid maintenance. Peripheral blood mononuclear cells were collected for polymorphisms and PAR levels, and paired tumor biopsies (pre-/post-cycle 1) for proteomics and apoptosis endpoints.RESULTS28 women were treated (median 5 prior regimens [0-12]). Dose-limiting toxicity was thrombocytopenia, and symptomatic hyponatremia with carboplatin AUC5. The maximum tolerated dose was olaparib 400mg bid+carboplatin AUC4. Grade 3 and 4 adverse events included neutropenia (36%), thrombocytopenia (11%), and anemia (11%). Responses included 1 complete response (CR; 69+months) and 5/27 partial responses (19%; median 4months [4-7]), for a response rate of 22%. Biomarker findings did not correlate with response. The long-term CR patient with prior negative BRCA testing was found to have deletion of BRCA1 exons1-2.CONCLUSIONSThe olaparib/carboplatin combination is tolerable and has modest activity in sporadic TNBC patients. Further evaluation of predictive biomarkers to identify those with BRCA wild type who had response is warranted.

BackgroundNY-ESO-1–specific T cells (letetresgene autoleucel [lete-cel]; GSK3377794) are autologous T cells transduced with a self-inactivating lentiviral vector to express an engineered NY-ESO-1–specific TCR that recognizes HLA-A*02–presented peptides derived from NY-ESO-1, a cancer/testis antigen expressed in 70%–80% of SS. NCT01343043 was a Phase I, open-label trial assessing safety, efficacy, and pharmacokinetics of lete-cel in patients with SS; activity was evaluated after different lymphodepletion conditioning regimens and in patients with differing levels of NY-ESO-1 expression.MethodsPatients with unresectable, metastatic, or recurrent SS who were intolerant/nonresponsive to standard first-line chemotherapy enrolled in 4 cohorts based on NY-ESO-1 tumor expression were lymphodepleted and received lete-cel infusion (table 1). Primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1; secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Transduced cell persistence was measured by qPCR of transgene vector copies in DNA extracted from PBMCs. Study was not designed/powered to compare cohorts.ResultsOverall, 50 patients enrolled; 45 received lete-cel infusion (modified intent-to-treat population). Demographics were similar between cohorts. Median time in study was 480/278/605/643 days in Cohorts 1/2/3/4, respectively. At study completion, ORR ranged from 20%–50% between cohorts, with 1 complete (lasting 34 weeks) and 14 partial responses (table 1). In Cohorts 1/2/3/4, respectively, median DoR was 31.0/8.6/32.1/16.4 weeks; median PFS was 15.4/13.1/8.6/22.4 weeks (table 1). As of 27Jan2020, median OS for Cohorts 1/2/3 was 24.3/9.9/19.9 months; Cohort 4 median OS was immature (table 1). Across cohorts, Grade ≥3 adverse events (AEs) in ≥40% of patients were mostly hematologic in nature; Grade ≥3 serious AEs (SAEs) were most frequently febrile neutropenia, dyspnea, and neutropenia (table 2). AEs of special interest included cytokine release syndrome in 44% of patients (n=20; maximum Grade 1/2/3/4 in 9/7/3/1 patients, respectively; 5 patients had SAEs [Grade ≥3 in 2 patients]; all AEs/SAEs resolved); Guillain-Barré syndrome in 2 patients (Grade 3 SAEs; resolved with sequalae); and multilineage cytopenias in 96% of patients (n=43; maximum Grade 5 in 1 patient, Grade 3/4 in others). Peak persistence of transduced cells was generally higher in responders vs non-responders (table 1); time to peak persistence was similar between these groups (median 8 days). No patients tested positive for replication-competent lentivirus.Abstract 298 Table 1NY-ESO-1 expression and lymphodepletion regimen in Cohorts 1–4, efficacy, and peak persistence in responders and nonresponders; mITT populationAbstract 298 Table 2Number of patients with Grade ≥3 AEs in the mITT population*ConclusionsIn patients with advanced SS who need effective treatment, lete-cel had a manageable safety profile; responses occurred in all cohorts, but patients with high NY-ESO-1 expression and more intensive lymphodepletion regimen received greatest benefit.AcknowledgementsThis study (208466) was funded by GlaxoSmithKline. Medical writing assistance was provided by Gemma Corr, DPhil, and Tiffany Brake, PhD, of Fishawack Indicia, UK, and funded by GlaxoSmithKline. We thank Ran Ji for contributions to statistical analysis.Trial RegistrationClinicaltrials. gov NCT01343043Ethics ApprovalThis study was approved by the appropriate institutional review boards and independent ethics committees.

Excessive hyperbilirubinemia in human neonates can cause permanent dysfunction of the auditory system, as assessed with brainstem auditory evoked potentials (BAEPs). Jaundiced Gunn rat pups (jjs) exhibit similar BAEP abnormalities as hyperbilirubinemic neonates. Sulfadimethoxine (sulfa) administration to jjs, which displaces bilirubin from serum albumin into tissues including brain, exacerbates acute toxicity. Minocycline administered prior to sulfa in jjs protects against BAEP abnormalities. This study evaluates the neuroprotective capabilities of minocycline HCl (50mg/kg) administered 30 or 120min after sulfa (200mg/kg) in 16 day old jjs. BAEPs are recorded at 6 or 24hr post-sulfa. Abnormal BAEP waves exhibit increased latency and decreased amplitude. The sulfa/saline treated jjs exhibited a significantly increased interwave interval between waves I and II (I–II IWI) and significantly decreased amplitudes of waves II and III compared to the saline/saline jjs. The minocycline 30min post-sulfa (sulfa/mino +30) group was not significantly different from the saline/saline control group, indicating neuroprotection. The minocycline 120min post-sulfa (sulfa/mino+120) group had a significantly decreased amplitude of wave III at both 6 and 24hr. These studies indicate that minocycline has a graded neuroprotective effect when administered after acute bilirubin neurotoxicity.

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