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This section contains details of all mixed models utilized in the statistical analyses. The inferential tests performed in this paper necessitates a multiple comparisons adjustment, and details of the adjustment procedure is included in this section as well.

Supplementary Figure S1. Mean concentration-time erdafitinib profiles after a single dose (cycle 1 day 1 [C1D1]) and at steady-state (cycle 2 day 1 [C2D1]) after daily dosing (Panel A) or intermittent dosing (Panel B). 9 mg QD Part 1 at Cycle 2 Day 1 (C2D1) was not reported as n=1.

Purpose:Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.Patients and Methods:Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested.Results:The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were Conclusions:Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

Purpose: Bone marrow–derived progenitor cells, including VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models.Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II–III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012).Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

'Figure S1: ONC201 doses versus (A) Cmax and (B) AUC determined after the first dose of ONC201.; Figure S2: Covariant analyses of pharmacokinetic parameters; Figure S3: Caspase-cleaved versus total cytokeratin 18 at baseline and 21 days following the first dose of 625mg ONC201 in (A) an ovarian cancer patient (disease progression within 3 weeks) and (B) a prostate cancer patient (stable disease > 20 weeks). Figure S4: Serum TRAIL ELISA assay following the first dose of ONC201; Figure S5: Serum prolactin induction; Figure S6: Serum prolactin induction versus ONC201 exposure; Table S1. Patient demographics with ONC201 administered every three weeks in dose escalation phase and in the expansion phase with ONC201 RP2D.; Table S2: Adverse events occurring on study that were not attributed to ONC201; Table S3: Individual ONC201 pharmacokinetic parameters for patients in the dose escalation phase; Table S4: Select characteristics of patients in the dose escalation phase. Table S5. Clinical responses and pharmacodynamic in the dose escalation phase.'

The top panel shows the reaction chemistry of established lysyl oxidase (LOX) activity assay. The bottom panel shows the Amplex Red/HRP-based LOX activity assay that detects LOX activity in vitro.

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D).Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information.Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients.Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163–9. ©2017 AACR.

This is the demographics table containing brief summary of baseline patient characteristics of patients enrolled on trial.

This is the demographics table containing detailed baseline patient characteristics listed for each of the 75 patients. The data is de-identified.

Supplementary Table S1. Arithmetic Mean {plus minus} SD Plasma Erdafitinib Pharmacokinetic Parameters after the First Erdafitinib Administration (Cycle 1 Day 1) or at Steady-State (Cycle 2 Day 1) in Patients Assigned to the Continuous Daily Dosing or the Intermittent (7 Days on/7 Days off) Dosing Regimen (Part 1 and Part 2 of the Study)

Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel.We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/mForty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance.We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m

Background:ER positive, HER2-negative breast cancer is the most common subtype in both early and late stages. Previous studies have demonstrated a subset of patients may derive benefit from immune check point inhibitors in combination with endocrine therapy. We hypothesize that Pembrolizumab in combination with fulvestrant will demonstrate anti-tumor activity measured by frequency of response. Trial Design: This is a non-randomized, multi-site, open-label Phase II trial for subjects with metastatic, hormone receptor positive, HER2 negative breast cancer. The study will enroll 47 patients to evaluate the anti-tumor activity of pembrolizumab with fulvestrant as measured by RECIST 1.1 and irRECIST tumor response and by progression free survival. (ClinicalTrials.gov Identifier: NCT03393845) Eligibility Criteria: Patients with advanced non-resectable/metastatic breast cancer that is estrogen receptor positive (ER+) and/or (PR+), HER2 negative (HER2-), with no more than two lines of prior hormonal therapy or no more than two lines of prior chemotherapy. Specific aims: To evaluate the overall response rate (ORR) of pembrolizumab plus fulvestrant in patients with hormone receptor positive, HER2 negative advanced/metastatic breast cancer. Secondary aims include safety and tolerability of the combination. Tumor genomic profiling on solid and/or liquid specimens using next generation sequencing assays to help identify biomarkers of response to immunotherapy. Statistical Methods: This is a phase II study that will enroll a total of 47 patients to evaluate the anti-tumor activity of pembrolizumab with fulvestrant as measured by RECIST 1.1 tumor response and by progression free survival in patients with breast cancer. For maximal 47 patients, 21 will be accrued during stage I and 26 during stage II. If 6 or fewer responses are observed during stage I, then the trial is stopped early for futility. If there are 7 or more responses during stage I, the trial will go on to stage II, in which an additional 26 patients will be accrued. If a total of 21 or more responses are observed by the end of stage II, then the trial will be considered successful, and the combination therapy considered worthy of further investigation. Present accrual and target accrual: The study is currently enrolling patients at Rutgers Cancer Institute of New Jersey, Michigan State University, and University of Nebraska. 20 of 47 patients have been enrolled on study to date. Citation Format: Nancy Chan, Dirk Moore, Pavankumar Tandra, Jatin Rana, Coral Omene, Mridula George, Jairam Krishnamurthy, Shruti Desai, Nayana Patel, Yue Wang, Marc Bicomong, Xiao-wei Tan, Kim Hirshfield, Shridar Ganesan, Deborah Toppmeyer. A phase II study of pembrolizumab plus fulvestrant in hormone receptor positive, HER-2 negative advanced/metastatic breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-17-02.

