bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients.
Authors: Newton Robert Charles , Scherle Peggy A , Bowman Kevin , Liu Xiangdong , Beatty Gregory Lawrence , O'Dwyer Peter J , Gajewski Thomas , Bowman Jill , Schaub Richard , Leopold Lance 
Published: March 2020

2500^ Background: The ineffectiveness of the immune system to control tumor growth is, in part, a result of immunosuppression imposed by negative regulatory mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme that catabolizes the first and rate-limiting step in the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn), has been shown preclinically to play an important role in tumor-mediated immunosuppression. In cancer patients (pts), elevated IDO1 levels are associated with poor prognosis and shortened survival in a number of tumor types. Here we describe the pharmacodynamic (PD) assessment of INCB024360, a novel inhibitor of IDO1. Methods: Plasma samples were obtained from consented pts in study INCB 24360-101, a phase I dose-escalation study in patients with advanced malignancies. Trp and Kyn levels in plasma were determined by LC/MS/MS. IDO1 activity in activated peripheral blood cells was also monitored. Results: Using anti-IDO1 specific antisera and archived tumor samples, we found IDO1 expression in various human tumors, including ovarian, colorectal, breast and prostate. Consistent with this result, higher Kyn/Trp ratios (1.5-3.4 fold above healthy volunteers) were detected in archived plasma samples from pts, indicative of higher IDO1 activity in cancer pts. To date, 23 pts have been treated with the selective IDO1 inhibitor INCB024360. When plasma samples from patients were collected pre- and post-INCB024360 treatment, significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected. As an additional biomarker measurement, whole blood samples collected from pts at various times after dosing were stimulated ex vivo with interferon-γ and lipopolysaccharide to increase IDO1 activity and also showed dose-dependent decreases in IDO activity. With the current dose regimens and assays we have successfully achieved sustained inhibition of >90% at a well tolerated dose of INCB024360. Conclusions: This is the first demonstration of PD activity of an IDO1-specific inhibitor in cancer pts. Our study also confirms that IDO1 is frequently activated in cancer pts. The methods described will be used to establish a phase II dose.
From bench to bedside: The use of the li-Key technology to improve helper peptides for clinical use in cancer vaccines.
Authors: Vreeland Timothy J , Hale Diane F , Sears Alan K. , Clifton Guy T. , Pappou Efi , Dabney Raetasha Sheavette , Ardavanis Alexandros , Patil Ritesh , Ponniah Sathibalan , Anastasopoulou Eleftheria , Perez Sonia A. , Shumway Nathan M. , Peoples George Earl , Mittendorf Elizabeth Ann 
Published: March 2020

2508 Background: Work involving peptide vaccines has shown that peptides containing MHC Class II epitopes, which elicit CD4+ T cell responses, may play a role in potentiating an immune response. The Ii-Key peptide (amino acids 77-80 of the immune-regulatory Ii protein), when covalently linked to an MHC Class II epitope, can induce conformational change in the epitope binding groove, increasing CD4+ T cell stimulation up to 250 fold. Here we present an update of results from clinical trials evaluating this novel technology in an adjuvant breast cancer vaccine targeting HER2/neu. Methods: We reviewed our trials investigating AE37, a hybrid peptide created by the addition of the Ii-Key peptide (LRMK) to AE36 (GVGSPYVSRLLGICL), an MHC Class II-binding peptide from the intracellular domain of the HER2 protein. We have completed a phase I study and are currently conducting a randomized phase II trial of the AE37 peptide + GM-CSF in the adjuvant treatment of disease-free breast cancer patients with any level of HER2 expression (IHC 1-3+ or FISH>1.2). Results: Phase I data showed the vaccine to be safe and effective in raising anti-HER2 immunity. Importantly, even the cohort of patients given AE37 without GM-CSF showed significant increases in both in vivo and in vitro immune responses. To date, we have enrolled 201 patients to our phase II trial (Vaccine (VG)=103, Control (CG)=98). Toxicity has been minimal (99% of local and systemic toxicities grade ≤2). VG patients have shown significant increases in both in vivo and in vitro responses to both AE36 and AE37, with consistently stronger responses to the AE37 hybrid peptide than the native AE36. With a median f/u of 22 months, Kaplan Meier projections estimate recurrence rates of 10.3% in the VG compared to 18% in the CG; a 43% risk reduction. Conclusions: The AE37 peptide vaccine appears to be effective in eliciting a strong immune response and possibly preventing breast cancer recurrence. These results provide an important proof of concept and suggest that additional studies evaluating Ii-Key hybrid peptide vaccines are warranted, whether in the field of immunotherapy or more traditional vaccines.
PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with solid tumors.
Authors: Tykodi Scott S. , Brahmer Julie R. , Hwu Wen-Jen , Chow Laura Q. , Topalian Suzanne Louise , Hwu Patrick , Odunsi Kunle , Camacho Luis H. , Kauh John S , Pitot Henry Clement , Hamid Omid , Pardoll Drew M. , Agrawal Shruti , Parker Susan , Goldberg Stacie , Gupta Ashok Kumar , Wigginton Jon 
Published: March 2020

