bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmaco-kinetics/dynamics (PK/PD) evaluation and individual patient cross-over studies with growth trajectory assessment to adaptively develop ilorasertib.
Authors: Maitland Michael L. , Sharma Manish , Zhao Binsheng , McKee Mark D. , Karovic Sanja , Thomeas Vasiliki , McIver Malcom , Yang Hao , Piha-Paul Sarina Anne , Falchook Gerald Steven , Karrison Theodore , Kurzrock Razelle , Janisch Linda A. , Hoening Elizabeth , Wong Shekman , Munasinghe Wijith , Ansell Peter J , Ratain Mark J. , Schwartz Lawrence H. , Hong David S. 
Published: September 2018

2563 Background: We evaluated PK/PD of the AURK B/VEGFR2 inhibitor ilorasertib. To detect activity in CDKN2A-deficient tumors, we measured changes-in-tumor-burden by CT-volume before, during, and after discontinuation of therapy. Methods: Study 1: open-label, dose-escalation, phase 1 in 58 patients (pts) with advanced solid tumors. Arms I, II, and III assigned: 23 pts (10–180 mg oral QD), 28 pts (40–340 mg oral BID), and 7 pts (8–32 mg i.v. QD), to ilorasertib monotherapy Days 1, 8, and 15 every 28 days. We evaluated PK/PD for validated biomarkers: change-in-diastolic blood pressure (ΔDBP), change-in-plasma [PlGF] (ΔPlGF), and change-in phosphorylated histone H3 (Δ%pHH3) in skin biopsies. Study 2: open-label trial, of 10 solid tumor pts with CLIA-lab-detected CDKN2A disruption. Pts received ilorasertib 250 mg oral BID on same schedule. On CT images collected prior to screening, and ~ study days -7, 49, and 98 individual lesion volumes were determined by central lab semi-automated segmentation algorithms on DICOM files. Pts who tolerated ilorasertib with RECIST-stable disease at day 98 discontinued ilorasertib for 42 days and underwent re-imaging before restarting ilorasertib. Results: Study 1: the DLTs and frequent adverse events reflected VEGFR2 inhibition. PK/PD analysis showed peak VEGFR2 inhibition on ΔDBP and ΔPlGF at lower systemic concentrations than for peak AURKB-inhibition detected with Δ%pHH3. Two pts in Arm II had partial response; one had homozygous deletion of CDKN2Aby FISH. Pre-clinically the CDKN2A-deficient cell lines (OVCAR5, MDA MB 231, A549) were among the most ilorasertib-sensitive. At time of submission, Study II enrolled 10 pts, with 5 evaluable for longitudinal tumor burden assessments. Three pts had sustained negative growth trajectories after ilorasertib therapy; one of these had positive growth after cessation of treatment but restabilization of disease after restarting ilorasertib. Conclusions: The development plan adapted to the in-human PK/PD assessment. We prospectively conducted individual change-in-tumor burden cross-over studies to assess clinically the sensitivity of CDKN2A-deficient tumors. Clinical trial information: NCT02540876 and NCT01110486.
A phase 1 dose escalation study of eFT508, an inhibitor of mitogen-activated protein kinase-interacting serine/threonine kinase-1 (MNK-1) and MNK-2 in patients with advanced solid tumors.
Authors: Falchook Gerald Steven , Infante Jeffrey R. , Meric-Bernstam Funda , Miller Langdon L. , Morison Karen , Vallner Debra , Sperry Sam , Goel Vikas , Chiang Gary Gene , Webster Kevin , Barton Jeremy , Patel Manish R. 
Published: September 2018