Background: Triple negative breast cancer (TNBC) is an aggressive subtype accounting for 15% of all breast cancer subtypes. It is characterized by larger tumor size, higher grade, early peak of recurrence, and a worse 5-year overall survival rate compared to other breast cancer subtypes. Treatment with immunotherapy has been shown to be beneficial in PD-L1 positive patients in the metastatic setting. Priming the tumor environment can upregulate PD-L1 expression. Pelareorep, a proprietary isolate of the unmodified replication competent reovirus type 3 Dearing (T3D) strain, a non-enveloped reovirus has been shown to upregulate PD-L1 expression in tumor and inflammatory cells and promote a favorable CD8:regulatory T cell ratio indicating a less immunosuppressive tumor microenvironment. Retifanlimab (INCMGA00012) is PD-1 inhibitor currently in development. A phase 2 study is currently underway studying the combination with the rationale that the administration of pelareorep will prime the tumor microenvironment for enhanced tumor response to PD-1 inhibitor retifanlimab. Trial design: This is a phase II multi-site single-arm clinical trial to study the combination of PD-1 inhibitor retifanlimab and the oncolytic virus pelareorep in patients with metastatic triple negative breast cancer. Eligible patients will receive pelareorep 4.5x1010 TCID50/day, on Days 1, 2, 15 and 16 and retifanlimab 500 mg on day 3 of every 28-day cycle. Patients will be monitored clinically and radiologically for response to treatment. Tumor tissue, stool and blood samples will be collected during treatment to evaluate changes in PD-L1 expression, gut microbiome and inflammatory cells induced by the study drugs. (ClinicalTrials.gov Identifier: NCT04445844) Eligibility criteria: Premenopausal/postmenopausal women with metastatic TNBC who have previously received 1-2 prior lines of chemotherapy in the metastatic setting are eligible for the study. They must have adequate performance status (ECOG PFS 0-2). Specific aims: Primary endpoint will be objective response rate (ORR) and safety, determined by the number, frequency, duration, and severity of AEs using CTCAE v5.0. The Secondary end-points will be progression free survival (PFS), overall survival (OS), duration of response (DOR) and quality of life measures using EORTC QLQ-C30. Statistical methods: Simon’s optimal 2-stage design will be used to calculate sample size. In the first stage, 14 patients will be accrued. If there are 1 or fewer responses in these 14 patients, the study will be stopped. Otherwise, 11 additional patients will be accrued for a total of 25. The null hypothesis will be rejected if 4 or more responses are observed in 25 patients. The first 6 patients will be enrolled in a staggering interval for the safety run-in phase of the study. Accrual: The study is currently enrolling patients at Rutgers Cancer Institute of New Jersey and Ohio State University Comprehensive Cancer Center. There are no safety signals with the combination in patients who have received both drugs to date. Citation Format: Mridula George, Nicole Williams, Coral Omene, Nancy Chan, Shou-En Lu, Danielle Tang, Grey Wilkinson, Shridar Ganesan, Deborah Toppmeyer. Irene study: Phase 2 study of Incmga00012 and the oncolytic virus pelareorep in metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-25-01.

Background: The addition of neoadjuvant platinums to standard chemotherapy regimens for triple negative breast cancer (TNBC) improves rates of pathologic complete response (pCR). Our prior trial combining carboplatin (CAR) with liposomal doxorubicin (DOX) for metastatic TNBC showed good response rates with minimal side effects and allows for higher platinum dosing. We hypothesized that the doublet of DOX+CAR is effective and tolerable in the neoadjuvant setting for TNBC and tumor genomics may identify biomarkers of complete response and actionable targets. Methods: A phase II single arm trial was conducted for patients (pts) diagnosed with stage II-III TNBC. Patients received 4 cycles of neoadjuvant carboplatin (AUC 5) and liposomal doxorubicin (30mg/m2) administered every 28 days, then underwent definitive breast surgery followed by 12 weeks of adjuvant paclitaxel 80 mg/m2 administered weekly. Primary and secondary clinical endpoints were rate of pCR and two year recurrence free survival (RFS) and overall survival (OS), respectively. Cardiac safety of the combination was assessed. Fresh residual tumor samples were obtained at time of surgery for generation of patient derived xenografts (PDX). Whole genome sequencing (WGS) and RNA sequencing will be performed to evaluate specific patterns of small-variant mutations and patterns of structural variants to identify which patients are likely to have pCR. Results: From 2/2015 to 6/2021, 62 pts were enrolled, 8 pts withdrew consent either prior to treatment or completion of neoadjuvant therapy and/or surgery. Median age of the cohort was 55.4 years. There was high participation by under-represented groups: 17.0% African American, 20.8% Asian, 13.2% Hispanic. Most histologies were invasive ductal carcinoma, but included apocrine, pleomorphic lobular, and metaplastic subtypes. 53 pts completed all 4 cycles of neoadjuvant DOX+CAR, followed by definitive surgery; 1 pt progressed after 1 cycle and proceeded to surgery thereafter. 30.2% (16) pts achieved pCR, and residual cancer burden (RCB) will be reported in patients with residual disease. Of the 53 pts who completed 4 cycles of treatment, 5 pts progressed (recurrence or death) within two years from time of surgery (4 distant and 1 local recurrence), yielding the 2-year recurrence-free-survival rate of 90.3% (95%CI 81.0%, 99.6%). The most common toxicities during DOX+CAR were grade 1 fatigue in 50 pts (92.6%), grade 1 anemia in 44 pts (81.5%), and grade 3/4 neutropenia in 16 pts (29.6%); these pts received GCSF support with subsequent cycles; febrile neutropenia occurred in 1 pt (1.9%) in this group. Only 10 pts (18.5%) had grade 1 alopecia, 5 pts (9.3%) had grade 2 alopecia, 2 pts (3.7%) had grade 3 thrombocytopenia. There were no delays in treatment due to cardiotoxicity or complications from surgical healing. Of the 37 pts who had residual disease, PDX was attempted in 21 pts, and 16 (76%) PDX were established, including those for 4 patients experiencing recurrence. WGS and RNA sequencing data from pre-treatment and residual disease samples will be analyzed and reported.Conclusion: 4 cycles of neoadjuvant DOX+CAR achieved rate of pCR similar to standard regimens and has good tolerability. Post chemotherapy PDX is feasible and may help identify targeted approaches for patients with resistant disease. These results warrant further evaluation of this combination for early stage TNBC. Citation Format: Nancy Chan, Shou-en Lu, Yue Wang, Gregory M Riedlinger, Coral Omene, Mridula George, Jyoti Malhotra, Maria Kowzun, Firas G Eladoumikdachi, Lindsay B Potdevin, Shicha Kumar, Kant Matsuda, Shruti Desai, Nayana Patel, Deborah L Toppmeyer, Shridar Ganesan, Kim Hirshfield. Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of early stage triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-15.

Background: HER2-positive breast cancer patients are commonly treated with neoadjuvant therapy including HER2-targeted therapy. Patients who have residual invasive disease have less favorable outcomes with an increased risk of recurrent disease than patients with complete pathologic response (pCR). It has also been observed that these non-pCR patients have low or absent anti-HER-2 CD4 Th1 responses. We hypothesized that correcting the anti-HER-2 CD4 Th1 response using vaccines will increase interferon gamma production which we have shown is a potent inducer of apoptosis and senescence in HER2-positive breast cancer. This study will be evaluating safety and immunogenicity of two vaccines (multivalent anti-oncodriver DNA vaccine (WOKVAC) or HER-2-pulsed dendritic cell vaccine (DC1)). Methods: This is a multi-center, phase 2, randomized study to determine the safety and tolerability of HER2 vaccines (DC1 and WOKVAC), assess immunogenicity, and evaluate recurrence free survival. Patients with HER2-positive early breast cancer (stage I-III) are eligible if they have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant chemotherapy plus HER2 -targeted therapy. Patients are randomly assigned in a 1:1 ratio to receive 1 of 2 adjuvant HER2 vaccines, either DC1 or WOKVAC for 1 year. A permuted-block randomization scheme was used with stratification according to residual cancer burden (RCB) (1+2 vs 3). The primary end points are safety and immunogenicity (immune response rate measured by ELISPOT). Each treatment arm will be assessed separately. Any statistical comparison between arms is purely exploratory, as this study is neither designed nor powered for comparative hypotheses. Secondary endpoints include recurrence-free survival. Exploratory analyses include the assessment of prognostic and predictive biomarkers including circulating tumor cells, serum HER2 levels, and other immune markers. The enrollment began in 2018 and we plan to accrue the total of 110 patients. ClinicalTrials.gov Identifier: NCT03384914 Citation Format: Hyo S Han, Mary Disis, Robert Wesolowski, Carla Fisher, Shipra Gandhi, Nancy Chan, William Gwin, Keerthi Gogineni, Rosemarie Mick, Christina Sierra Rodriguez, Deanna Hogue, Hien Liu, Ricardo Costa, Brian Czerniecki. A multicenter phase II study of vaccines to prevent recurrence in patients with HER-2 positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-16-01.

