bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 clinical trial of KOS-953 + bortezomib (BZ) in relapsed refractory multiple myeloma (MM)
Authors: Chanan-Khan A. , Richardson P. , Alsina M. , Lonial S. , Krishnan A. , Carroll M. , Albitar M. , Hannah A. L. , Johnson R. G. , Anderson K. 
Published: March 2020

3066 Background: KOS-953 (17-AAG in Cremophor) inhibits HSP90 chaperone function, resulting in disruption of protein complexes and proteasomal degradation. Single-agent 17-AAG is active in relapsed/refractory MM patients (pts) (ASH 2005 A#361), with a recommended dose ≥ 275 mg/m2. In vitro, BZ + KOS-953 show additive cytotoxicity of myeloma cells. Objectives: Define phase 2 dose of BZ+KOS-953 in pts with relapsed refractory MM. Determine PK of KOS-953 and its active metabolite. Evaluate proteasome inhibition in whole blood lysates and explore changes in intracellular signaling proteins in pt PBMCs and MM cells. Methods: Pts received BZ as IV bolus followed by 1-hour infusion KOS-953 twice weekly for 2 out of 3 weeks. Dose escalation occurred in a step-wise manner. PK and collection of surrogates are performed following the 1st and 4th infusion. Pts assessed for response by EBMT criteria. Results: 20 pts were enrolled in 4 cohorts: BZ+KOS-953 (mg/m2): 0.7+100 (n=3); 1.0+100 (n=3); 1.0+150 (n=8); and 1.3+150 (n=6), receiving a total of 103+ cycles (median 5 cycles; range <1 - 17). Demographics: 10F/10M; median age/KPS 64y/90; median # of prior regimens 4 (range 2–16); 75% prior BZ (5 with ≥2 prior BZ); 95% prior thalidomide; 15% prior lenalidomide; 70% prior SCT(s). DLT observed in Cohort 2 (n=1 grade 4 hepatotoxicity in a setting of congestive heart failure secondary to cardiac amyloidosis) and in Cohort 3 (n=1 pancreatitis). Other Grade 3–4 toxicity (1 each): thrombocytopenia with Herpes Zoster recurrence and pneumonia; septic thrombophlebitis. Drug-related toxicity (mild-to-moderate): diarrhea (n=8), fatigue (n=8), constipation (n=7), neuropathy (n=7), ↑AST (n=5), muscle cramps (n=5) and rash (n=4). PK similar to single-agent trial; stationary kinetics noted upon twice weekly dosing. 20S proteasome function (1.3 mg/m2, end of infusion): 50% decrease (similar to predicted values). Response was seen in 6 out of 12 BZ-refractory patients (1 nCR, 5 MR) and 3 out of 4 BZ-naïve pts (1 nCR, 2 MR). Conclusions: Dose escalation continues with no additive toxicity or PK interactions to date. Similar inhibition of the 20S proteasome is observed compared to BZ alone. Encouraging activity is seen in both BZ-naïve and BZ-refractory heavily pre-treated MM pts. [Table: see text]
Phase I trial of a sequence-specific combination of the HDAC inhibitor, valproic acid (VPA), and the topoisomerase II inhibitor, epirubicin, in advanced solid tumors: Clinical results and correlative studies
Authors: Munster P. N. , Marchion D. C. , Bicaku E. , Schmitt M. L. , Padilla B. , Stauffer P. , Garrett C. , Chiappori A. , Sullivan D. M. , Daud A. I. 
Published: March 2020

