bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of anthracycline extravasation with dexrazoxane: Pharmacokinetics and update on efficacy and safety from three multicenter trials
Authors: Giacone G. , Handskemager L. , Mouridsen H. , Tjornelund J. , Langer S. , Buter J. , Rasmussen A. , Buhl P. , Dahlstrom K. , Grundtvig P. 
Published: March 2020

2555 Background: Dexrazoxane prevented tissue necrosis in 98% of patients (pts) with biopsy proven anthracycline extravasation (AEV) in two international multicenter studies, TT01 and TT02 (Mouridsen HT et al Ann Onc Advance Access Dec 21, 2006). However, the pharmacokinetics (PK) of IV dexrazoxane in the three-day schedule is not established. Study TT04 was initiated to investigate PK. Patients and methods: TT04 is a prospective, open-label, single-arm, multicenter studies in pts with AEV. Consecutive pts with AEV are treated with a three-day schedule of IV dexrazoxane (1,000, 1,000, and 500 mg/m2) starting within 6 hr of AEV. Primary objective: Establish PK of IV dexrazoxane in the three-day schedule. Secondary objectives: obtaining additional efficacy and safety data. Plasma samples at 0, 1, 2, 4 and 24 hr day 1–3 are analyzed by HPLC-MS. PK parameters were calculated by a non compartmental method. TT01 and TT02 were open-label, single-arm, multicenter studies enrolling pts with biopsy proven AEV from 24 EU centers. Primary objective was to avoid tissue necrosis leading to surgery. Secondary objectives were to minimize delay of planned chemotherapy, reduce hospitalization, and avoid long term sequelae. Results: Six pts have entered the PK study. The average elimination was T½ ± SD of 127 ± 23, 144 ± 21, and 107 ± 29 min, day 1, 2 and 3, respectively. Pre-dose concentrations day 2 and 3 are = LOQ. Average AUC 0-t ± SD are 193 ± 93 (t= 24 hr), 196 ± 101 (t= 24 hr), and 46 ± 24 μg hr/ml (t= 4 hr), on day 1, 2 and 3, respectively. Cumulative data from the 3 studies: Surgery was avoided in 59/60 pts (98.3%). No delay in planned chemotherapy in 71%. 41% were hospitalized (median 3 days) due to the EV or its treatment. Mild pain (19%) and mild sensory disturbances (17%) were the most frequent sequelae: Reversible CTC grade 3–4 leucopenia/neutropenia in 45%, thrombocytopenia in 21% of the pts. Conclusion: There was no accumulation of dexrazoxane during the three-day schedule. Dexrazoxane was well tolerated and highly effective against anthracycline extravasation. Updated results will be presented. No significant financial relationships to disclose.
Pharmacokinetic results of a phase I trial of sorafenib (S) in combination with dacarbazine (DTIC) in patients with advanced metastatic melanoma or other solid tumors
Authors: Brendel E. , Zafarana E. , Figuerola C. , Ludwig M. , Lathia C. , Burk K. , Robert C. , Soria J. C. , Armand J. P. 