2510 Background: Blocking the interaction between programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, and its ligand PD-L1 may enhance T-cell function. Here we describe the safety and activity from the first clinical study of BMS-936559 in patients (pts) with advanced solid tumors, further validating the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was given Q2 wk IV in a 6-wk cycle at doses of 0.3−10.0 mg/kg during dose escalation and/or cohort expansion; pts could receive up to 16 cycles (48 doses). Results: As of August 1, 2011, 162 pts with melanoma (MEL, n=53), non-small-cell lung (NSCLC, n=50), colorectal (n=18), renal cell (RCC, n=17), ovarian (n=17), and pancreatic (n=7) cancer were treated. Median therapy duration was 11 wks (max 99 wks). Common related adverse events (rAEs; ≥5% pts) included fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritus. The incidence of grade 3-4 rAEs was 8.6%. AEs of special interest included hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drug-related deaths. Clinical activity was observed in MEL, RCC, and NSCLC. Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting ≥1 yr. Two other pts had ongoing ORs with durations of 2.3 and 8.5 mo at data lock. Several pts had prolonged stable disease. Some pts had a persistent reduction in overall tumor burden in the presence of new lesions but were not categorized as responders. In NSCLC, ORs were observed irrespective of histology. Conclusions: BMS-936559 was active and generally well tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from anti-PD-1/BMS-936558 trials, this study concurrently validates the importance of the PD-1/PD-L1 pathway for cancer immunotherapy and supports further clinical development of anti-PD-1/PD-L1 directed therapy. [Table: see text]
Safety of the antimyostatin monoclonal antibody LY2495655 in healthy subjects and patients with advanced cancer.
Authors: Jameson Gayle S. , Von Hoff Daniel D. , Weiss Glen J. , Richards Donald A. , Smith David A. , Becerra Carlos , Benson Mitchell C. , Yuan Zheng , Robins Deborah A , Turik Michael , Wagner Margaret , Hu Leijun , Lin Boris K. 
Published: March 2020

2516 Background: Skeletal muscle wasting (cachexia) is a prevalent and not readily managed condition in advanced cancer patients. LY2495655 is a humanized monoclonal antibody to myostatin, which has demonstrated positive effects on cachexia measures in animal models. We present phase I trial data on use of LY2495655 in healthy volunteers (Study 1) and interim data from an ongoing phase I study in patients with advanced cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, blinded, single-dose, parallel, dose-escalation study evaluating the safety and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics (PKs) of LY2495655 in patients with advanced cancer not receiving chemotherapy. Dose cohorts (2 mg-700 mg, ≥3 patients per cohort) were to be treated until the maximum tolerated dose (MTD) was met, or the highest dose (700 mg) cohort was completed. Final locked data from Study 1 and interim data from the dose escalation phase of Study 2 were used in the analyses. Results: In Study 1, 64 healthy volunteers were enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had received treatment with LY2495655 at the time of the analysis. In both studies, all doses of LY2495655 were well tolerated (no DLTs were observed and MTD was not reached), and nonlinear PKs were observed (most evident in lower dose levels). In Study 1, thigh muscle volume generally increased with LY2495655. In Study 2, increased muscle volume was observed only at 21-mg and 70-mg doses. Consistent increases in hand grip strength and improvements in functional tests were observed at doses ≥21 mg. Conclusions: There were no unusual safety concerns in healthy subjects or cancer patients. PK results were consistent between the 2 studies. Increases in muscle volume were observed in both studies, with concomitant improvement in functional measures. However, there is no clear trend in dose-dependent efficacy, possibly due to extremely small sample sizes and patient heterogeneity. Enrollment in Study 2 continues with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic cancer patients.
A phase I safety study of NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers.
Authors: Arlen Philip M. , Diaz Luis A. , Azad Nilofer Saba , Sleer Leanne Sophia , Haley Sherri , Morse Michael 
Published: March 2020

