bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial)
Authors: Gallo-Stampino C. , Rizzardi G. , Toma S. , Corti A. , Scifo P. , Citterio G. , Gregorc V. , Del Maschio A. , Caligaris-Capio F. , Bordignon C. 
Published: March 2020

3540 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007. [Table: see text]
A phase I dose-escalation and pharmacokinetic (PK) study of sunitinib (SU) plus docetaxel (D) in patients (pts) with advanced solid tumors (STs)
Authors: Robert F. , Sandler A. , Schiller J. H. , Ilagan J. , VerMeulen W. , Harper K. , Liu G. , Tye L. , Chao R. , Traynor A. 
Published: March 2020

3543 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. In mouse xenograft models of breast cancer, SU enhanced the antitumor activity of D. This study was designed to assess the safety/maximum tolerated doses (MTDs), PK profile and preliminary efficacy of SU+D in pts with advanced STs. Methods: This is a phase I, dose-finding study in pts with advanced STs. The primary objective is to determine the MTD and safety of SU and D administered in combination. Successive cohorts of pts with advanced STs were to receive oral SU at 25, 37.5 or 50 mg daily for 4 wks of a 6-wk cycle (4/2 schedule) or for 2 wks of a 3-wk cycle (2/1 schedule) in combination with IV D at 60 or 75 mg/m2 every 21 days (q21d). The MTD was defined as the highest dose at which 0 of 3 or 1 of 6 pts encountered dose-limiting toxicities (DLTs) during cycle 1. Antitumor activity was assessed by CT or MRI scan. Results: 37 pts (most common primary tumor types: mRCC [n=10], NSCLC [n=13]) have been enrolled as of Nov. 2006: 10 pts on the 4/2 schedule and 27 pts on the 2/1 schedule (see table ). The most commonly observed DLT was neutropenia (with or without fever; maximum grade 4), which occurred in 5 pts and was manageable/reversible. There was 1 grade 5 event on the 2/1 schedule (C1D3), of pulseless electrical activity and pulmonary hemorrhage. The MTDs on the 4/2 schedule were SU 25 mg and D 60 mg/m2. The MTDs on the 2/1 schedule were SU 37.5 mg and D 75 mg/m2; PK analysis at this dose level is ongoing. Stable disease has been observed in 5 of 9 evaluable pts (56%) on the 4/2 schedule and 20 of 25 evaluable pts (80%) on the 2/1 schedule at the MTD. Conclusions: The combination of oral SU 37.5 mg/day on the 2/1 schedule with D 75 mg/m2 IV q21d has a manageable safety profile in pts with advanced STs. PK and preliminary efficacy analyses are ongoing to support these dosing combinations for further study. [Table: see text] No significant financial relationships to disclose.
Dyamic contrast enhanced MRI (DCE-MRI) pharmacodynamic (PD) study of sorafenib in metastatic renal cell carcinoma (RCC): Results of a randomized, phase II trial
Authors: hahn O. M. , Yeng C. , Medved M. , Karczmar G. , Kistner E. , Manchen B. , Mitchell M. , Karrison T. , Ratain M. , Stadler W. M. 
Published: March 2020

