bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two immunoglobulin G fragment C receptor polymorphisms associated with clinical outcome of EGFR-expressing metastatic colorectal cancer patients treated with single agent cetuximab
Authors: Zhang W. , Gordon M. , Schultheis A. M. , Nagashima F. , Azuma M. , Yang D. , Iqbal S. , Lenz H. 
Published: March 2020

3028 Background: Cetuximab is a chimeric immunoglobulin G1 anti-EGFR monoclonal antibody with efficacy in metastatic colorectal cancer patients refractory to irinotican chemotherapy. Recent studies show that Antibody-dependent cellular cytotoxicity (ADCC) mediated through Fc receptors plays an important role in the antitumor effect of IgG1 antibody. There are three classes of FcγRs involved in the regulation of ADCC. FcγRIIa(CD32) and FcγRIIIa(CD16) activates and FcγRIIb inhibits activation. Clinical studies show FcγRIIIa 158 V/F polymorphism was associated with tumor response and progression-free survival in the follicular lymphoma patients treated with rituximab as first line treatment. Also, a H/R polymorphism at position 131 of FcγRIIa has been found to affects its affinity to human IgG and independently predict response to Rituximab. Since Cetuximab and Rituximab belong to the same chimeric IgG1 monoclonal antibody, we test hypothesis whether these two FcγR polymorphisms associated with clinical outcome in colorectal cancer patients treated with single agent Cetuximab. Methods: we tested both FcγRIIIa 158 V/F and FcγRIIa 131 H/R gene polymorphisms using PCR-RFLP method in genomic DNA extracted from peripheral blood from 39 EGFR-expressing metastatic colorectal cancer patients enrolled in a phase II single agent Cetuximab treatment clinical trial (IMCL-0144). Results: We found patients with FcγRIIa 131 HH or HR genotype show better time to progression and overall survival compare to patients with R/R genotype (p=0.037, p=0.22, respectively, log-rank test). Also, there is trend significance in tumor response when we compare patients with RR genotype and patients with HH or HR genotype (p=0.08, fisher’s exact test). FcγRIIIa 158 V/F also show trend significance in tumor response (p=0.067, fisher’s exact test). Conclusions: These data suggest Two Immunoglobulin G Fragment C Receptor polymorphismsFcγRIIIa158V/F andFcγRIIa 131 H/R may be potential molecular markers for clinical outcome of refractory metastatic colorectal caner patients treated with single agent EGFR inhibitor Cetuximab. Prospective studies are needed to confirm these preliminary findings. [Table: see text]
A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts)
Authors: Sosman J. A. , Flaherty K. , Atkins M. B. , Puzanov I. , McDermott D. F. , Vermeulen W. , Harlacker K. , Hsu A. , Rothenberg M. 
Published: March 2020

3031 Background: In an effort to enhance the efficacy of vascular endothelial growth factor (VEGF) pathway blockade in mRCC we initiated a Phase I-II trial of combination S and B to block VEGFR signaling and VEGF binding, as well as, platelet derived growth factor receptor β (PDGFR) signaling. Methods: Pts with measurable (RECIST) mRCC, adequate organ function, and PS 0–1 were eligible for this trial. Cohorts of 6 pts were enrolled at 3 sites to define the MTD and DLT of the combination of S and B. The schedule was B IV q 14 days and S daily with cycles of 28 days. Response and toxicity were assessed at the end of 2 cycles. Dose levels began with S at 200mg BID and B at 5 mg/kg (level 1) with the hope to reach phase II doses of both agents (S at 400mg BID and B at 10mg/kg). The MTD or the phase II dose of each agent would then be administered to up to 45 pts with mRCC, clear cell histology, and prior nephrectomy. Results: A total of 18 patients have been enrolled to date, with 15 completing their first response evaluation. Pts were median age 61 years (46–74 range); M/F: 15/3; PS: 0/1= 12/6; 17 clear cell, 1 chromophobe, 11 prior nephrectomy; 4 with prior cytokine therapy. Two pts in level 1 experienced DLT with recurrent and intolerable (grade 3) hand-foot syndrome (HFS). An additional 6 patients were treated at dose level -1 (S at 200mmg QD and B at 3mg/kg) with no DLTs. Six more pts have been treated at dose level 1 with Vit B6 at 300mg/d in an attempt to minimize HFS. Toxicity data in this cohort is incomplete. Additional toxicities among the 18 pts included grade 3 hypertension (4), grade 3 proteinuria (2), and grade 2 stomatitis (3). Responses including 4 objective PRs, and 4 pts with 20–30% regression have been seen in the 14 evaluated pts. Only 2 patients have had disease progression. Conclusions: The phase II doses for this combination have not yet been established, but will likely be lower than the full phase II doses of the individual agents. The toxicities from HFS (primarily) and hypertension and stomatitis appear to be limiting. Even at the initial low doses of S and B, significant anti-tumor activity has been observed. The completion of this phase I trial will be reported. The phase II studies in mRCC are highly anticipated. Support by phase I contract UO-1 CA099177 [Table: see text]
A phase I dose-escalation study of weekly IMC-1121B, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR2) IgG1 monoclonal antibody (Mab), in patients (pts) with advanced cancer
Authors: Camidge D. R. , Eckhardt S. G. , Diab S. , Gore L. , Chow L. , O’Bryant C. , Temmer E. , Ervin-Haynes A. , Katz T. , Fox F. , Cohen R. B. 
Published: March 2020