Published: March 2020

2563 Background: Sorafenib (S) is a multikinase inhibitor that prevents tumor cell proliferation and angiogenesis via receptor tyrosine kinases, VEGFR-1, -2, -3 and PDGFR-a and -β, and the Raf/MEK/ERK pathway at the level of Raf kinase. Single-agent studies show S is well tolerated with manageable and reversible side effects, most commonly, diarrhea, rash, fatigue, and hand-foot skin (HFS) reaction. This phase I study assessed the safety and pharmacokinetics (PK) of the combination of S and DTIC. Methods: 23 patients (pts) received a fixed dose of DTIC (1,000 mg/m2 given every 3 wks) starting on Day 1 of cycle 1 (C1). S (400 mg bid) was given on days 2–21 in C1 and continuously thereafter. PK profiles of DTIC and 5-aminoimidazole-4-carboxamide (AIC; an inactive D metabolite that is formed in an equal proportion to the active moiety, diazomethane, that cannot be analytically measured) were obtained from day 1 of both C1 and C2 and PK profiles of S from Day 1 of C2. Results: 23 pts (M:F, 11:12; mean age 57±9 yrs) were treated with S and DTIC. Of these pts, 15 were valid for PK analysis. Following simultaneous administration of S, mean AUC and Cmax of DTIC were moderately reduced by 23% and 16%, while mean AUC and Cmax of AIC were increased by 41% and 45%, respectively. Mean AUC (0–12)ss and Cmax,ss of S were 28.3 mg*h/L (84%) and 3.67 mg/L (77%), respectively, upon concomitant dosing of S and DTIC. These sorafenib exposures are within the range of exposures observed in phase I studies. Six pts had an increase of either Cmax or AUC of AIC of at least 70%, and in 4 of the 6 pts, this increase was correlated with grade 4 thrombocytopenia. Conclusions: The combination of S and DTIC resulted in moderate decreases of DTIC exposure; however, more pronounced increases in AIC exposure were observed. In patients with a distinct increase (=70%) in AIC, a correlation between exposure and toxicity cannot be excluded, however, all toxicities were manageable. No significant financial relationships to disclose.
A simulation study to define the number of patients necessary to meet primary pharmacokinetic (pk) aims of phase I oncology trials
Authors: Adamson P. C. , Zhao H. , Sievert A. , Troxel A. , Aplenc R. 
Published: March 2020

2579 Introduction: The primary pharmacokinetic parameters defined in oncology phase I trials include estimates of drug clearance and determining the relationship between dose and drug exposure as measured by AUC. The numbers of patients needed for reliable estimates of these parameters, however, has not been defined. We hypothesized that a threshold number of patients existed above which meaningful improvement in such estimates would not occur. Methods: We identified 28 English language adult phase 1 oncology publications (2004-2006) from which individual patient dose and AUC data could be extracted. Analyses of clearance precision were performed in PASS 2000. Simulations were performed by determining a distribution of r2 coefficients for the regression of AUC on dose for each trial, for sample sizes of 2 to n-1, where n was the total patient number studied. Median values for the simulated r2 and a 90% confidence interval (CI) were obtained for every simulation. A stability boundary of 0.1 around the simulated r2 value was calculated. A 90% confidence interval around the observed r2 value was also bootstrapped. An r2 value was considered stable when the simulated r2 CI fell within the stability boundary for all subsequent sample sizes. Results: Analyses of the precision of mean clearance estimates over a range of confidence intervals demonstrated that the incremental gain in clearance precision estimates was marginal beyond the study of 8 to 12 patients. Linearity simulations of AUC vs dose demonstrated the median (range) of patients needed to determine a stable r2 estimate was 7 (4 - 16), with a mean (±SD) of 7.8 ± 3.2. Conclusions: These simulations show that, in general, only 8–12 patients are needed to meet the primary PK objectives of phase I oncology trials. While such modest sample sizes are not sufficient to define pharmacokinetic-dynamic-genetic relationships, such relationships rarely emerge from phase I trials. Our simulations indicate that the number of patients needed to meet PK objectives may be more modest than previously anticipated, and should be readily achievable with voluntary participation in the PK component of oncology phase 1 trials. No significant financial relationships to disclose.
Phase I study of bi-weekly pemetrexed (P) plus cisplatin (C) in patients with advanced cancer
Authors: Lopez-Martin A. , Paz-Ares L. , Calvo E. , Castellano D. , Valverde C. , Neciosup S. , Vilar E. , San Antonio B. , Garcia-Ribas I. , Cortes-Funes H. , Bellmunt J. 