2517 Background: NPC-1C (NEO-101; Ensituximab) is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC that is expressed specifically by human colon and pancreatic tumors with minimal cross-reactivity to normal GI tract tissues. Methods: A phase I open label, multi-center dose escalation clinical trial with NPC-1C has completed accrual of subjects with advanced pancreatic and colorectal cancer refractory to standard therapy. The primary objectives are to determine safety and tolerability of escalating doses of NPC-1C and to assess pharmacokinetics (PK) and select immune responses to the antibody at each dose level. Secondary objectives are to evaluate evidence of clinical benefit and to explore immunologic correlates Results: Three cohorts of subjects have been treated with NPC-1C at escalating dose levels of 1, 1.5, and 2 mg/kg IV every two weeks. All 15 subjects (10 colorectal, 5 pancreatic) have enrolled on study (5/15 non-evaluable). No DLT was noted at the 1mg/kg dose level with 2 of 3 patients showing stable disease at completion of Course 1. At the 2 mg/kg dose level, one patient demonstrated stable disease after course 1. At escalating rates of infusion, 3 subjects experienced mild to moderate hemolysis that resolved without intervention. All 6 patients who have received 1.5 mg/kg at a constant rate of infusion have been evaluated, with no dose limiting toxicity. One of 5 patients re-staged thus far in the 1.5 mg/kg cohort showed stable disease on scans after completing the first course of treatment (4 doses), and continued to receive additional doses. Preliminary data show no drug induced antibody responses in treated subjects. PK, HAMA and cytokine evaluation is ongoing. Conclusions: NPC-1C is tolerated well at the current dose level of 1.5 mg/kg every 2 weeks without producing any DLT We plan to continue accrual in the Phase 2A to evaluate clinical responses and additional safety data.
The immunological impact of the RAF inhibitor BMS908662: Preclinical and early clinical experience in combination with CTLA-4 blockade.
Authors: Callahan Margaret , Masters Gregg , Katz Jessica , Russell Valerie , Roman Ruth Ann , Montefusco Mary , Vyas Shachi , Yuan Jianda , Merghoub Taha , Gupta Ashok Kumar , Wigginton Jon , Jure-Kunkel Maria , Wolchok Jedd D. 
Published: March 2020

2521 Background: Two new approaches to treat advanced melanoma have transformed the standard of care: the CTLA-4 blocking antibody, ipilimumab, and the targeted inhibitor of mutated BRAF, vemurafenib. These agents are mechanistically unique and combination therapy is a promising next step. We evaluated the combination of BMS908662 (662), a pan RAF inhibitor, with CTLA-4 blockade in preclinical studies and report first-in-human clinical experience with this combination. Methods: 1) We tested the impact of 662 on T cells in vitro, using cultured human T cells, and in vivo, using OT-1 transgenic mice. T cell activation and MAPK pathway signaling were assessed in parallel. 2) Preclinical studies measuring the anti-tumor activity of combination therapy were performed in CT-26 and SA1N tumor models. 3) Three pts with BRAF mutant stage IV melanoma were treated at MSKCC on CA206005, an IRB-approved protocol, receiving ipilimumab (3 mg/kg) and 662 (25 mg bid) (NCT01245556). Two pts consented to an IRB-approved protocol permitting immune monitoring. Results: 1) In vitro studies demonstrate that 662 can potentiate T cell activation after stimulation. This corresponds with increased MAPK pathway signaling, consistent with paradoxical activation of the MAPK pathway in wild type cells, a class effect of RAF inhibitors. In vivo, enhanced expansion of OT-1 cells after ovalbumin challenge was seen in mice treated with 662. T cell expansion was greatest in mice treated with a combination of CTLA-4 blockade and 662 (p<0.05). 2) Both preclinical models demonstrate superior anti-tumor activity with combination therapy compared to monotherapy (p<0.05). 3) All pts treated on protocol CA206005 tolerated combination therapy. New keratoacanthomas and SCCs, likely related to 662, were identified. One pt has an ongoing response at 10 mos (-85%), one had stable disease for 24 wks (-19%) and a third had disease progression. Enhanced MAPK signaling in PBMCs after treatment with 662 was detected ex vivo. Conclusions: RAF inhibitors may potentiate T cell activation in vitro and in vivo, offering one explanation for the enhanced anti-tumor activity seen in combination with CTLA-4 blockade in pre-clinical models.
Safety and long-term maintenance of anti-HER2 immunity following booster inoculations of the E75 breast cancer vaccine.
Authors: Dabney Raetasha Sheavette , Hale Diane F , Vreeland Timothy J , Clifton Guy T. , Sears Alan K. , Patil Ritesh , Ponniah Sathibalan , Shumway Nathan M. , Peoples George Earl , Mittendorf Elizabeth Ann 
Published: March 2020