2579 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors. eFT508, a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, and thereby selectively regulates translation of a small set of mRNAs. In addition to direct antitumor activity, eFT508 triggers an anti- tumor immune response and enhances responses to checkpoint inhibitors in preclinical models. Methods: Using a 3+3 dose escalation schema, cohorts of solid tumor patients (pts) were treated with eFT508 administered orally once daily at doses ranging from 50 mg to 600 mg. Results: 28 pts were treated, and the most common tumor types were colorectal cancer (8), prostate cancer (3), and soft tissue sarcoma (3). Median number of prior therapies was 4. The most common observed adverse events (AEs) included nausea (47%), vomiting (47%), dyspepsia (23%), fatigue (20%), and constipation (20%). Two pts treated at 600 mg experienced Gr 3 related AEs, including one pt with Gr3 nausea and vomiting (met criteria for dose limiting toxicity) and one pt with reversible Gr3 AST/ALT elevation. 6 pts achieved stable disease with duration ranging from 82 to 196 days. Pharmacokinetic analysis revealed that eFT508 is bioavailable and rapidly absorbed, with median Tmax of 2 hours and a mean T1/2 of 12 hours. Minimal accumulation was observed between Days 1 and 14/15, with mean accumulation factor of 1.2-fold. Analysis of eIF4E phosphorylation in peripheral blood cells suggested that doses ≥ 300 mg achieved engagement sufficient for maximal efficacy as predicted by preclinical models. Conclusions: Preliminary results suggest that eFT508 is well tolerated, and dose escalation continues with a cohort of pts providing pretreatment and on treatment biopsies for evaluation of target engagement and immunomodulatory effects. After determination of the recommended phase 2 dose, further evaluation will include monotherapy cohorts in specific tumor types as well as cohorts to evaluate efficacy and tolerability in combination with checkpoint inhibitors. Clinical trial information: NCT02605083.
Phase I dose escalation study of CVM-1118, a novel anti-vascular mimicry agent, in patients with advanced cancers.
Authors: Tolcher Anthony W. , Su Wu-Chou , Lakhani Nehal , Gutheil John , Melink Teresa J. , Chu Yi-Wen , Chen Yen-Ling , Chien Du-Shieng 
Published: September 2018

2580 Background: CVM-1118 is an oral NCE that demonstrated potent anti-tumor effects in several tumor xenograft models, via multiple MOAs including induction of cancer cell cycle arrest and apoptosis, and reducing vasculogenic mimicry (VM) network formation in cancer cells, providing a promising therapeutic means in the treatment of malignant tumors that have metastatic potential. Methods: Patients with advanced tumors are being enrolled into 2 ongoing open-label Phase I dose escalation studies in both US (CVM-001) and Taiwan (CVM-002) to evaluate ethnic differences in drug responses. CVM-1118 capsules are administrated orally QD/BID in a 28-day cycle for 4 cycles. The primary objectives are to evaluate the safety, tolerability and pharmacokinetics (PK) and establish the Recommended Phase 2 Dose (RP2D). The secondary objective is to evaluate the therapeutic response after receiving treatment. Beyond 4 cycles, patients showing clinical benefit with CVM-1118 may enter extension cohort to continue the treatment. Results: To date, 28 pts (16 M/12 F)received CVM-1118 across 6 dose levels (50 to 800 mg daily). Median number of days was 52 (range 2 to 135). For CVM-001, 2 DLTs (grade 5 dehydration and grade 3 fatigue) were reported at cohort 6 (800 mg/daily) and the MTD is currently under evaluation. For CVM-002, 3 cohorts (100 to 400 mg/daily) have been completed without DLT. Enrolment to cohort 5 (600 mg/daily) is in progress. From both studies, the most common drug-related AEs included manageable diarrhea, nausea, and vomiting. Rapid oral absorption was observed with Tmax < 2 hr. Bioconversion to active metabolite, CVM-1125, occurred rapidly and the drug exposure increased with increasing dose levels. However, patients in US study showed higher drug exposure than those in Taiwan study. Two patients at 200 mg/daily cohort in Taiwan completing 4-cycle treatment and showing stable disease continued into extension cohort with higher dose. Conclusions: In this ongoing study, Asian patients in Taiwan appear to have better tolerance for CVM-1118 than those in US, likely due to lower drug exposure at same dose level, and some patients have experienced clinical benefit. Clinical trial information: NCT02507544; NCT02703298.
Proof-of concept phase I study of everolimus, letrozole and trastuzumab in hormone receptor-positive, HER2-positive/amplified or mutant metastatic breast cancer or other solid tumors: Evaluating synergy and overcoming resistance.
Authors: Pant Shubham , Wheler Jennifer J. , Fu Siqing , Hong David S. , Karp Daniel D. , Subbiah Vivek , Tsimberidou Apostolia Maria , Holley Veronica R. , Brewster Abenaa M. , Koenig Kimberly Higginbotham , Ibrahim Nuhad K. , Murthy Rashmi Krishna , Meric-Bernstam Funda , Janku Filip 
Published: September 2018