Published: March 2020

2580 Background: Cisplatin and pemetrexed have demonstrated clinical activity in several malignant tumors including mesothelioma and non small cell lung cancer. There is preclinical evidence of synergism between both agents as well as clinical non-overlapping toxicities, thus providing the rationale for their evaluation in combination. Our aim was to develop a well-tolerated combination of bi-weekly CP able to deliver higher dose intensity than the every 3-week standard. Methods: Escalating doses of P from a starting dose level of 300 mg/m2, with a fixed-dose of C 50 mg/m2, both biweekly on 28-day cycles, were administered to patients with refractory advanced solid malignancies and calculated creatinine clearance = 45 mL/min. Results: Twenty one patients (5 female/16 male); median age 61 (39–76); ECOG 0 (16), 1 (5); lung cancer (9); soft-tissue sarcoma (3); unknown primary, bladder, breast, rectum, esophagus, melanoma, mesothelioma, prostate, and tonsil (1, each) have received a total of 48 courses (median 2, range 0–5), at P dose levels of 300 mg/m2 [8 pts, Dose level 1 (DL1)], 400 mg/m2 (7 pts, DL2), and 500 mg/m2 (6 pts, DL3), with full doses of C. Four patients were non-evaluable (2 at DL1, 1 at DL2 and 1 at DL3) because of early PD (2) and non-drug related serious adverse event (2 pt). Dose Limiting Toxicities (DLT) were G4 neutropenia (1 pt) at 300 mg/m2; and prolonged G 1/2 thrombocytopenia (1 pt) at 500 mg/m2. There were also 2 pts with non-DLT G4 neutropenia at DL3. The rest of toxicities were mild to moderate being the most frequent asthenia, nausea, anorexia, stomatatis, and sensory neuropathy. DL3 was considered the Maximum Tolerated Dose (MTD) and the previous level with P at 400 mg/m2 was declared the recommended phase II dose. Three additional patients were treated at DL2 for dose confirmation. A PR has been observed in 2 pts with NSCLC, 1 pt with breast, and 1 with esophagus cancer. Conclusions: Biweekly administration of pemetrexed (400 mg/m2) plus cisplatin (50 mg/m2) is clinically well tolerated and can be used safely. The regimen delivers higher dose intensity of P and equal of C as the standard. This regimen is currently being studied in a phase 2 trial in patients with locally advanced, non resectable or metastatic urothelial cancer. No significant financial relationships to disclose.
Phase I trial of huA33 antibody plus 5-fluorouracil (5FU), leucovorin, and oxaliplatin in patients with metastatic colorectal cancer [LUD2003–005]
Authors: Renner C. , Ritter G. , Pan L. , Venkatramin E. , Hoffman E. W. , Venhaus R. , Old L. , Knuth A. , Jäger E. , Pfreundschuh M. 
Published: March 2020

3022 Background: The selective targeting of tumors with monoclonal antibodies (mAb) has emerged as a new therapeutic approach in cancer therapy with the A33 glycoprotein being a promising target in colorectal cancer. Specific tumor localization and low toxicity of a humanised A33 specific mAb (huA33) has previously been demonstrated in patients with colorectal carcinoma. In the present study, we determined the safety and efficacy of the combination of huA33 and 5FU plus leucovorin and oxaliplatin (FOLFOX-4) in patients with metastatic colorectal cancer. Methods: Patients had to present with metastatic colorectal cancer with an expected survival of at least 4 months and no more than 2 different pre-treatment regimens. Patients were excluded if they had previously received oxaliplatin or huA33 mAb. Eligible patients received huA33 (10 mg/m2) by iv infusion weekly for 12 weeks (cycle 1). On study day 15, standard FOLFOX-4 chemotherapy was administered every 2 weeks for 10 weeks. Responding patients received a second cycle of weekly huA33 (10 mg/m2) and biweekly FOLFOX-4 chemotherapy. Results: A total of 19 patients (11 female, 8 male) with a median age of 60 years entered the study. 5 patients had received prior chemotherapy, 2 radiation therapy and 18 surgery. Toxicities observed were as expected for FOLFOX-4 treatment alone with hematological side effects to be most prominent and included (only G3 and G4) 1 anemia and 10 neutropenias. The addition of huA33 to FOLFOX-4 did not change the pattern of known non-hematological toxicities with a low rate (14%) of huA33 mAb associated allergic reactions. One sudden death occurred at cycle five that was neither therapy nor disease related. Within the 16 patients currently available for response assessment, the overall response rate was 38% with 1 CR, 5 PR and 5 disease stabilizations. Conclusion: The combination of FOLFOX-4 as standard chemotherapy for this cohort of patients in combination with the humanized A33 antibody did not increase toxicities and was well tolerated. The overall response rate of 38% is in the response range published so far for the FOLFOX-4 regimen in this setting and warrants further analysis in a larger cohort of patients. [Table: see text]
Mesenchymal stem cells selectively engraft into tumor stroma and produce potent antitumor proteins in situ
Authors: Andreeff M. , Dembinski J. , Studeny M. , Ling X. , McQueen T. , Klopp A. , Marini F. 