Purpose Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. Methods Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. Results Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. Conclusion V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

ObjectivePreclinical evidence and early clinical trials have demonstrated the activity of SPL-108, a targeted agent that inhibits CD44 mediated induction of multidrug resistance specifically to paclitaxel and platinum agents. We conducted a phase I, open label, dose escalation study of the safety and tolerability of the combination of SPL-108 with weekly paclitaxel in patients with platinum resistant CD44+ ovarian, primary peritoneal, or fallopian tube cancer.MethodsPatients with platinum resistant histologically proven epithelial ovarian, primary peritoneal, or fallopian tube cancers and measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1 were selected. Tumors were tested for CD44 expression for eligibility, defined as strong (+++) or moderate (++) staining in ≥20% of the tumor tissue or diffuse + staining. Patients were treated with daily and then twice daily SPL-108 subcutaneous injections and weekly intravenous paclitaxel on days 1, 8, and 15 of a 28 day cycle. Endpoints included safety, determination of maximum tolerated dose, and efficacy. Tumors underwent comprehensive genomic profiling, and cell lines and western blotting were used to study markers of response.ResultsWe screened 16 patients, and 14 were enrolled based on CD44+ expression. A total of 86% of patients had high grade serous tumors and all had received multiple prior therapies. There were no grade 4–5 toxicities. One patient had grade 3 peripheral sensory neuropathy attributed to paclitaxel and one patient developed presumed colonic perforation attributed to the study drug. No dose reductions or treatment discontinuations were required. All patients tolerated the maximum planned dose; no maximum tolerated dose was reached. Overall response rate was 36%; 5 (36%) patients had partial response and 5 (36%) patients had stable disease.ConclusionsThe combination of SPL-108 with weekly paclitaxel was safe and well tolerated. Encouraging antitumor activity was observed, with 72% of patients deriving a clinical benefit.Trial registrationNCT03078400.

Although PD-1/PD-L1 therapies have shown significant activity across a range of tumor types, only a subset of patients (10-30%) achieve durable responses. With the goal of improving response and application to PD-1/PD-L1 therapies, we have leveraged our proprietary Xilio Advanced Cytokine Therapies (X-ACT) platform to develop PD1/IL2-ACT, a PD-1 blocker enhanced with a tumor-activated, engineered IL-2 agonist. The activity of IL-2 is blocked by a protein domain that prevents IL-2Rβγ binding until activated in the tumor microenvironment by matrix metalloproteinases . Tumor selective activation of IL-2 enables dosing of PD1/IL2-ACT at sufficient exposure levels to block immunosuppressive PD1/PD-L1 signaling as well as mitigating systemic IL-2 driven toxicity. PD1/IL2-ACT is designed to enable in cis engagement of IL-2 receptors on antigen experienced PD-1+ CD8+ T cells in the tumor microenvironment (TME), inducing effector T cell functions while preventing regulatory T cell (Treg) mediated immune suppression. In a preclinical model, PD1/IL2-ACT, compared to anti-PD1 alone, induced significant tumor growth inhibition. Further, PD1/IL2-ACT was better tolerated than a PD-1 directed unmasked IL-2Rβγ biased agonist in the same preclinical model. Pharmacodynamic studies showed that PD1/IL2-ACT did not significantly change immune cell profiles in the periphery but increased antigen specific CD8+ T cells in the TME, consistent with preferential engagement of PD1+ effector T cells at the tumor site. Ex vivo protease cleavage assays performed in human tumors demonstrated significant activation of PD1/IL2-ACT by tumors of multiple indications but minimal activation in human plasma. A pharmacokinetic study in nonhuman primates revealed PD1/IL2-ACT can achieve comparable exposure levels to existing PD-1 blocking immunotherapies. Taken together, these data illustrate that PD1/IL2-ACT has the potential to broaden the activity of existing immunotherapies by inhibiting the PD1/PDL1 axis as well as directing an immunostimulatory cytokine to antigen specific T cells in the TME. Citation Format: Ertan Eryilmaz, Wilson Guzman, Dheeraj S. Tomar, Parker Johnson, Stephanie Hsiao, Lisa Quinn, Nancy Chan, Jimit Lakhani, Brendan Whalen, Rosa Quiroz, Kurt Jenkins, Oleg Yerov, Will Scott, Justin Greene, Zhen Liu, Megan McLaughlin, Sallyann Vu, Chelsea Turcotte, Hanumantha R. Madala, Jacob Taylor, Caitlin O'Toole, Magali Pederzoli-Ribeil, Haley Duprey, Natalia Malkova, Damiano Fantini, David Crowe, Sean Yang, Kyle Smith, Joseph Card, Janice Lee, Kerri Smith, Benjamin Nicholson, Jijun Dong, Jennifer O'Neil, Carl U. Bialucha. Tumor-activated PD1-directed IL-2 increased antigen specific T cells in tumors and demonstrated anti-tumor activity in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 572.