2583 Background: Preclinical models suggested synergistic antineoplastic activity of anti-estrogen therapy with HER2 and mTOR inhibitors. Methods: We designed a 3+3 dose escalation phase I study of the aromatase inhibitor letrozole 2.5mg PO daily, mTOR inhibitor everolimus 2.5-10mg PO daily and HER2 antibody trastuzumab 4-8mg loading dose followed by 2-4mg maintenance dose IV on day 1 of 21-day cycle in patients with hormone-receptor positive, HER2-positive/amplified or mutant advanced cancers (confirmed by immunohistochemistry and/or FISH and/or next-generation sequencing). The primary objectives were to determine maximum tolerated dose (MTD), dose limiting toxicities (DLT), overall safety and response. Results: A total of 18 patients (men, 1; women, 17; HER2 amplification, 14; HER2 mutation, 4; breast cancer, 15; ovarian cancer, 1; cervical cancer, 1; gastroesophageal junction cancer, 1), median age 56 years, median of 6 prior therapies (including letrozole [9] or other aromatase inhibitor [8]; everolimus [3]; trastuzumab [14] or other HER2 targeted therapy [1]) were enrolled in the planned 6 dose levels. The MTD has not been reached and grade 3 (G3) mucositis at the dose level 4 was the only DLT. Other G3 or G4 drug-related toxicities included G4 hyperglycemia in 1 patient, G3 hyperglycemia in 3 patients, G3 thrombocytopenia in 1 patient, G3 anemia in 1 patient and G3 headache in 1 patient. Of 18 patients, 3 (17%) had a partial response (all with heavily-pretreated breast cancer with HER2 amplification [2] or HER2A775_G776insYVMA mutation [1]), 11 (61%) stable disease (SD) including 7 (39%) patients with SD > 6 months (all with heavily-pretreated breast cancer), 3 (17%) progressed and 1 had pending evaluation. The median change in size of target lesions per RECIST 1.1. was -11% (-68% to +47%). Median progression-free survival was 9 months (95% CI 5.8-12.2). Conclusions: The combination of letrozole, everolimus and trastuzumab is well tolerated with encouraging activity in heavily-pretreated patients with HER2-amplified or mutant advanced breast cancer. Clinical trial information: NCT02152943.
Phase I study combining the aurora kinase A (AURKA) inhibitor alisertib (Ali) with mFOLFOX in gastrointestinal (GI) cancer.
Authors: Goff Laura Williams , Azad Nilofer Saba , Stein Stacey , Whisenant Jennifer , Vaishampayan Ulka N. , Hochster Howard S. , Connolly Roisin M. , Weise Amy M. , LoRusso Patricia , El-Rifai Wael , Berlin Jordan 
Published: September 2018

2593 Background: Overexpression and cellular mis-localization of AURKA in GI cancers results in chromosomal instability, activation of several oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 causing cell death. Our preclinical data showed synergy of Ali and platinum agents in GI cells and xenografts, and suggested an optimal timing window of the combination. The purpose of this study was to assess safety of Ali + mFOLFOX, as this is a standard platinum-based therapy for GI cancers. Methods: This CTEP-sponsored, investigator-initiated, study (NCT02319018) used standard 3+3 dose escalation to determine the maximum tolerated dose (MTD) of Ali + mFOLFOX. Eligible patients (pts) had metastatic or unresectable GI cancer where standard therapies did not exist or were no longer effective, or for whom FOLFOX was appropriate. Pts received escalating doses of Ali starting at 10 mg twice daily (D1-3), with leucovorin + oxaliplatin (85 mg/m2) on D2 followed by continuous 5FU (2400 mg/m2) infusion on D2-4 in 14-day cycles. Dose-limiting toxicity (DLT) was any treatment-related non-hematologic ≥Gr3 toxicity (except diarrhea or nausea, vomiting, controllable with meds) or ≥Gr4 hematologic toxicity observed during the first 28 days. Results: 13 pts were enrolled and 2 dose levels explored; 2 pts were not evaluable for DLT and replaced. Zero DLTs observed in first 3 pts. Ali was escalated to 20 mg where 2/6 had a DLT [Gr3 fatigue (n = 2); Gr3 nausea, vomiting, dehydration with hospitalization (n = 1)]. Ali was de-escalated and 2 of 3 pts have been enrolled; 0 DLTs observed thus far. Most frequent toxicities (%) were nausea (54), fatigue (46), neuropathy (46), anorexia (38), and anemia (38), most ≤Gr2. One of 10 evaluable pts had a partial response, and 6 had stable disease for a 70% disease control rate. Conclusions: The MTD will be 10 mg Ali (D1-3) + oxaliplatin (D2, 85 mg/m2) + continuous 5FU (D2-4, 2400 mg/m2). The combination was tolerable, and preliminary clinical activity was seen in a majority of pts. Correlative biomarker studies to evaluate AURKA target inhibition are ongoing and will be reported. Clinical trial information: NCT02319018.
A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.
Authors: Glasspool Rosalind Margaret , Blagden Sarah Patricia , Lockley Michelle , Paul James , Hopkins Carol , Thomson Fiona , Brown Jennifer , Fernandes Ricardo , Douglas Nivea , Pou Chantevy , Hanif Aishah , Campbell Craig , Multani Pratik S. , Tucker Trevor , McNeish Iain A. , Evans T.R. Jeffry 
Published: September 2018