Published: March 2020

3025 Background: The formation of stroma is essential for tumor growth and involves complex interactions between malignant cells and non-tumor stromal cells. We have previously demonstrated that IV injected bone marrow derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements (Cancer Res 62:3603, 2002; JNCI 96:1593, 2004). Methods: MSC were labeled by a fiber modified Ad vector expressing firefly luciferase (AdLux-F/RGD), injected into normal or tumor-bearing SCID mice, and biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS system. Results: After IP injection, no hMSC-LUX were detected in normal animals after 7 days, while strong punctate regions of LUX-activity were observed in ovarian tumors. Tumor cells transduced with renilla luciferase constructs co- localized with firefly luciferase MSC. Next, we examined whether hMSC-producing interferon-beta (IFNβ-MSC) could inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 106 MSC/week) into SCID mice with pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared with untreated or vector-control MSC controls (p= 0.007). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001). In an orthotopic, chemoresistant breast cancer model in syngeneic immunocompetent mice, MSC producing IFN-β completely abrograted tumor growth. Localized low-dose XRT to tumors significantly increased the number of tumor-resident MSC. Conclusions: The data suggest that systemically administered gene-modified MSC selectively engraft into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-β inhibit the growth of melanomas, gliomas, metastatic breast and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Clinical trials are in preparation. No significant financial relationships to disclose.
Induction of apoptosis of myeloid leukemia with CSC17.1, a unique monoclonal antibody targeting CD45RA
Authors: Tesi R. J. , Tran H. , Christensen J. , Morales J. , Karimi M. , Sagy M. , Palath V. 
Published: March 2020

3030 Background: Blast crisis from myeloid leukemia is may be responsive to chemotherapy, but a majority of patients die from their disease. Relapse may be due to persistence of cancer stem cells (CSC). A monoclonal antibody (mAb) that targets myeloid blast cells including the CSC without targeting the hematopoietic stem cell (HSC: CD34+90+) may be of value. CSC phenotype of CML-BC (CD34+38+123+45RA+) and AML (CD34+38–90-) have been defined. Method: We developed a biologically based mAb platform with 2 important steps after generating the mAb library: i) mAb must not bind the HSC (SS; safety screen); and ii) must bind the target cells (RxS; therapeutic screen). HSC for the SS were from G-CSF mobilized blood; cells for RxS was patient specimens of CML-BC and AML. After screens, the target was indentified, in vitro and in vivo functional assays are performed. Results: 5 of 400 mAb passed the SS and RxS. CSC17.1, an IgG2b isotype binding a unique, linear, 12 amino acid sequence of CD45RA has been selected. CML (Kasumi4), AML (Kasumi3 and KG1a), ALL (MOLT3) and NHL (Pfeiffer) cel lines express high levels of CD45RA. Five of 5 CML-BC and 3 of 3 AML patient specimens express CD45RA in high levels. Kausmi4 and Pfeiffer cell lines and patient specimens of CML-BC and AML undergo apoptosis in a dose and time dependent manner after exposure