3068 Background: Multiple lines of evidence indicate that histone deacetylase inhibitors (HDACi) potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explored a sequence-specific combination of VPA and epirubicin in solid tumors. A VPA loading dose and 6 oral doses (q12h) were given prior to epirubicin in 3-week cycles. Histone acetylation and topo II expression were evaluated in pre-and post-VPA peripheral blood mononuclear cells and tumor samples. Results: To date, 42 patients [median age 53 (39–78)] have been treated in 12 cohorts: IV VPA loading (mg/kg)/epirubicin (mg/m2): 15/75, 30/75, 45/75, 60/75, 75/75 and 75/100, oral loading: 75/100, 90/100, 100/100, 120/100, 140/100 and 160/100. Tumor types included: breast (10), melanoma (11), lung (6), sarcoma (2), GYN (2), GI (5) and others (6). Dose-limiting toxicities included somnolence (1) and neutropenia (1). No exacerbation of epirubicin-related toxicities was observed. Objective responses were seen across different tumor types in anthracycline-resistant and -refractory tumors, despite a median number of 3 (0–6) prior regimens: Partial response; 7/37 (19%), stable disease/minor response: 16/37 (43%). Patients received a median number of 4 (1–10) treatment cycles. Study treatment was stopped despite a clinical benefit or response in 4/33 patients after reaching maximal epirubicin doses (≤750 mg/m2). VPA peak and trough plasma concentrations increased linearly up to 120 mg/m2. MTD is being defined at 160/100 mg/kg/d VPA. H3 and H4 histone acetylation and topo II expression have been correlated with VPA dose, plasma concentration and response. Conclusion: A sequence-specific combination of VPA and epirubicin is active without exacerbation of epirubicin toxicity. VPA plasma peak and trough levels exceeding concentrations needed for biological effects and in vitro synergy are easily achievable with minimal toxicity. The noteworthy anti-tumor activity seen in this heavily pretreated Phase I population warrants further exploration. [Table: see text]
An open label phase I study of ABR-217620, a fusion protein of the 5T4 antibody moiety and an engineered superantigen, in patients with non-small cell lung, renal cell or pancreatic cancer
Authors: Cohen R. B. , Langer C. J. , Alpaugh R. K. , Dueland S. , Aamdal S. , Hawkins R. E. , Griffiths R. W. , Hedlund G. , Forsberg G. , Kilany S. 
Published: March 2020

3083 Background: ABR-217620 (naptumomab estafenatox) is a recombinant fusion protein that consists of the 5T4Fab moiety genetically fused to the engineered superantigen variant SEA/E-120. This fusion protein is a new generation tumor-targeted superantigen based on the previously described ABR-214936 (anatumomab mafenatox). ABR-217620 was designed to reduce antigenicity and toxicity. The 5T4 antigen is expressed on more than 95 % of tumors from patients with non-small cell lung (NSCLC), renal cell (RCC) and pancreatic cancer (PC). In clinical PET studies 124I-labeled ABR-217620 has been shown to localize to 5T4 positive tumors. Methods: The compound was administered as a 5 min bolus infusion for 5 consecutive days. Patients with disease control at day 28 were offered a second cycle of therapy. Dose escalation has been performed using a Bayesian model starting at 0.5 μg/kg/day. The primary endpoint is determination of MTD. Secondary endpoints include characterization of side effects, immunological response, efficacy and pharmacokinetics. Results: 31 patients to date have been treated (19 NSCLC, 8 RCC, 4 PC). 3 patients have had dose limiting toxicities (fever, hypotension and nausea, grade 3) at doses between 23 and 28 μg/kg/day. The side effects were resolved quickly. Based on the experience from ABR-214936, these side effects were expected, but the MTD is ∼ 200 times higher. ABR-217620 leads to a dose dependent systemic increase of cytokines including IL-2 and IFN-γ after infusion. It also leads to an expansion of the superantigen reactive T cell population. 16/29 evaluable patients investigated had SD while 13 patients had PD. In contrast to ABR-214936, the first cycle of ABR-217620 treatment can be given without factoring in the titer of preformed anti-superantigen antibodies. Conclusions: ABR-217620 treatment had predicted and manageable side effects with fever, hypotension and nausea being dose limiting toxicities. Treatment with ABR-217620 resulted in a restricted systemic activation of the immune system. A large fraction of the patients have had stable disease. [Table: see text]
Assessment of response using FDG-PET and CT in a phase I study of AMN107 alone or in combination with imatinib (IM) in patients with imatinib-resistant (IM-R) gastrointestinal stromal tumors (GIST)
Authors: Van Den Abbeele A. D. , Barnes A. S. , De Vries D. J. , Yap J. T. , Reichardt P. , Casalli P. G. , Von Mehren M. , O’Neel J. , Hayes W. , Demetri G. D. 
Published: March 2020