Ductal carcinoma in situ (DCIS) represents approximately 20–25% of newly diagnosed breast cancers. DCIS is treated by surgery and possibly radiotherapy. Chemotherapy is only used as adjuvant or neoadjuvant therapy but not as primary therapy. The present study investigated the intraductal administration of Ciclopirox (CPX) formulated in nanosuspensions (NSs) or nanoparticles (NPs) to treat DCIS locally in a Fischer 344 rat model orthotopically implanted with 13762 Mat B III cells. Slow converting esterase responsive CPX prodrugs (CPDs) were successfully synthesized at high purity (> 95%) by directly acetylating the hydroxyl group or by appending a self-immolative linker between CPX and a phenolic ester. Direct esterification CPDs were not sufficiently stable so self-immolative CPDs were formulated in NSs and NPs. Prodrug release was evaluated from poly(lactic-co-glycolic acid) NPs, and CPD4 demonstrated the slowest release rate with the rank order of CPD2 (R = methyl) > CPD3 (R = t-butyl) > CPD4 (R = phenyl). Intraductally administered CPX NS, CPD4 NS, and an innovative mixture of CDP4 NS and NPs (at 1 mg CPX equivalent/duct) demonstrated significant (p

ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks. Dose escalation was by an exposure-adjusted, continual reassessment method. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Nineteen patients received ABBV-176 at doses from 2.7-109.35 μg/kg. Patients enrolled had colorectal cancer (n = 11), breast cancer (n = 6), or adrenocortical carcinoma (n = 2). DLTs occurred in 4 patients and included thrombocytopenia (n = 2; both at 99.9-μg/kg dose level), neutropenia (n = 2; 78.3-μg/kg and 99.9-μg/kg dose levels), and pancytopenia (n = 1; 109.35-μg/kg dose level). The most common treatment-emergent adverse events related to ABBV-176 were thrombocytopenia, neutropenia, increased aspartate aminotransferase, nausea, fatigue, and pleural effusions. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity. Tumor expression of PRLR varied among patients enrolled and analyzed. No patient had an objective response. MTD was not formally determined, as identification of a tolerable dose was confounded by late-onset toxicities. ABBV-176 was associated with significant toxicity in this phase 1, dose-escalation study. Although cytopenias were often dose limiting, effusions and edema were also common and had late onset that suggested cumulative toxicity. No responses were observed, although data were available from a small number of patients with variable tumor PRLR expression. This study was terminated after the dosing of 19 patients.

Triple negative breast cancer (TNBC) is a high-risk and aggressive malignancy characterized by the absence of estrogen receptors (ER) and progesterone receptors (PR) on the surface of malignant cells, and by the lack of overexpression of human epidermal growth factor 2 (HER2). It has limited therapeutic options compared to other subtypes of breast cancer. There is now a growing body of evidence on the role of immunotherapy in TNBC, however much of the data from clinical trials is conflicting and thus, challenging for clinicians to integrate the data into clinical practice. Landmark phase III trials using immunotherapy in the early-stage neoadjuvant setting concluded that the addition of immunotherapy to chemotherapy improved the pathologic complete response (pCR) rate compared to chemotherapy with placebo while others found no significant improvement in pCR. Phase III trials have investigated the utility of immunotherapy in previously untreated metastatic TNBC, and these studies have similarly arrived at inconsistent conclusions. Some studies showed no benefit while others demonstrated a clinically significant improvement in overall survival in the PD-L1 positive population. It is not yet clear which biomarkers are most useful, and assays for these biomarkers have not been standardized. Given the often serious and severe side effects of immunotherapy, it is important and necessary to identify predictive biomarkers of response and resistance in order to enhance patient selection. In this review, we will discuss both the challenges of traditional biomarkers and the opportunities of emerging biomarkers for patient selection.

BACKGROUND: STK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis. METHODS: Forty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test. RESULTS: In the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P

Health-related quality of life; Metastatic breast cancer; Neratinib Calidad de vida relacionada con la salud; Cáncer de mama metastásico; Neratinib Qualitat de vida relacionada amb la salut; Càncer de mama metastàtic; Neratinib Purpose To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. Methods In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan–Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. Results Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63–1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32–2.23]). Conclusion In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC. This work was supported by Puma Biotechnology Inc., Los Angeles, CA, USA [no grant number is applicable]. Puma Biotechnology Inc. funded the provision of editorial support provided by CMD Consulting and Miller Medical Communications.

Purpose:Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.Patients and Methods:Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested.Results:The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were Conclusions:Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor. ExteNET, a randomized placebo-controlled phase III study, showed that neratinib given for 12 months after trastuzumab-based adjuvant therapy significantly improved 2-year (HR 0.67; 95% CI 0.50–0.91; p=0.0091) and 5-year (HR 0.73; 95% CI 0.57-0.92; p=0.008) iDFS in pts with early-stage HER2+ breast cancer. Anti-diarrheal prophylaxis was not mandated by protocol; grade 3/4 diarrhea occurred in 40% of pts with a median cumulative duration of 5 days. The phase II CONTROL study was initiated to investigate the effectiveness of various prophylactic regimens in the prevention of neratinib-associated diarrhea. Loperamide (L) alone or in combination with add-on agents targeting underlying inflammation [i.e. budesonide (BUD)] or bile acid malabsorption [i.e. colestipol (COL)] were tested. We report longitudinal HRQoL findings from both ExteNET and CONTROL. Methods: Pts with early-stage HER2+ breast cancer who had received trastuzumab-based adjuvant therapy were eligible for both studies. In ExteNET, pts received neratinib or placebo for 12 months. In CONTROL, pts received neratinib for 13 x 28-day cycles combined with L, L + BUD or L + COL for 1 or 2 cycles (see table for schedules). HRQoL was assessed using Functional Assessment of Cancer Therapy–Breast (FACT-B), v4.0, at baseline, months 1, 3, 6, 9, 12 (ExteNET) or baseline, cycles 2, 4, 7, 10, 13 (CONTROL). Changes in scores from baseline were considered to be clinically meaningful if greater than the lowest estimate for an 'important difference' (ID) reported in the literature. Evaluable pts were required to have HRQoL assessments at baseline and at least 1 post-baseline. ClinicalTrials.gov: NCT00878709 (ExteNET); NCT02400476 (CONTROL). Results: HRQoL findings are summarized in the table. Hospitalization rates due to diarrhea: 1.5% (neratinib + L), 0% (other cohorts) in CONTROL; and 1.4% (neratinib), 0.1% (placebo) in ExteNET. Mean change from baselineStudyCohort/GroupM1M3M6M9M12 FACT-B TOTAL (ID range: 7–8 points)CONTROLN + La,b (N=40)–3.8–4.5–1.5–2.5–3.3 N + L + BUDa,b,c (N=62)–6.0–4.9–1.6–3.6–4.5 N + L + COLa,b,d (N=125)–3.8–2.0–4.0–4.6–3.6 N + L prn + COLa,d (N=85)–1.8–1.54.0e––ExteNETN + L prna (N=1124)–4.6–3.4–3.5–3.3–3.7 P (N=1188)–1.7–3.5–2.9–2.9–2.8 FACT-B PWB (ID range: 2–3 points)CONTROLN + La,b (N=40)–4.0–2.3–1.9–2.4–2.3 N + L + BUDa,b,c (N=62)–3.2–2.1–1.4–1.7–1.7 N + L + COLa,b,d (N=125)–2.8–2.0–2.4–2.5–2.4 N + L prn + COLa,d (N=85)–2.8–1.80.0e––ExteNETN + L prna (N=1124)–2.9–1.9–1.7–1.6–1.5 P (N=1188)–0.6–0.8–0.7–0.6–0.4C, cycle; L, loperamide; M, month; N, neratinib; prn, as needed; PWB, physical well-being. CONTROL cut-off: 1 May 2018. aN 240 mg qd for 13 x 28d cycles or 12 months; bL 4 mg, then 4 mg tid d1-14, then 4 mg bid d15-28 or d15-56, then prn; cBUD 9 mg qd d1-28; dCOL 2 g qd d1-28; en=1. Conclusions: Adjuvant neratinib with or without anti-diarrheal prophylaxis was associated with small decreases in HRQoL. With the exception of the FACT-B PWB subscale, HRQoL changes did not reach clinically meaningful thresholds. Follow-up in CONTROL is ongoing. Citation Format: Delaloge S, Hurvitz S, Chan N, Bose R, Jankowitz RC, Thirlwell M, Láng I, ten Tije A, Trudeau M, Osborne CR, Shen Z-Z, Lalla D, Xu F, Hunt D, Olek E, Tripathy D, Rugo HS, Chien J, Chan A, Barcenas CH. The impact of neratinib with or without anti-diarrheal prophylaxis on health-related quality of life in HER2+ early-stage breast cancer: Analyses from the ExteNET and CONTROL trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-03.