to CSC17.1 (>80% apoptosis at 1ug/ml@8h). KG1a is refractory to apoptosis despite high levels of target on the cell surface (15% apoptosis at 1ug/ml@8h). Normal T,B and NK cells express high levels of CD45RA, but do not undergo apoptosis or activation when exposed to CSC17.1. CSC17.1 causes capping and patching, but not internalization of CD45RA in cell lines and CD8+ normal cells. Commercially available antibodies to CD45RA do not inhibit binding of CSC17.1 to CD45RA, do not cause apoptosis, do not cause patching and capping, but do undergo internalization. In vivo murine models with cell lines and patient specimens of CML-BC and AML are underway. Conclusions: 1) CSC17.1 binds a previously undefined epitope of CD45RA that causes apoptosis of selected hematopoietic tumor cell lines and patient specimens of CML-BC and AML; 2) apoptosis, is a unique function of CSC17.1 compared to other mAb against CD45RA; 3) CML-BC and AML CSC include the CD45RA antigen suggesting CSC17.1 will target these cells. No significant financial relationships to disclose.
Lung cancer-derived EGFR mutations affect responses to tyrosine kinase inhibitors, but not to monoclonal antibodies
Authors: Dechant M. , Peipp M. , Schneider-Merck T. , Beyer T. , Lammerts van Bueren J. J. , Bleeker W. K. , Parren P. W. , van de Winkel J. G. , Valerius T. 
Published: March 2020

3044 Background: The epidermal growth factor receptor (EGFR) serves as a molecular target for novel cancer therapeutic approaches. Two groups of anti-EGFR agents are clinically most advanced: tyrosine kinase inhibitors (TKI) and EGFR antibodies. Recently, somatic mutations in the EGFR kinase domain were identified in tumors from lung cancer patients, which affected EGFR signaling and which correlated with responses to TKI therapy. Since interference with tumor cell signaling is also considered an important mechanism of action for therapeutic antibodies, we investigated the influence of these intracellular EGFR mutations on cell killing by EGFR antibodies, in comparison to TKI. Methods: For this purpose, we established an EGF-responsive, non-transformed cell line model for the three most common lung cancer-derived intracellular EGFR mutations L858R, G719S and delE746-A750. EGFR phosphorylation status was analyzed by Western Blots. MTT assays were performed to compare TKI gefitinib and erlotinib with antibodies C225 and 2F8 in their capacity to inhibit cell growth of wild type and mutated EGFR-transfectants. Impact of intracellular EGFR mutations on immune cell-mediated killing by EGFR antibodies was measured in classical 3 hours 51-chromium-release assays. Results: Mutated EGFR transfected cells were growth factor- responsive, and significantly more sensitive to both gefitinib and erlotinib than wild type (WT) EGFR expressing cells. However, anti-tumor effector functions of both EGFR-directed IgG1 antibodies—chimeric C225 and fully human 2F8—were not affected by the mutations. Conclusions: Intracellular mutations of EGFR may, therefore, be less relevant for EGFR antibodies than for TKI. No significant financial relationships to disclose.
Agonist anti-GITR antibody induces CD8 T cell-mediated tumor rejection
Authors: Cohen A. D. , Diab A. , Perales M. A. , Duan F. , Jenq R. , Rizzuto G. , Hirschorn-Cymmerman D. , Merghoub T. , Wolchok J. D. , Houghton A. N. 