2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.
Clinical results with combination of anti-CD27 agonist antibody, varlilumab, with anti-PD1 antibody nivolumab in advanced cancer patients.
Authors: Sanborn Rachel E. , Pishvaian Michael J. , Kluger Harriet M. , Callahan Margaret K. , Weise Amy M. , Lutzky Jose , Yellin Michael Jay , Rawls Tracey , Vitale Laura , Halim Abdel , Keler Tibor , Davis Tom , Rizvi Naiyer A. 
Published: September 2018

3007 Background: A phase 1 trial to assess the safety and immunological activity of the combination of varlilumab (V) and nivolumab (N), and recommend a dose of V for the phase 2 study was conducted. Methods: The study was performed using the approved dose of N (3 mg/kg Q2W) and escalating doses of V (0.1, 1, or 10 mg/kg Q2W) in anti-PD-(L)1 naïve patients with advanced cancer. Results: A total of 36 patients (21 CRC, 8 ovarian [OVA], 4 melanoma and 3 SCCHN) were enrolled. Toxicity was consistent with the safety profile of each agent individually; no unexpected toxicities were seen with the combination. No MTD was identified. An OVA cancer patient in the 10 mg/kg cohort had a DLT: hepatitis (G4) and acute kidney injury (G3). A CRC patient in the 10 mg/kg cohort had a drug-related SAE of mixed motor sensory neuropathy (G2) and a CRC patient in the 1 mg/kg cohort had rash (G3). No additional drug related SAEs or DLTs were reported. The majority of tumors were PD-L1 negative (24/27) by IHC at baseline. For patients with post treatment biopsies, PD-L1 expression was observed in 43.5% (10/23) and correlated with increases in CD8 T cell infiltration, consistent with the generation of anti-tumor immunity. Other treatment related biomarker changes included transient increases in serum chemokine levels, and a prominent decrease in circulating Tregs. Biomarker analysis did not clearly differentiate between dose levels, or delineate an optimal V dose. Three patients had objective PR by RECIST [CRC MSI-low (1 mg/kg V), SCCHN (10 mg/kg V) and OVA (10 mg/kg V, uPR)]. The response in the CRC patient is ongoing with a 94% decrease in target lesion diameter and a PFS of 19+ months. There were also 11 patients with SD. Phase 2 cohorts are ongoing in RCC, SCCHN, OVA, CRC and GBM. The Phase 2 portion includes exploration of different dose/regimens of V, including high and low exposure, to better characterize the optimal dosing strategy for V, in combination with a fixed dose of N (240 mg Q2W). Conclusions: The combination of V and N was well tolerated, associated with strong biological signals, and has evidence of clinical activity in subsets of patients with tumor types that are typically resistant to PD-1 inhibitor monotherapy. Clinical trial information: NCT02335918.
A phase I/II clinical trial of E6 T-cell receptor gene therapy for human papillomavirus (HPV)-associated epithelial cancers.
Authors: Hinrichs Christian S. , Doran Stacey L. , Stevanovic Sanja , Adhikary Sabina , Mojadidi Michelle , Kwong Mei Li , Faquin William C , Feldman Steven , Somerville Robert , Sherry Richard Mark , Yang James C. , Rosenberg Steven A. 
Published: September 2018