Background: The use of neoadjuvant platinum with taxane for triple negative breast cancer (TNBC) has gained increased attention for improving rates of pathologic complete response (pCR). Our prior trial combining carboplatin (CAR) with liposomal doxorubicin (DOX) for metastatic TNBC showed good response rates with minimal side effects while allowing for greater platinum dosing compared to a taxane combination. We hypothesized that the doublet of DOX+CAR is effective and tolerable in the neoadjuvant setting for TNBC and that tumor genomics may aid in determining those patients most likely to benefit. Methods: A phase II single arm trial was conducted for patients (pts) diagnosed with stage II-III TNBC. Patients received 4 cycles of neoadjuvant carboplatin (AUC 5) and liposomal doxorubicin (30mg/m2) administered every 28 days, then underwent definitive breast surgery followed by 12 weeks of adjuvant paclitaxel 80 mg/m2 administered weekly. Primary and secondary clinical endpoints were rate of pCR and two year recurrence free survival (RFS) and overall survival (OS), respectively. Cardiac safety of the combination was assessed. Fresh residual tumor samples were obtained at time of surgery for generation of patient derived xenografts (PDX). Tumor genomic profiling was done to determine the mutational spectrum, association of this spectrum in primary tumors with achieving pCR, and identifying alternative treatment strategies for PDX evaluation for patients with resistant disease. Results: From 2/2015 to 5/2018, 36 pts were enrolled and 32 completed treatment; 4 pts await definitive surgery; 12 (33%) are two years from diagnosis. Median age of the cohort was 53 years. There was high participation by under-represented groups: 23% African American, 20% Asian, 14% Hispanic. Most histologies were invasive ductal but included apocrine, pleomorphic lobular, and metaplastic subtypes. Of the 32 pts who completed surgery, 34% (11) achieved pCR and 64% (23) had clinical response on serial physical exam. At 2 years, there were 2 distant and 1 local recurrence. The most common toxicities during DOX+CAR were grade 1 nausea in 19 pts (53%), grade 3/4 neutropenia occurred in 10 pts (28%); these pts received GCSF support with subsequent cycles; febrile neutropenia occurred in 1 pt (3%) in this group. Grade 3 thrombocytopenia (2 pts), pruritis (1 pt), and mucositis (1 pt) were observed. Only 6 pts (17%) had grade 1 alopecia. There were no delays in treatment due to cardiotoxicity or complications from surgical healing. TP53 (93%), PI3K/PTEN (26.6%), and NOTCH (20%) were the most commonly altered pathways. Structural variants, such as amplifications, rearrangements, and frameshifts were the most frequent alterations detected. Of the 25 pts who had residual disease, PDX was attempted from 14 pts, and 10 (71%) PDX were established, including those for all 3 patients experiencing recurrence. Conclusion: Neoadjuvant DOX+CAR demonstrated good efficacy and tolerability. Post-chemotherapy PDX is feasible and may help identify targeted approaches for patients with resistant disease. These results warrant further evaluation of this combination for early stage TNBC. Citation Format: Chan N, Riedlinger GM, Lu S-e, Pham KT, Kirstein LJ, Eladoumikdachi FG, George MA, Potdevin LB, Kowzun MJ, Desai SA, Tang DM, Omene CO, Wong ST, Rodriguez-Rust L, Kumar S, Kearney TJ, Liu C, Ganesan S, Toppmeyer DL, Hirshfield KM. Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-14.

11002 Background: Gender disparity is an important issue in medicine, as women occupy a minority of academic leadership positions despite increased representation in the physician workforce. One important aspect is the gender gap of speakers at academic meetings, which limits opportunities for career advancement and mentorship. This underrepresentation of women is largely anecdotal in oncology. We hypothesized that original research is less frequently presented by women at the annual ASCO meeting. We sought to examine presentation patterns from recently featured ASCO speakers, categorized by presentation type and gender. Methods: We conducted a retrospective, observational review of data from the 2018-2021 ASCO annual meetings. Mixed-gender coders extracted data from the ASCO Annual Meeting library and institutional public websites. Speaker-identified gender was unavailable; binary gender was determined by presenter name, pronouns, and video files. For original research, we collected data on last authors as well as these roles are also considered meritorious. Cochran–Mantel–Haenszel tests were used to investigate the association of gender and roles adjusted for each stratification variable individually. Common odds ratios (ORs) were estimated for each association. Breslow-Day Tests were used to test the homogeneity of these ORs among the different levels of each stratification variable. No adjustments for multiple testing were used. Results: We reviewed 4267 unique presentations, including those which highlighted original research (Poster Discussion, Oral Abstract, Clinical Science Symposium, Plenary) vs. education (Case-Based Panel, Education Sessions, Highlights of the Day). For original research, women were significantly more likely to have an ASCO-appointed role (discussant, speaker, or chair) than a first or last author role (48% vs. 32.7% of presentations, p < 0.0001), even after adjusting for conference year (OR 0.53, 95% CI: 0.45-0.61), session type (0.52, 0.45-0.61), degree (0.50, 0.43-0.58), academic rank (0.55, 0.47-0.64), and geographic region (0.58, 0.50-0.68). There was no difference between in-person and virtual conferences (p = 0.584). For education sessions, women comprised 46.1% (n = 626), nearly half, of these speaking roles (all ASCO-appointed) compared with men. 38% of the data was independently re-reviewed to confirm accuracy; 96.4% concordance was observed in presenter gender. Conclusions: Women are less likely to present highlighted original research and are more likely to have an appointed educational role at ASCO annual meetings. This likely reflects broader gender disparity within academia. Future analyses could be improved by examining speaker-identified gender. As high-profile original research can elevate careers, examining factors contributing to this observed disparity may reveal important approaches to address gender leadership gaps in oncology.