2529 Background: We have completed accrual and are in the follow up portion of phase I/II clinical trials evaluating the E75 HER2 peptide vaccine. E75 has been proven safe, capable of stimulating HER2 immunity, and effective in decreasing breast cancer recurrence rates. During the conduct of this trial, it was noted that E75-specific immunity waned after the Primary Vaccine Series (PVS) which corresponded with late recurrences. To maintain long-term immunity, a voluntary booster program was started. Here we present analysis of the booster inoculations. Methods: The trial enrolled node-positive or high-risk, node-negative breast cancer patients (pts) with tumors expressing any level of HER2 (IHC 1-3+). HLA-A2/A3+ pts comprised the vaccine group (VG), HLA-A2/A3- pts were followed as the control group (CG). The VG received 4-6 monthly inoculations of E75+GM-CSF. Volunteer booster program pts (BG) received inoculations every 6 months after the PVS. Pts were monitored for toxicities, in vivo responses by local reactions (LR) and DTH, and in vitro responses measured by enumeration of E75 specific cytotoxic T lymphocytes. Results: 53 pts received at least 1 booster, 34 received 2, 24 three, 20 four, 12 five, and 8 at least 6. 24% of pts had no local toxicity, 73% Grade 1 (G1), 3% G2. 74% had no systemic toxicity, 35% G1, 1% G2. LRs increased significantly from the initial vaccine (R1) during PVS to each booster (B) (R1: 59.5±3.1 v B1: 89.2±3.3, p<0.001; v B2: 95.15±5, p<0.001; v B3: 86.63±5.5, p<0.001; v B4: 83.26±4.6, p=<0.001; v B5: 80.67±6.7, p=0.006; v B6: 78.75±9.4, p=0.04). Dimer values increased from the end of PVS to each post-booster value (pre B1:1.29±0.25 v post B1: 1.46±0.38; post B2: 1.41±0.4; post B3: 1.84±0.35; post B4: 2.23±0.4; post B5:1.94±0.31; post B6: 2.73±0.09, p=0.02). At median 60 months, the recurrence rate for BG was 3.8% vs 18.9% in the CG (p=0.01). Conclusions: Booster inoculations are well-tolerated and appear to assist in the maintenance of long term peptide-specific immunity. Boosted pts have improved recurrence rates. Based on the success of this program, we have incorporated the practice of booster inoculations in our current cancer vaccine trials.
Pharmacological interactions of TKIs with the P-gp drug transport protein.
Authors: Roche Sandra , Pedersen Kasper , Dunne Grainne , Collins Denis , Devery Aoife , Crown John , Clynes Martin , O'Connor Robert 
Published: March 2020