Published: March 2020

3058 Background: Signaling through GITR (glucocorticoid-induced tumor necrosis factor receptor) can abrogate the suppressive effects of CD4+foxp3+ regulatory T cells and co-stimulate activated effector CD4+ and CD8+ T cells. We have previously shown that in vivo GITR ligation using the agonist anti-GITR mAb DTA-1 augments concomitant immunity and immunity generated by active immunization with self- tumor antigens. In the present study, we assessed the activity of anti-GITR mAb used alone, focusing on the effects of GITR ligation on CD8+ T cells during tumor growth. Methods: C57BL/6 mice were injected intradermally with B16 melanoma and received 1mg of DTA-1 or control rat IgG intraperitoneally on various days after tumor injection. In some experiments, naïve, CFSE-labeled pmel-1 CD8+ transgenic T cells (specific for the melanoma antigen gp10025–33 epitope) were transferred into naïve recipients 1 day prior to B16 inoculation. Results: DTA-1 treatment on days 0 and 4 led to tumor rejection in 20–30% and 50–60% of mice, respectively, compared with rejection in 0–5% of mice treated with control IgG (p<0.05 for both). Treatment at day 7 or later had no significant impact on tumor-free survival. The importance of CD8+ T cells in mediating DTA-1-induced tumor immunity was demonstrated by 4 findings: 1) in untreated mice, tumor-infiltrating CD8+ lymphocytes significantly upregulated GITR expression during tumor growth; 2) DTA-1-treated mice had greater CD8+ T cell infiltration into tumors than IgG-treated mice; 3) depletion of CD8+ cells completely abrogated the tumor protection provided by DTA-1; and 4) tumor-specific CD8+ cells proliferated more extensively, became more activated, and exhibited greater effector function following DTA-1 administration compared with control IgG. This was most dramatically seen within the tumor (compared with spleen or draining lymph node), suggesting that a major mechanism of tumor immunity induced by anti-GITR mAb may be overcoming impaired CD8+ T cell function within the tumor microenvironment. Conclusions: Ligating GITR using an agonist mAb can by itself augment tumor-specific CD8+ T cell responses and induce rejection of an aggressive, poorly immunogenic tumor. This strategy merits further consideration as an immune-modulating therapy for cancer. No significant financial relationships to disclose.
The changing face of phase I protocols: A closer look at study requirements
Authors: Craft B. S. , Kurzrock R. , Herbst R. , Culotta K. , Stewart C. , Dorsey V. , Lippman S. , Gingher D. , Bekele N. , Karp D. 
Published: March 2020

3061 Background: We have studied our recent experience in the MDACC Clinical Translational Research Center (CTRC), the Phase I Program, and the Dept. of Thoracic/Head & Neck Medical Oncology to compare the extent of regulatory and other requirements for current phase I and II cancer clinical trials. Methods: We developed a comprehensive database, together with a Microsoft Excel spreadsheet matrix to analyze the number and extent of diagnostic and therapeutic requirements for each protocol. We then examined the demands for pharmacokinetic (PK) sampling as well as electrocardiography (ECG) in the first cycle of a protocol as a surrogate for study complexity. Results: Since October, 2002, 250 protocols have been conducted in the CTRC; 54.6% were Phase I clinical trials. We reviewed 65 trials, approximately one quarter of the total. Of these, 48 were phase I trials carried out by the Phase I Program. For comparison, we identified 17 phase II trials managed by the Dept. of Thoracic/Head & Neck Medical Oncology during the same time period. In the phase I trials there were significantly more PKs (mean ± SE = 16.69 ± 1.93) than in the phase II trials (mean ± SE = 1.82 ± 1.17) (p<0.0001). Similarly, there were more ECGs in the phase I versus phase II trials (4.46 ± 1.18 vs. 1.41 ± 0.35; p=0.017). Conclusions: Pharmacokinetic collection and ECG monitoring in Phase I trials are complex and labor-intensive. In addition, they represent only a small portion of time-intensive requirements, with increasingly complicated correlates and monitoring (physical exams, imaging, etc.). Successful and accurate Phase I clinical trials require resources and commitment for research infrastructure considerably greater than later phase studies. No significant financial relationships to disclose.