3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. Methods: Cohorts of 3–6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. Results: 12 pts (8 M; 4 F), median age 58 years (range: 36–76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxicities ≥ grade 2, considered definitely or probably related to study drug, have occurred. Toxicities ≥ grade 2 possibly drug-related include anorexia, vomiting, anemia, depression, fatigue, and insomnia. To date, there has been one unconfirmed partial response (melanoma) and 5 pts with stable disease for >3 months (colon: 2, breast, gastric, thyroid). Preliminary non-compartmental PK analysis reveals dose-dependent elimination and non-linear exposure, consistent with saturable clearance mechanism(s): mean t1/2 = 63.62, 93.46, 99.63 hrs, mean Cmax = 43.67, 80.25, 264 ug/mL, and AUC0-Inf = 3860, 9242, 27437 hr*ug/mL, at the 2, 4, and 6 mg/kg dose levels, respectively. Conclusions: Weekly administration of IMC-1121B is well tolerated at doses up to 6mg/kg/week. There is early evidence of a non-linear dose-PK relationship. Dose escalation continues. Updated safety, PK, PD, HAHA, and efficacy data will be presented. [Table: see text]
An enriched phase I, pharmacokinetic and pharmacodynamic study of the N-cadherin (NCAD) cyclic competitive binder exherin (ADH-1) in patients with solid tumors
Authors: Sessa C. , Perotti A. , Maur M. , Fasolo A. , Scaramuzza D. , Braghetti A. , Marsoni S. , Malik R. K. , Peters W. P. , Gianni L. 
Published: March 2020

3042 Background: N-cad is a cell adhesion molecule expressed by vascular endothelium and tumor cells of invasive tumors. ADH-1, a cyclic pentapeptide, antagonizes N-cad, causing rapid tumor vascular disruption and apoptosis in preclinical models. We report results from a Phase I study of weekly doses of intravenous ADH-1 given to patients with N-cad+ solid tumors, to evaluate safety, PK, antitumor activity, and effect of ADH-1 on tumor vasculature assessed by DCE-MRI. Methods: ADH-1 starting dose was 150 mg/m2 administered weekly for 3 W in 28 D cycles. DCE-MRI was performed to assess changes in tumor perfusion 90 mins after the first dose of ADH-1, and repeated on D 15 if no changes were noted. Following the 3rd dose level (DL 3, 600 mg/m2 ), the schedule was amended to weekly ADH-1 without interruption, in 21 D cycles. Results: 55 pts with refractory solid tumors were screened, 56% were N-cad+ [screened/N-cad+: GYN 16/21 (Ovarian 13/17), GI 5/14, breast 2/6, renal 5/5, head & neck 2/3, others 2/6]. 13 pts (5 males, median age 53 yrs.) received 20 cycles of ADH-1 by bolus injection at 150, 300 and 600 mg/m2/weekly ×3 W Q21–28 D. No DLTs have occurred to date. No pts have experienced > grade 2 study drug related AEs. One pt, with fallopian tube ca. had a mixed response. There was a 30% reduction in retroperitoneal nodal disease at the end of cycle 3, and a 37% reduction at the end of Cy 4. However, new bone lesions were also noted at the end of cycle 4 assessment. Tumor blood flow reduction of ≥40% was noted in this patient, and she also reported pain in the region of the tumor following multiple doses of ADH-1. PK parameters are available for the first 3 DLs (150, 300, and 600 mg/m2): mean Cmax 22.1, 37.0, and 50.8μg/mL, respectively; AUCinf 24.3, 60.6, and 110.3 h·μg/mL; Vss 12.6, 15.1, and 16.3 L/m2; and T1/2 1.8, 2.7, and 2.4hr. Conclusions: ADH-1 has been well tolerated in 4 dose levels tested to date, dose escalation is proceeding. No DLTs have occurred and the MTD has not been reached. Anti-tumor activity has been noted. Updated clinical, PK and PD results will be presented. [Table: see text]
A phase I and pharmacokinetic study of continuous infusion EMD 121974 (EMD), an antiangiogenic αvβ3 and αvβ5 integrin antagonist, in patients with advanced solid malignancy
Authors: Undevia S. D. , Janisch L. , Stadler W. M. , Wittemer S. M. , Ratain M. J. 
Published: March 2020