3087 Background: Although IM induces durable clinical benefit in pts with metastatic GIST, resistance to this single agent may emerge over time and new approaches are needed. AMN107 is a new agent rationally designed to inhibit in a structurally different manner the tyrosine kinase activities of KIT, PDGFR, and Bcr-Abl. Since AMN107 has demonstrated the ability to inhibit the proliferation of both IM-sensitive and IM-R GIST cells in vitro, a clinical trial was begun to test this agent with rapid assessment of impact using FDG-PET. Methods: Pts with IM-R GIST were treated with AMN107 alone (400 mg p.o. bid), or a combination of IM (400 mg p.o. bid) and inter-cohort dose escalations of AMN107 (200 mg qd, 400 mg qd, and 400 mg p.o. bid). FDG-PET and CT were performed at baseline and after 1 and 4 wks on therapy. Maximum standardized uptake values (SUVmax) were measured in 11 pts in up to 5 lesions with the greatest FDG uptake/pt (n=46 lesions). For each patient, the summation SUVmax (sSUVmax) of all lesions was calculated at each time point. Percentage change in SUVmax and sSUVmax was calculated at wks 1 and 4 compared to baseline. Metabolic response was assessed using EORTC thresholds for % SUVmax change (PR≤ -25% <SD< +25%≤ PD). The longest diameters of all lesions analyzed by PET were measured on corresponding CT images, summed at each time point, and the % change was calculated at wks 1 and 4 compared to baseline. CT response was assessed using conventional RECIST thresholds. Results: At 1 wk, PET imaging of 11 evaluable pts documented metabolic PR in 3/11, SD in 7/11, and PD in 1/11. After 4 wks on therapy, 2 pts whose PET was stable after 1 wk had converted to metabolic PR, and all other imaging results were unchanged. The CT response for all 11 pts was SD after 1 and 4 wks on therapy. Conclusions: These findings suggest that a metabolic response to AMN107, or the combination of AMN107 plus IM, is seen with FDG-PET while CT anatomic response remains SD at 1 and 4 wks. [Table: see text] [Table: see text]
Phase II study of Sorafenib (BAY 43–9006) in hormone-refractory patients with prostate cancer: A study of the Central European Society for Anticancer Drug Research—EWIV (CESAR)
Authors: Steinbild S. , Mross K. , Morant D. , Köberle D. , Dittrich C. , Strumberg D. , Hochhaus A. , Hanauske A. , Burkholder I. , Scheulen M. E. 
Published: March 2020

3094 Background: Sorafenib (BAY 43–9006) is a novel, orally active multi-kinase inhibitor with anti-angiogenic and anti-proliferative activity, blocking both Raf/MEK/ERK pathway and receptor tyrosine kinases VEGFR-2 and PDGFR. Activity of sorafenib in hormone-refractory progressive patients (pts) with prostate cancer (PC) was investigated in a Phase II clinical study. Methods: Pts received sorafenib 400 mg bid by continuous oral dosing. Pts with progressive disease during hormonal treatment and no prior chemotherapy therapy for advanced prostate cancer, and either one uni-dimensional measurable lesion according to RECIST-criteria or increasing PSA values reflecting a hormone-refractory situation, were eligible for study entry. Tumor PSA-based response was defined as: increase of PSA from baseline or lowest measured value by 100% = progressive disease (PD); decrease of PSA by >50% in two consecutive measurements = responder; PSA levels in between the two definitions above = stable disease (SD). Primary study objective was the proportion of patients with time to progression of ≥12 weeks (PP-TTP-12) using target lesions and PSA based response evaluation. At least 45 evaluable pts were required to detect an increase in PP-TTP-12 from 20 to 40% in a one stage design. Secondary endpoints were overall response and survival, and toxicity according to Common Toxicity Criteria (CTC v3.0). Results: A total of 55 pts with PC were enrolled between October 2004 and June 2005. The majority of pts (40/55, 72.7%) were treated for at least 6 weeks. Among the 42 pts evaluable for PP-TTP-12, 2 pts (4.8%) had a response and 15 pts (35.7 %) showed SD ≥12 weeks and 25 pts (59.5 %) showed PD. The one-sided binomial test of the null-hypthesis of PP-TTP-12 = 20% can be rejected at a significance level of 5% (p= 0.0019). All 55 pts were included in the evaluation of adverse events. Drug-related serious adverse events (diarrhea (1), constipation (1), fatigue (1), skin (1) cardiac (2) were seen in six patients. Conclusions: These results of a PSA-based evaluation indicate that sorafenib has some clinically useful activity in PC. Further investigations are necessary to evaluate the clinical benefit. Final results will be presented. No significant financial relationships to disclose.
Direct cost-survival analysis of therapies for metastatic colorectal cancer
Authors: Wong Y. , Meropol N. J. , Sargent D. , Goldberg R. , Beck J. R. 
Published: March 2020