2536 Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug transport proteins. P-gp is a transporter with two important roles in cancer drug therapy. If overexpressed in tumour cells it can cause drug resistance. However, P-gp, expressed in tissues as part of normal drug clearance mechanisms, is also involved in termination of drug action. Hence, TKI-mediated interactions with P-gp have significant therapeutic consequences. Methods: P-gp over-expressing cancer cell lines were used to determine the inhibitor or substrate status of tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib). Cell proliferation assays in combination with a potent P-gp inhibitor, or P-gp substrate were also employed. Findings were augmented using LC-MS-based quantitation of cellular levels of target drugs. Results: We summarise our findings of four distinct interactions with P-gp among various TKIs. Some agents have little interaction at conventional doses; others can act as P-gp inhibitors without being substrates; substrates without being inhibitors or substrates which also prevent the actions of the transporter.Eachof the investigated TKIs has a distinct relationship with P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is a substrate but not an inhibitor, while pazopanib has little interaction with P-gp. Other agents also have an effect on or are affected by P-gp to varying amounts with some of these interactions likely to be suprapharmacological. Conclusions: P-gp protein has important roles both in resistance and drug toxicology, hence, a clear understanding of the interaction of emerging drugs with this transporter is vital. Agents which are inhibitors of P-gp may have applications in drug resistance circumvention but may also greatly exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics; conversely the activity of P-gp substrate TKIs may be reduced by tumour overexpression of the transporter. Hence in vitro screening of TKI-transporter interactions may identify putative TKI resistance mechanisms, help guide the development of combination schedule trials and/or reducing unwanted treatment side effects.
Pharmacogenetic study in metastatic colorectal cancer (CRC) patients receiving third-line panitumumab-irinotecan: A GERCOR ancillary study.
Authors: Etienne-Grimaldi Marie-Christine , Llorca Laurence , Formento Patricia , Chibaudel Benoist , Tournigand Christophe , Mabro May , Bachet Jean-Baptiste , Blons Helene , Laurent-Puig Pierre , Formento Jean-Louis , De Gramont Aimery , Andre Thierry , Milano Gerard A. 
Published: March 2020

2537^ Background: Test the predictive value of gene polymorphisms potentially linked to panitumumab and irinotecan pharmacodynamics. Methods: 45 patients with metastatic CRC refractory to standard therapy were enrolled in this ancillary pharmacogenetic study as part of a phase II trial that included 63 patients. Inclusion required wild-type KRAS tumor status (codons 12-13, analyses performed in each center). After inclusion, central KRAS re-assessment was performed (codons 12-13-59-61) and 9 patients over 45 were found to carry a KRAS mutation. Patients received panitumumab (6 mg/kg, day 1) associated with irinotecan (180 mg/m2, day 1), Q2W until disease progression or unacceptable toxicity. Analyzed polymorphisms on blood DNA were : EGFR (CA repeats in intron 1, -216G>T, -191C>A), EGF (61A>G), CCND1 (870A>G), UGT1A1 (*28). Results: Cutaneous toxicity imputable to panitumumab i.e. folliculitis and paronychia was not linked to EGFR, EGF or CCND1 polymorphisms. Diarrhea (12 grade 1, 13 grade 2, 8 grade 3) was linked to CCND1 polymorphism: 22% grade 2-3 in AA patients vs 63% in AG+GG patients (p = 0.007). As expected, neutropenia (6 grade 1, 4 grade 2, 5 grade 3) was more frequent in patients bearing the *28 allele of UGT1A1 gene (33% grade 2-3 vs 5% in *1/*1, p = 0.020). In these 45 patients, response rate, progression-free survival and overall survival (OS) were only significantly related to re-assessed KRAS status. Of note, a tendency for a longer OS was observed in patients bearing the *28 allele of UGT1A1 gene (p = 0.091, analysis adjusted for KRAS). Interestingly, the frequency of KRAS mutation was higher in patients with long CA repeats in EGFR gene intron 1: 54.5% i.e. 6 mutated patients among the 11 patients with both alleles ≥17 vs 10.5% i.e. 2 mutated patients among the 19 patients with intermediary alleles vs. 6.7% i.e. 1 mutated patient among the 15 patients with both alleles <17 (p = 0.004). Conclusions: Present data indicate that A870 allele of CCND1 gene (40% AA patients) may protect from diarrhea induced by panitumumab-irinotecan. Also, these results report an original relationship between EGFR polymorphism in intron 1 and KRAS mutation status that merits further confirmation.