3052 Background: Integrins αvβ3 and αvβ5 are cell-surface receptors that play a significant role in angiogenesis by mediating the ligation signal that allows endothelial cells to attach to the extracellular matrix. These integrins share the binding epitope Arg-Gly-Asp (RGD). EMD is an RGD-containing cyclic pentapeptide. In clinical studies to date, EMD has been administered in an intermittent fashion. However, EMD has a short half-life of 3–5 hours with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion EMD. Methods: EMD was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 hours after infusion bag change. Results: To date 21 patients (15 male/6 female, median age 56, median Karnofsky performance status 90%) have been treated at the following dose levels: 1, 2, 4, 8, 12, 18, and 27 mg/h. Hematologic toxicities have been limited to grade 2 anemia and grade 3 lymphopenia. Non-hematologic toxicities have been limited to grade ≤ 2 and include alopecia, anorexia, diarrhea, fatigue, hypokalemia, hyponatremia, hypophosphatemia, insomnia, mucositis, nail changes, nausea, and transaminase elevation. One patient treated at 27 m/h experienced an unobserved death of unknown cause after two weeks of therapy. Pharmacokinetic analysis has been completed for patients treated at the 12 mg/h dose level and below. Mean values for half-life, clearance, and volume of distribution were comparable across dose levels, and steady-state concentration increased proportionally to dose. Conclusions: EMD can be safely administered as a continuous infusion at doses of up to at least 18 mg/h. No single toxicity has been consistently observed. A patient death in cycle 1 has resulted in the expansion of the 27 mg/h dose level. The pharmacokinetics of continuous infusion EMD were predictable and in general agreement with the published data of twice weekly infusion. Study enrollment is ongoing. [Table: see text]
Final results of a phase I study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor receptors (VEGFR), in combination with carboplatin (C) + paclitaxel (T) in patients with advanced non-small cell lung cancer (NSCLC): A study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG)
Authors: Laurie S. A. , Arnold A. , Gauthier I. , Chen E. , Goss G. , Ellis P. , Shepherd F. A. , Matthews S. , Robertson J. , Seymour L. 
Published: March 2020

3054 Background: AZD2171 is a potent oral inhibitor of the tyrosine kinase activity of all VEGFR subtypes. This study was undertaken to determine the recommended phase II dose of AZD2171 in conjunction with standard doses of C and T, and to assess the tolerability, safety, PK profile and anti-tumor activity of this combination. Methods: Patients with stage IIIB / IV NSCLC (any histology); PS 0–2; no prior chemotherapy for metastatic disease and no significant hemoptysis / bleeding, were eligible. Treated, clinically stable brain metastases were permitted. C - AUC 6, and T - 200 mg/m2 over 3 hours, q3weekly. AZD2171 commenced day 2 cycle 1 at a starting dose of 30 mg po daily. PK profile of all was drugs performed during cycles 1 and 2. Response was assessed by RECIST every second cycle. Results: 20 patients were enrolled: AZD2171 30 mg (9 pts) and 45 mg (11 pts). Median age 58; 19 PS 0 / 1; 8 females. At 30 mg, one confirmed DLT was observed (grade 3 ALT); hypertension ≥ grade 2 was seen in 6 pts, prompting the institution of a standardized algorithm for management of this predictable toxicity. Of the first 3 pts enrolled to the 45 mg dose level, one DLT was observed (grade 3 febrile neutropenia with grade 3 mucositis); no further DLT was observed in the expanded cohort. Other common toxicities: fatigue, anorexia, mucositis and diarrhea. Hematologic toxicity was not greater than that expected with CT alone. No hemoptysis was seen. To date, 15 pts are evaluable for response: 6 PR, 8 SD and 1 PD. Many SD pts had evidence of tumor shrinkage, including central cavitation. Conclusions: Toxicities of this combination appear manageable and predictable. Full single-agent dose of AZD2171 may be administered with standard C+T. Hypertension, a typical toxicity of inhibitors of VEGF signaling, was observed but manageable. Encouraging anti-tumor activity of the combination has been observed. NCIC CTG BR.24, a phase II/III trial of C+T with AZD2171/placebo is underway. [Table: see text]
Phase I study of rapamycin (R) in combination with CYP3A4 modifier, ketoconazole (K), in patients with advanced malignancies
Authors: Cohen E. E. , Moshier K. , Innocenti F. , Kocherginsky M. , House L. , Ramirez J. , Undevia S. D. , Fleming G. F. , Ratain M. J. 
Published: March 2020