Ductal carcinoma in situ (DCIS) represents approximately 20-25% of newly diagnosed breast cancers. DCIS is treated by surgery and possibly radiotherapy. Chemotherapy is only used as adjuvant or neoadjuvant therapy but not as primary therapy. The present study investigated the intraductal administration of Ciclopirox (CPX) formulated in nanosuspensions (NSs) or nanoparticles (NPs) to treat DCIS locally in a Fischer 344 rat model orthotopically implanted with 13762 Mat B III cells. Slow converting esterase responsive CPX prodrugs (CPDs) were successfully synthesized at high purity ( 95%) by directly acetylating the hydroxyl group or by appending a self-immolative linker between CPX and a phenolic ester. Direct esterification CPDs were not sufficiently stable so self-immolative CPDs were formulated in NSs and NPs. Prodrug release was evaluated from poly(lactic-co-glycolic acid) NPs, and CPD4 demonstrated the slowest release rate with the rank order of CPD2 (R = methyl) CPD3 (R = t-butyl) CPD4 (R = phenyl). Intraductally administered CPX NS, CPD4 NS, and an innovative mixture of CDP4 NS and NPs (at 1 mg CPX equivalent/duct) demonstrated significant (p 0.05) in vivo anti-tumor efficacy compared with immediate release (IR) CPX NS and non-treated controls. CPX mammary persistence at 6 h and 48 h after CPD4 NS or NP administration was also greater than after the immediate release CPX NS. A strong correlation between CPX mammary persistence and efficacy is demonstrated. In conclusion, nanoformulations utilizing a slow releasing/slow bioconverting CPX prodrug delivery strategy resulted in significant dose de-escalation (~ five fold) while maintaining anti-tumor efficacy.

Correlations are prevalent in the geotechnical engineering practice. This paper presents a practical machine learning approach for establishing improved geotechnical correlations. In the realm of machine learning, multiple input variables of significance can be readily and coherently incorporated into the model. This approach is illustrated in the context of correlation between undrained shear strength and the combination of depth, water content, liquid limit and plastic limit. The methodology is presented in a general form to facilitate adaptation to other geotechnical correlations. The machine learning model is created in TensorFlow which is an open source machine learning platform. A dataset which consists of 1013 groups of undrained shear strength from undrained-unconsolidated triaxial test, depth of sample, water content, liquid limit and plastic limit data are compiled. 70 % of the randomised dataset are used for training and validating the model while the remaining 30 % are used to test the performance of the model. The machine learning model consists of an artificial neural network model with one input layer, four hidden layers and one output layer. The training takes several minutes on a laptop equipped with a Graphics Processing Unit. The classical approach would have been to correlate the undrained shear strength to liquidity index which is a combined parameter computed from water content, liquid limit and plastic limit. By comparing the predictions of the machine learning model on the test dataset against those computed based on dataset-specific correlation between undrained shear strength and liquidity index, it is evident that a significantly improved correlation is obtained using the machine learning approach. Due to the intricacy of multi-dimensional regression analysis, classical geotechnical correlations are typically determined by method of curve-fitting with just a single independent variable. Soil, by nature, is a complex material that is characterised by multiple index properties. Therefore, it is intuitive that geotechnical correlations can be improved by incorporating multiple classification properties or measurements. The machine learning approach described in this paper, which is implemented using an open source platform and readily accessible to industry practitioners, alleviates the legacy limitation of a single independent variable leading to improved geotechnical correlations. More importantly, this machine learning approach fits in perfectly with the digitalisation initiative increasing embraced by the oil and gas industry to improve on safety, efficiency and profitability.

Ductal Carcinoma In Situ (DCIS) represents a significant fraction (~20-25%) of all newly diagnosed breast cancer cases and, if left untreated, a significant fraction of patients will progress to invasive disease. Surgery is the only treatment option. Ciclopirox (CPX), an FDA-approved antifungal drug, has exhibited promising antitumor activity by down-regulating the expression of vital antiapoptotic cellular proteins and inhibiting the genetic expression of several oncogenic pathways. In this study, the feasibility of using nanoscale delivery systems to control release and prolong mammary tissue persistence of a lipophilic metal complex of CPX and Zinc (CPXZn) after intraductal administration was investigated.CPX and CPX-Zn nanosuspensions (NSs) were prepared using an evaporative nanoprecipitation-ultra-sonication method. Flash nanoprecipitation was used to prepare PLGA nanoparticles (NPs) loaded with CPXZn. Our established orthotopic DCIS rat model was used to evaluate efficacy. Briefly, two days after 13762 Mat B III cell intraductal inoculation, rats were divided into treatment groups and a single intraductal injection of CPX NS, CPX-Zn NS or CPX-Zn NPs was administered. In the first study arm, the efficacy of CPX NS (1, 3, 5 mg/duct) was evaluated. In the second arm, the in vivo efficacy of CPX NS, CPX-Zn NS and CPX-Zn loaded NPs was evaluated and compared at equivalent CPX doses. The mammary persistence of CPX from CPX NS, CPX-Zn NS, and CPX-Zn PLGA NPs was also assessed.CPX-Zn complex was successfully synthesized and characterized by several spectral analyses. CPX release was slowed from the CPX-Zn NS and further slowed by incorporating CPX-Zn into PLGA NPs as compared to the CPX NS with release half times following the order: CPX NS CPX-Zn NS CPX-Zn NP. Intraductal CPX NS administration was dose and time dependent in suppressing tumor initiation suggesting prolonged mammary exposure may improve efficacy. In the second arm, mammary tissue persistence of CPX followed the rank order CPX NS CPX-Zn NS CPX-Zn NP at 6 h and 48 h post-administration. Prolonged mammary CPX exposure was highly correlated to improved efficacy. Prolonged CPX tissue persistence, attributed to slower release from the zinc complex and the PLGA NPs, resulted in a 5-fold dose reduction compared to the CPX NS.The current results demonstrate that slowing drug release in the mammary duct after intraductal administration overcomes the rapid ductal clearance of CPX, prolongs mammary tissue persistence, improves efficacy against DCIS lesions in vivo, and requires 5-fold less CPX to achieve equivalent efficacy. The studies also provide a strategic path forward for developing a locally administered drug delivery system for treating DCIS, for which no primary chemotherapy option is available.