3515 Background: Patients with metastatic colorectal cancer (mCRC) treated with 5Fluorouracil plus leucovorin (5FU/LV) have a median life expectancy (LE) of approximately12 months. The addition of irinotecan, oxaliplatin, bevacizumab and cetuximab has increased LE significantly. Although they have been widely adopted, little is known about the financial impact of these new drugs. Methods: Using published reports and aggregate data from NCCTG 9741, we developed a Markov Model which assumes forward progression through up to three lines of therapy compared to 5FU/LV alone. Patients who do not die of toxicity (tox) transition through supportive care prior to death. State changes are based on progression and dose-limiting toxicity. Drug costs are based on Average Sales Price. No other direct or indirect costs are included. Dose modifications for toxicity are defined as 80% of standard doses. Sensitivity analyses (SA) were performed on key variables. Results: LE, total drug costs, and cost-effectiveness (CE) ratios compared to single line-5FU/LV and FOLFOX for 9 commonly used treatement sequences are presented below. SA show that results are sensitive to progression rates,drug costs and length of time on supportive care. Changes in 1st line tox rates have a greater impact on final results than changes in 2nd or 3rd line therapy tox rates. Conclusions: Using drug costs alone, this model shows sequential combination therapy including all available agents to cost $2000-$2800K/week life gained ($100-$145K/year) compared to both 5FU/LV and FOLFOX. For clarity only 9 strategies are presented, but the model presented will contain multiple sequences consisting of 1–3 lines of therapy. Refined tox data, associated costs and quality of life adjustments are needed for realistic comparisons among specific combinations. Combination therapy may have CE ratios similar to other currently accepted intensive medical interventions. These data can help inform discussions of how the cost of care impacts patients, providers, and societies. [Table: see text] [Table: see text]
Preliminary safety of bevacizumab with first-line Folfox, Capox, Folfiri and capecitabine for mCRC—First B.E.A.Trial
Authors: Berry S. R. , Cunningham D. , Michael M. , Dibartolomeo M. , Rivera F. , Kretzschmar A. , Mazier M. , Lutiger B. , Vancutsem E. 
Published: March 2020

3534 Background: In a phase III pivotal trial in patients (pts) with metastatic colorectal cancer (mCRC), bevacizumab (BEV) increased overall survival by 30% when added to first-line IFL chemotherapy (CT). Safety data from controlled BEV trials have been described, and indicate that certain serious adverse events (SAE), primarily gastrointestinal (GI) perforations and arterial thromboembolic events (TE) occurred more often in pts who received CT with BEV than those who received CT alone. First BEAT was opened to evaluate safety events of BEV in a broader pt population using a variety of CT regimens. Methods: First BEAT started in June 2004 and aims to enrol up to 2000 mCRC pts in 41 countries. Eligible pts starting with first-line CT (physician’s choice) are treated until progression with BEV (5mg/kg q2w [5FU based CT] or 7.5mg/kg q3w [capecitabine based CT]). SAEs include deaths, new and prolonged hospitalizations, life-threatening as well as medically significant events and are reported within 24 hours. There BEV-relatedness is assessed by investigators. Results: By Dec 20, 2005, 1915 pts had been enrolled in 40 countries. 1603/1915 pts (male 58%; median age 59 years [29% were > 65 years]; PS 0–1 99%) had baseline data available for analyses. Median follow-up was 6.7 months (mean 7.3); 1509 pts had been followed-up for >60 days. The most common first-line CT regimens used with BEV were FOLFOX (28%), CAPOX (17%), FOLFIRI (25%) and capecitabine (8%). Among the 1603 pts that had started treatment with BEV, 638 SAEs were reported in 394 pts (25%). 60-day mortality was 2.4%. The most common SAE were diarrhoea 2.7% and pyrexia 2.2% and were usually not attributed as related to BEV. Related SAEs were reported in 132 (8%) pts. venous TE 1.7%, pulmonary embolism 1.1%, bleeding 1.0%, GI perforation 0.9%, arterial TE 0.8%, hypertension 0.5% wound healing complications 0.3% were usually classified as related SAEs. Conclusions: In this ongoing, large community-based study, the safety profile of BEV in first line mCRC pts receiving a variety of CT regimens, namely FOLFOX, CAPOX, FOLFIRI and capecitabine, appears consistent with that observed in large phase III randomised studies. Updated safety data, including grade 3/4 CTC toxicities, will be presented. [Table: see text]
Bevacizumab improves outcomes of patients with metastatic colorectal cancer (mCRC) treated with IFL with or without bevacizumab (BV) independent of baseline risk
Authors: Kabbinavar F. , Zurlo A. , Irl C. , Hurwitz H. 
Published: March 2020