3061 Background: R is currently FDA approved for the treatment of renal allograft rejection but mTOR is a relevant target in several cancer types. K, a CYP3A4 inhibitor, increases the area under the concentration curve (AUC) of R and co-administration of R and K can overcome poor R bioavailability and decrease costs substantially. The aims of this study were to find the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of R administered weekly in combination with K and describe the pharmacokinetics (PK) of the combination in patients with advanced malignancies. Methods: R and K were administered concurrently to successive cohorts of patients. R starting dose was 1 mg once weekly and was escalated by 1 mg per dose level. K was administered at a constant dose of 200mg BID 1 day prior to each R dose then 200 mg QD on the next 3 consecutive days. Results: 34 subjects (median age 60 years) have been enrolled. The highest dose of R administered thus far was 5mg without DLT. Most frequent toxicities observed of any grade included hyperglycemia (41%), lymphopenia (35%), hyperlipidemia (35%), fatigue (29%), anemia (26%), anorexia (24%), and nausea (24%). Observed grade 3 toxicities included 2 patients with lymphopenia, 2 patients with elevated transaminases, and 1 patient each with emesis and hyperglycemia. One patient experienced grade 3 confusion likely due to a drug-drug interaction of K with concomitant psychotropic medications. PK analysis of the first 2 dose levels confirms that K significantly increases Cmax and AUC of R ( Table ). R Cmax (with K) averaged 22.5 (11.7) and 27.4 (7.9) (mean/SD) ng/ml at the 1 and 2 mg dose levels, respectively. R AUC (with K) averaged 408.9 (225.4) and 663.8 (201.8) (mean/SD) ng*h/ml at the 1 and 2 mg dose levels, respectively. Conclusions: Low dose weekly R plus K results in potentially efficacious concentrations, as demonstrated by classic mTOR inhibitor toxicity. Higher doses on this schedule without K are probably also feasible, but would have higher costs. [Table: see text] No significant financial relationships to disclose.
International multicenter phase II study of the HDAC inhibitor (HDACi) depsipeptide (FK228) in cutaneous T-cell lymphoma (CTCL): Interim report
Authors: Whittaker S. , McCulloch W. , Robak T. , Baran E. 
Published: March 2020

3063 Background: Depsipeptide, a unique bicyclic peptide histone deacetylase inhibitor (HDACi), has shown activity in a range of in vitro and in vivo tumor models and clinical activity in T-cell lymphomas and prostate cancer. This study seeks to confirm the CTCL activity previously reported by the NCI (Piekarz, et al., ASCO, 2004). Methods: Single-arm, open label study, in 25 centers in the UK, Germany, Poland and the US. Patients aged ≥18 years with biopsy-confirmed CTCL (centrally reviewed) who have failed at least one prior systemic treatment receive up to 6 cycles of depsipeptide as a 4-hour IV infusion on Days 1, 8 and 15 q 28 days. Eligibility criteria include: mycosis fungoides and Sézary syndrome plus variants, Stages IB - IVA, adequate organ function, ECOG PS ≤ 1. Patients with significant cardiovascular abnormalities are excluded in addition to those taking QTc-prolonging or CYP3A4-inhibiting drugs. The primary endpoint is overall reponse rate measured by a combination of imaging, circulating cell counts and a weighted skin average instrument, confirmed by standardized photography. A subset undergoes pharmacokinetic assessments. Correlative studies include acetylation status, apoptotic markers and proteomic analyses where possible. Target accrual is 76 to yield 64 evaluable patients. Results: 30 patients have received treatment with 17 evaluable for efficacy. Responses seen are 1 cCR, 4 PRs (duration 2+ to 6 months) 9 SD and 3 PD. 3 patients withdrew early for PD and 2 for other reasons. The remaining patients on study are too early to assess. Most frequent toxicities are: nausea/vomiting, fatigue, myelosuppression and asymptomatic ECG changes. No patient has withdrawn for toxicity and there have been no treatment-related deaths. Conclusions: The previously reported efficacy of depsipeptide in CTCL has also been seen in the present study. Duration of response is encouraging. Toxicity is manageable and the study continues to accrue. [Table: see text]
Molecular basis of altered uracil catabolism in individuals with 5-FU toxicity and normal DPD enzyme activity
Authors: Reed H. A. , Ezzeldin H. H. , Mattison L. K. , Diasio R. B. 
Published: March 2020