Purpose Inherited germline defects are implicated in up to 10% of human tumors, with particularly well-known roles in breast and ovarian cancers that harbor BRCA1/2-mutated genes. There is also increasing evidence for the role of germline alterations in other malignancies such as colon and pancreatic cancers. Mutations in familial cancer genes can be detected by high-throughput sequencing, when applied to formalin-fixed paraffin-embedded tumor specimens. However, because of the frequent lack of patient-matched control normal DNA and/or low tumor purity, there is limited ability to determine the genomic status of these alterations (germline v somatic) and to assess the presence of loss of heterozygosity (LOH). These analyses, especially when applied to genes such as BRCA1/2, can have significant clinical implications for patient care. Materials and Methods LOHGIC (LOH-germline inference calculator) is a statistical model selection method to determine somatic versus germline status and predict LOH for mutations identified via clinical grade, high-depth, hybrid capture, tumor-only sequencing. LOHGIC incorporates statistical uncertainties inherent to high-throughput sequencing as well as specimen biases in tumor purity estimates, which we used to assess BRCA1/2 mutations in 1,636 specimens sequenced at Rutgers Cancer Institute of New Jersey. Results Evaluation of LOHGIC with available germline sequencing from BRCA1/2 testing demonstrates 93% accuracy, 100% precision, and 96% recall. This analysis highlights a differential tumor spectrum associated with BRCA1/2 mutations. Conclusion LOHGIC can assess LOH status for both germline and somatic mutations. It also can be applied to any gene with candidate, inherited mutations. This approach demonstrates the clinical utility of targeted sequencing in both identifying patients with potential germline alterations in tumor suppressor genes as well as estimating LOH occurrence in cancer cells, which may confer therapeutic relevance.

Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti–programmed death–ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low–mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.

Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor with a single agent maximum tolerated dose (MTD) of 1mg orally qd. Primary dose-limiting toxicity (DLT) was thrombocytopenia. This phase I study combines T with the commonly used chemotherapy regimen of carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. In both schedules, C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B) starting on day 1. A 3+3 design is used for dose escalation. Key eligibility criteria include age 318 with a measurable or evaluable solid incurable malignancy. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation. Stable, treated brain metastases are allowed. No prior C for metastatic disease is allowed. Pts must have platelets>150 and no need for anticoagulation. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone with continuous daily dosing. Each schedule will have a 6 subject dose expansion at the MTD. The starting dose level for schedule B will be the MTD from schedule A. Results: Schedule A cohort results are reported: 11 pts (median age 59 [range 39-68]; 8 female; 3 male) have been enrolled. Pts had breast (6), ovarian (2), pancreatic (1), and SCC of oropharynx (1) and concurrent ovarian and pancreatic (1). Five pts are BRCA2+ and 3 pts are BRCA1+. Dose level 3 on schedule A (T 350mcg with C AUC 6 and P 80mg/m2) exceeded the MTD with 2 of 3 pts experiencing hematologic dose limiting toxicities (DLTs) including 1 pt with grade (gr) 3 neutropenic fever and gr 4 thrombocytopenia and another pt with grade 3/4 neutropenia lasting > 7 days. Most common AEs include neutropenia (grade 3-4: 7), anemia (grade 3-4: 3), and thrombocytopenia (grade 3-4: 4). Results from expansion of dose level 2 (T 250mcg with C AUC 6 and T 80mg/m2) will be presented. The 11 pts were on study a median of 9 weeks (range 9-36+). Four pts have discontinued study therapy: 1 due to need for anticoagulation for PE, 1 for prolonged cytopenias, and 2 for disease progression. Of the 8 pts with measurable disease evaluated for response to date, 4 had SD, 1 had a cPR, 1 had radiographic CR, and 2 with PD. A pt with BRCA 1+ triple negative breast cancer has maintained a prolonged PR (36+ weeks) even after dose reductions to T 100mcg with C AUC 3. One pt with ovarian cancer (BRCA WT) has radiographic CR (CA 125 remains mildly elevated) after 15+ weeks of therapy. Conclusion: PARP inhibition with talazoparib days 1-7 in combination with carboplatin and paclitaxel leads to DLT of myelosuppression. However, clinical responses are seen even with lower dose combinations. Citation Format: Turk A, Chan N, Leal T, O'Regan R, Tevaarwerk A, Rice L, Campbell T, Barroilhet L, Mehnert J, Eickhoff J, Kolesar J, Liu G, Wisinski K. NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-21.

Background ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors). Electronic supplementary material The online version of this article (10.1186/s40425-019-0599-8) contains supplementary material, which is available to authorized users.