3009 Background: Engineered T-cell therapy has shown promise in B-cell malignancies and melanoma, but clinical investigation in epithelial cancers has been limited. Methods: We conducted a phase I/II clinical trial of T cells genetically engineered to express a T-cell receptor that targets an HLA-A*02:01-restricted epitope of E6 (E6 TCR T Cells) for patients with metastatic HPV-16+ carcinoma. The cell dose was escalated in cohorts of single patients (1 x 109, 1 x 1010, and 1-2 x 1011cells). Patients received a nonmyeloablative conditioning regimen of cyclophosphamide and fludarabine, a single infusion of E6 TCR T Cells, and systemic high-dose aldesleukin. Results: Twelve patients were treated, 9 at the highest cell dose, plus one retreatment. The cancer types were 6 cervical, 4 anal, 1 oropharyngeal, and 1 vaginal. No dose-limiting toxicity, autoimmune adverse events, or cytokine storm were observed. Two patients with anal cancer treated at the highest cell dose experienced partial tumor responses lasting 6 and 3 months after treatment. The patient with a 6-month response had complete regression of one tumor and partial regression of two tumors that were resected upon progression; she has no evidence of disease 22 months after treatment. T-cell receptor gene transfer efficiency was 45 and 51% in the responding patients, and 47-76% (median 61%) in the non-responding patients. Responding patients showed robust levels of E6 TCR T cell memory (30 and 46% of circulating T cells 1-month after treatment). Non-responding patients showed wide-ranging levels of E6 TCR T cell memory (range 4-53%, median 29%). Expression of programmed cell death protein 1 (PD-1) by circulating E6 TCR T Cells 1-month after treatment was low in all patients ( < 5%). The patient with a 6-month response had 7% E6 TCR T Cells in a resected tumor 10 months after treatment, 25% of which expressed PD-1. A patient with no response had no detectable E6 TCR T Cells in a resected tumor 3 months after treatment. Conclusions: E6 TCR T-cell therapy was safe at doses up to 2 x 1011 cells. Regression of metastatic HPV+ carcinoma occurred in two patients following treatment, suggesting that TCR T-cell therapy can mediate epithelial cancer regression. Clinical trial information: NCT02280811.
Safety of epacadostat 100 mg bid plus pembrolizumab 200 mg Q3W in advanced solid tumors: Phase 2 data from ECHO-202/KEYNOTE-037.
Authors: Hamid Omid , Bauer Todd Michael , Spira Alexander I. , Smith David C. , Olszanski Anthony J. , Tarhini Ahmad A. , Lara Primo , Gajewski Thomas , Wasser Jeffrey S. , Patel Sandip P. , Borges Virginia F. , Balmanoukian Ani Sarkis , Schmidt Emmett V. , Zhao Yufan , Jones Mark M. , Gangadhar Tara C. 
Published: September 2018

3012 Background: The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) facilitates immune tolerance in cancer via T-cell suppression, and IDO1 overexpression is associated with poor survival. Epacadostat, an oral inhibitor of IDO1, has been shown to be well tolerated as monotherapy and in combination with checkpoint inhibitors. ECHO-202/KEYNOTE-037 is a phase 1/2 study evaluating the safety and efficacy of oral epacadostat plus IV pembrolizumab in patients (pts) with advanced tumors. Based on phase 1 outcomes, epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was selected for phase 2 evaluation. This analysis summarizes phase 2 safety experience in the overall population of ECHO-202/KEYNOTE-037 (pooled across tumor types) at an October 29, 2016 data cutoff. Methods: Phase 2 pts were ≥18 years of age with advanced or recurrent melanoma (MEL), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma (UC), triple-negative breast cancer, squamous cell carcinoma of head and neck (SCCHN), ovarian cancer, diffuse large B-cell lymphoma, or microsatellite instability–high colorectal cancer. Results: The overall safety population comprised 244 pts receiving ≥1 study treatment dose. Median age was 63 years, 52% were women, and 91% were white. As of data cutoff, 134 study pts (55%) discontinued study treatment, primarily due to disease progression (n = 97). Median exposure to study treatment was 86 days (range, 1–374 days). TRAEs occurring in ≥5% of pts were fatigue (23%); rash (16%); diarrhea and nausea (7% each); increased alanine aminotransferase, increased aspartate aminotransferase, and pruritus (6% each); and pyrexia (5%). A total of 37 pts (15%) had grade ≥3 TRAEs; the most common grade ≥3 TRAEs were increased lipase (asymptomatic) and rash (3% each). TRAEs led to discontinuation in 3% of pts. Conclusions: Epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was associated with an acceptable safety profile in pts with advanced cancers, supporting continued evaluation of the combination. The phase 3 ECHO-301/KEYNOTE-252 MEL study is ongoing and additional phase 3 studies (NSCLC, UC, RCC, SCCHN) are planned. Clinical trial information: NCT02178722.