3070 Background: Dihydropyrimidine dehydrogenase (DPD) deficiency accounts for approximately 43% of grade 3–4 toxicity to 5-Fluorouracil (5-FU). However, a significant number of patients with normal DPD enzyme activity remain with unexplained molecular basis of 5-FU toxicity. It has been suggested by the few cases previously reported that deficiency of dihydropyrimidinase (DHP)enzyme encoded by the DPYS gene and/or beta-ureidopropionase enzyme, encoded by the BUP-1 gene, could also be implicated in 5-FU toxicity. Methods: This study included 40 volunteers with known 13C-UraBT and DPD enzyme activity, 25 cancer patients with 5-FU toxicity despite normal DPD enzyme activity, and 25 liver biopsies from cancer patients with different grades of toxicity. All samples were analyzed for molecular defects in the DPYS and BUP-1 genes, using DHPLC and RT-PCR techniques. Results: Molecular analysis of the DPYS gene revealed the presence of two non-conservative amino acid changes, one frame-shift mutation that leads to a stop codon and premature termination of the DHP protein, five silent mutations, nine intronic sequence variations, two sequence variations in the 5’UTR and one in the non-coding region of exon 10. Molecular analysis of the BUP-1 gene revealed the presence of two non-conservative amino acid changes, one of which (314C>A: A85E) has already been reported to abolish enzyme activity; six silent mutations, four intronic sequence variations, one polymorphism in the 5’upstream sequence, and one sequence variation in each of the 5’UTR and the 3’UTR. Conclusions: The molecular basis of 5-FU toxicity is not limited to DPD deficiency; since molecular defects in genes downstream of DPD can potentially also impair 5-FU catabolism. Genetic testing for molecular defects in DPYS and BUP-1 may predict patients at risk of developing 5-FU toxicity despite having normal DPD enzyme activity. Assessing the integrity of the entire uracil catabolic pathway might be crucial to avoid toxicity in a significant group of patients receiving 5-FU or a related drug (CA62164). No significant financial relationships to disclose.
Pharmacogenetic pathway analysis of irinotecan
Authors: Rosner G. L. , Panetta J. C. , Xiao L. , Innocenti F. , Ratain M. J. 
Published: March 2020

3073 Background: Irinotecan (IRN), a chemotherapeutic agent for various solid tumors, is the parent compound for SN-38, the active metabolite. The pharmacokinetics (PK) of IRN are complex and associated with variability in clinical outcomes. We sought to learn about the pharmacogenetics (PGx) of IRN by relating the drug’s PK to polymorphisms (SNPs) in drug-metabolizing enzyme and transporter genes potentially relevant to IRN. Methods: We measured concentrations of IRN and 3 metabolites in 86 patients. We fit a novel 7-compartment (15 parameter) model (including enterohepatic circulation) to the concentration data for IRN and metabolites. We applied principal components (PCs) analysis to the patient-specific PK model parameters to reduce the number of outcome variables and to identify appropriate linear combinations of the parameters that relate to IRN’s metabolic pathways. We then analyzed associations between SNPs and PCs to learn about functional polymorphisms. Associations are significant if p < 0.05. Results: We found that 8 PCs accounted for 90% of the total variation in the 15 fitted parameters. PC #1 corresponded to SN-38 in plasma and was associated with SNPs in the CYP3A4, MRP2, and ABCG2 genes. PC #2, the IRN compartments’ PC, was associated with a SNP in OATP-C*1b. The APC PC was associated with a CYP3A5 SNP. The SN-38 glucuronidation PC was associated with UGT1A1 and UGT1A9 polymorphisms. Conclusions: PC analysis is a useful way to reduce the dimension of multiple PK parameters and to produce pathway-specific and interpretable measures relating to PK. The use of PCs in PGx analysis allows identification of potential functional polymorphisms, which can be further evaluated in other data sets. [Table: see text]