Background: The FDA approved neratinib (N), an irreversible pan-HER tyrosine kinase inhibitor, in combination with capecitabine (C) for patients with HER2+ advanced or metastatic breast cancer who have received ≥2 prior HER2-directed regimens in the metastatic setting based on the NALA clinical study, where N+C significantly improved PFS vs. lapatinib (L)+C. Characterizing HRQoL associated with this regimen can help inform treatment decision-making for these patients. The objective of this analysis was to characterize HRQoL among patients with HER2+ metastatic breast cancer from the NALA clinical study. Methods: NALA was a multinational, randomized, open-label, phase III clinical study of N+C vs. L+C in patients with HER2+ metastatic breast cancer and ≥2 prior HER2-directed regimens. From May 2013 to July 2017, patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid 14d/21d) with loperamide prophylaxis during the first cycle, or to L (1250 mg qd) + C (1000 mg/m2 bid 14d/21d). HRQoL, a prespecified secondary endpoint of the NALA study, was measured using the EORTC QLQ-C30 and the breast cancer-specific QLQ-BR23 at baseline and every 6 weeks (±3 days) until the end of treatment (data collection through treatment cycle 19, 12.5 months). The QLQ-C30 summary and global health status scores range from 0 (worst) to 100 (best) and the systemic therapy side-effects scores range from 0 (best) to 100 (worst). Patients were included in the analysis for a particular scale if they had a baseline assessment and at least 1 follow-up assessment. For these analyses, a change of ≥10 points was considered to be clinically meaningful. Descriptive statistics summarized observed scores and changes from baseline, Kaplan-Meier and log-rank tests were used for time-to-deterioration (TTD) of ≥10 points and mixed models estimated the change over time for 7 prespecified scales: QLQ-C30 summary score, global health status, physical functioning, fatigue, constipation and diarrhea, and the EORTC QLQ-BR23 systemic therapy side effects subscale. No adjustments for multiplicity were performed. Results: 621 patients from 28 countries were randomized (307 N+C; 314 L+C). The mean completion rate of the QLQ-C30 over the course of the study was 91% for both treatment arms. Discontinuation due to any treatment-emergent adverse event (TEAE) was lower in the N+C vs. L+C arm (14% vs. 18%). At baseline, the mean (SD) QLQ-C30 summary scores were 79.8 (14.1) for N+C and 79.9 (15.7) for L+C. After 19 treatment cycles, the mean (SD) QLQ-C30 summary scores were similar to baseline scores: 81.8 (16.7) for N+C and 81.3 (15.3) for L+C. There were no differences in TTD of ≥10 points for the QLQ-C30 summary score between treatment arms; the HR for N+C vs. L+C was 0.94 (95% CI 0.63-1.40). All prespecified HRQoL subscales had similar statistically non-significant results for TTD with the exception of diarrhea (HR=1.71; 95% CI 1.32-2.23). The mixed models analyzing change in HRQoL from baseline did not demonstrate persistent declines nor meaningful differences between the treatment arms. Conclusion: In these results from the NALA study, among patients with HER2+ metastatic breast cancer, at study end and throughout most of the study, there were no differences observed between the two treatment arms in HRQoL scores. HRQoL was sustained over the study period despite the early transient presence of diarrhea in some patients. Discontinuation due to any TEAE was lower in the N+C vs. the L+C arm. These results may help guide healthcare providers, patients and carers in selection of optimal treatment for HER2+ metastatic breast cancer. Citation Format: Beverly Moy, Mafalda Oliveira, Cristina Saura, William Gradishar, Sung-Bae Kim, Adam Brufsky, Sara Hurvitz, Larisa Ryvo, Daniele Fagnani, Nancy Chan, Sujith R Kalmadi, Paula Silverman, Suzette Delaloge, Richard Bryce, Kiana Keyvanjah, Judith Bebchuk, Bo Zhang, Nina Oestreicher, Ron Bose. Neratinib + capecitabine sustains health-related quality of life (HRQoL) while improving progression-free survival (PFS) in patients with HER2+ metastatic breast cancer and ≥2 prior HER2-directed regimens [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-02.

Background: Triple negative breast cancer (TNBC) is an aggressive subtype accounting for 15% of all breast cancer cases. It is characterized by larger tumor size, higher grade, early peak of recurrence, and a worse 5-year overall survival rate compared to other breast cancer subtypes. Chemotherapy serves as the backbone for the treatment of metastatic TNBC. Treatment with immunotherapy in combination with Abraxane, a taxane-based chemotherapy, is of benefit only in PD-L1 positive tumors, which represents a minority of the patients. Pelareorep, a proprietary isolate of the unmodified, replication competent reovirus type 3 Dearing (T3D), has been shown to upregulate PD-L1 expression in tumor and inflammatory cells and downregulate intra-tumoral regulatory T-cells in the tumor microenvironment in pre-clinical and early clinical studies. Retifanlimab is a PD-1 inhibitor currently in development. The rationale for this clinical study is that the administration of pelareorep will prime the tumor microenvironment for enhanced tumor response to PD-1 inhibitor retifanlimab.Trial design: This is a phase II multi-site single-arm clinical trial to study the combination of PD-1 inhibitor retifanlimab and the oncolytic virus Pelareorep in metastatic triple negative breast cancer who have progressed on chemotherapy. Eligible patients will receive pelareorep 4.5x1010 TCID50 /day IV, on Days 1, 2, 15 and 16 and retifanlimab 500mg IV on day 3 of every 28-day cycle until disease progression or unacceptable toxicity. Patient will be monitored clinically and radiologically for response to treatment. Tumor tissue, stool and blood samples will be collected while on treatment to evaluate changes in PD-L1 expression, gut microbiome and inflammatory cells induced by the study drugs. (ClinicalTrials.gov Identifier: NCT04445844) Eligibility criteria: Eligible patients will include premenopausal/postmenopausal women with metastatic TNBC who have previously received 1-2 prior lines of chemotherapy in the metastatic setting. ECOG PFS 0-2. Specific aims: Primary endpoint will be objective response rate (ORR) and safety, determined by the number, frequency, duration, and severity of AEs using CTCAE v5.0. The secondary end-points will be progression free survival (PFS), overall survival (OS) and duration of response (DOR) and quality of life measures using EORTC QLQ-C30. Statistical methods: Simon’s optimal 2-stage design will be used to calculate sample size. In the first stage, 14 patients will be accrued. If there are 1 or fewer responses in these 14 patients, the study will be stopped. Otherwise, 11 additional patients will be accrued for a total of 25. The null hypothesis will be rejected if 4 or more responses are observed in 25 patients. The first 6 patients will be enrolled in a staggering interval for the safety run-in phase of the study. Accrual: The study will enroll up to 25 patients at Rutgers Cancer Institute of New Jersey and Ohio State University Comprehensive Cancer Center Contact information: Mridula George, MD Email: mridula@cinj.rutgers.edu Citation Format: Mridula George, Nicole Williams, Maryam Lustberg, Coral Omene, Nancy Chan, Nisha Ohri, Maria Kowzun, Lindsay Potdevin, Firas Eladoumikdachi, Shicha Kumar, Robert Wesolowski, Grey Wilkinson, Danielle Tang, Sinae Kim, Shridar Ganesan, Bruce Haffty, Deborah Toppmeyer. Irene study: Phase 2 study of incmga00012 (retifanlimab)and the oncolytic virus pelareorep in metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-32-02.

Purpose This study examines the accuracy of neophyte clinicians' assessments of central corneal clearance (CCC) of a corneoscleral lens using lens center thickness (CT) as a biometric scale. Methods A normal participant was fit with a corneoscleral lens on both eyes. Observers (n = 34) from the final semester of their fourth year in optometric clinical training were instructed to estimate the amount of CCC through the approximate geometrical center of the lens using a standardized script which included a photograph identifying various zones. Observer estimates were then compared against anterior segment-OCT (AS-OCT) values obtained during calibration. Results Mean observer estimates of central corneal clearances were OD 220.5 ± 121.microns (range 50 to 480 microns) and OS 398.0 ± 159.1 microns (range 140 to 800 microns). The mean AS-OCT values were OD 105.5 ± 11.microns (range 84 to 121 microns) and OS 340.8 ± 15.2 microns (range 315 to 362 microns). Mann-Whitney test was statistically significant for comparison of median values OD (177.0; p = 0.001) and OS (260.0; p = 0.012). Conclusions Neophyte clinicians in the final semester of their fourth year of optometric clinical training tend to significantly overestimate the amount of CCC in a normal subject with declining accuracy as the amount of clearance diminishes.