3539 Background: It has been reported that patients with mCRC obtain benefit from BV independent of baseline risk factor status. Analysis of 3,825 patients treated with 5-FU/LV in 19 randomised trials conducted by Koehne et al. [Ann Oncol 2002;13:308–17] showed that four baseline prognostic variables can be used to categorise patients into three prognostic groups with different overall survival (OS). We have retrospectively applied this model to data from a phase III trial of first-line IFL with placebo or BV (AVF2107g). Methods: Data on ECOG performance status (PS), tumour site, alkaline phosphatase (AP) levels and white blood cell counts (WBC) were prospectively collected for the 813 patients randomised in AVF2107g. These data were retrospectively used to categorise patients in the IFL/placebo (n=411) and IFL/BV (n=401; data not available for 1 patient) arms into three risk groups: Low - ECOG PS 0/1, one tumour site; intermediate - ECOG PS 0/1, >1 tumour site, AP level <300U/L, or ECOG PS >1, low WBC count, one tumour site; high - ECOG PS 0/1, >1 tumour site, AP level >300U/L, or ECOG PS >1, high WBC count, >1 tumour site. Median OS and PFS in these groups were calculated. Results: OS (Table) and PFS were significantly longer in the IFL/BV groups compared to the IFL/placebo groups, as well as in the lower compared to the higher risk groups in both arms. Conclusions: The analysis supports previous analyses showing that adding BV to IFL improves OS independent of baseline patient risk. Furthermore, high-risk patients, who are less likely to benefit from IFL, benefit from IFL/BV. The model developed by Koehne et al may be applicable to regimens other than 5-FU/LV and validates the efficacy of BV first line in mCRC. [Table: see text] [Table: see text]
Phase II study of FOLFOX, bevacizumab and erlotinib as initial therapy for patients with metastatic colorectal cancer (MCRC)
Authors: Meyerhardt J. A. , Stuart K. , Zhu A. , Fuchs C. , Bhargava P. , Earle C. , Blaszkowsky L. , Lawrence C. , Battu S. , Ryan D. P. 
Published: March 2020

3545 Background: Cytotoxic chemotherapy with targeted therapy against the vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) has become a standard approach in MCRC, though combining VEGF and EGFR inhibition with chemotherapy as initial treatment is not well established. We conducted a phase II study of the combination of infusional 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX), bevacizumab, and erlotinib in chemotherapy naïve patients with MCRC. Methods: Eligible patients had measurable MCRC, no prior systemic therapy for MCRC or at least one year since completion of adjuvant therapy (only 5-FU and leucovorin acceptable), performance status 0–1. The regimen consisted of 14-day cycles of FOLFOX started on day 1 (oxaliplatin 85 mg/m2, bolus 5-FU 400 mg/m2, leucovorin 400 mg/m2 and 46-hour infusion 5-FU 2.4 g/m2), day 1 bevacizumab 5 mg/kg and erlotinib 150 mg daily. This isa single stage trial with goal of 35 patients. The primary endpoint was progression-free survival (PFS). Results: Between Jan and Dec 2005, 31 patients have been enrolled with the following characteristics: male/female, 19/12; PS ECOG 0/1, 15/16; median age 58, range 38–81. Of the 28 patients who completed at least 1 cycle, the most common grade 3/4 adverse events include: 8/28 (29%) diarrhea, 8/28 (29%) neutropenia, 5/28 (18%) rash, 4/28 (14%) fatigue, 3/28 (11%) nausea/vomiting, 3/28 (11%) neuropathy. 22/28 (78%) of patients had at least 1 grade 3/4 toxicity. 14/31 patients remain on trial, 13/31 (42%) came off for toxicity or withdrew consent due to treatment-related toxicities, 4 withdrew consent for other reasons. Efficacy data is not available at time of submission but will be more mature by June 2006. Conclusions: The combination of FOLFOX, bevacizumab and erlotinib appears to have moderate toxicity, with ∼40% of patients coming off trial due to side effects. Further characterization of the tolerability profile will be necessary when interpreting the efficacy of the combination. We expect full accrual as well as reasonable point estimates of PFS by June 2006. Supported by: Sanofi-Synthelabo, a member of the Sanofi-Aventis group, Genentech [Table: see text]