3545 Background: SOR is an antiangiogenic drug for metastatic RCC. We conducted a randomized, dose ranging trial to investigate if DCE-MRI is a PD marker for SOR. Methods: Patients (pts) were randomized to placebo, 200 or 400 mg bid SOR. DCE-MRI was performed at baseline and after 4 weeks (wks) of therapy at which time placebo pts were rerandomized to 200 or 400 mg bid of SOR. RECIST based response was determined by CT every 12 wks. DCE-MRI parameters, area under the contrast concentration vs. time curve for 90 seconds after contrast injection (IAUC90) and Ktrans, were calculated for a tumor region-of-interest selected in a blinded manner. Ktrans was calculated with the Tofts model using a tumor local arterial input function from a multiple reference tissue method. Blood pressure (BP) was obtained from clinic charts. Primary endpoint: change in Ktrans or IAUC90 over 4 wks with a planned 66 pts to detect 20% and 40% decrease in 200, 400 mg groups. Results: Due to SOR approval 57 pts were enrolled, 48 with two MRIs (5 early progression, 3 withdrew, 1 toxicity); 44 are evaluable for study endpoints. Analyses were conducted with log ratio of IAUC90 and Ktrans at 4 wks relative to baseline. Mean IAUC90 log ratio (± SD) in the placebo, 200 and 400 mg cohorts were 0.041 (± 0.197), -0.040 (± 0.132), -0.356 (± 0.411) respectively (p = 0.0003 for linear trend), corresponding to changes of +4%, -4% and -30%. Ktrans log ratios were 0.131 (± 0.315), -0.148 (± 0.382), -0.271 (± 0.499) respectively (p = 0.0077 for trend) corresponding to changes of +14%, -14% and -24%. In 27 pts with plasma SOR levels, change in IAUC90 and Ktrans did not correlate with steady state levels on day 28. Using a Cox proportional hazards model, IAUC90 and Ktrans change are not predictors of progression-free survival (median f/u 24 wks). The mean BP increased with SOR dose (0.8 ± 8.0, 8.3 ± 10.4, and 10.5 ± 11.1 for the placebo, 200, and 400 mg doses) but no correlation with IAUC90 or Ktrans change was seen. Conclusions: DCE-MRI parameters IAUC90 and Ktrans have high variability and are PD markers for SOR, but the magnitude of effect in this prospective blinded study is less than previously reported. With this small study, no correlations with PK or clinical outcome are detectable. No significant financial relationships to disclose.
Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor: Preliminary results from a phase 1 study in patients with advanced malignant solid tumors
Authors: Messersmith W. A. , Krishnamurthi S. , Hewes B. A. , Zacharchuk C. M. , Abbas R. , Martins P. , Dowling E. , Volkert A. , Martin E. , Daud A. I. 
Published: March 2020

3552 Background: Bosutinib (SKI-606) is a potent, low molecular weight, orally active, competitive inhibitor of both Src and Abl tyrosine kinases. Elevations of Src kinase activity occur in a variety of human tumor types and are correlated with aggressiveness. We conducted a phase 1 study in patients (pts) with advanced solid tumors to assess tolerability, safety, pharmacokinetics (PK), and preliminary antitumor activity of bosutinib. Methods: Patients in cohorts of 3–6 received 50, 100, 200, 300, 400, 500 or 600 mg bosutinib orally on study day 1 and then once daily beginning on day 3. Timed blood samples were collected on days 1–3, 15 and 16 for PK analysis. Tumor assessments (modified RECIST criteria) were made at baseline and the end of every third cycle (21 days/cycle). Collection of tissue samples for analysis of Src biomarkers was optional. Results: Preliminary data are presented for 51 pts (median 57 years, 57% women). Three pts who received 600 mg bosutinib/day had drug-related dose-limiting toxicity of grade 3 diarrhea (2 pts) and grade 3 rash (1 pt). Gastrointestinal (GI) toxicity was reported among 6 pts in the 500-mg maximum tolerated dose (MTD) lead-in cohort so that 400 mg was selected as the MTD. Drug-related adverse events (AEs), any grade, occurring in =25% of pts were nausea (67%), diarrhea (55%), anorexia (45%), vomiting (43%), asthenia (41%). The only grade 3 drug-related AE occurring in =5% of pts was diarrhea (14%). After oral administration, bosutinib exposure increased in a dose-dependent manner. Multiple-dose exposure was nearly 2- to 3-fold higher than single-dose exposure. Mean elimination half-life was approximately 17 to 21 hours, supporting a once-daily dosing regimen. Six pts had stable disease >15 weeks (2 pts each with breast, colorectal cancer, non-small cell lung cancer [NSCLC]) and 1 pt had stable disease >52 weeks (pancreatic cancer). Conclusions: Bosutinib was generally well tolerated with predominantly gastrointestinal AEs. Accrual and evaluation of an expanded cohort restricted to patients with colorectal, pancreatic, and NSCLC tumors is ongoing. The patient with pancreatic cancer has had stable disease >52 weeks. No significant financial relationships to disclose.
Phase I trial of daily lenalidomide and docetaxel given every three weeks in patients with advanced solid tumors
Authors: Sanborn S. L. , Cooney M. , Gibbons J. , Brell J. , Savvides P. , Krishnamurthi S. , Bokar J. , Horvath N. , Ness A. , Remick S. 
Published: March 2020

3570 Background: Lenalidomide is a potent anti-angiogenic and immune modulating agent. This phase I trial of docetaxel and lenalidomide was undertaken to evaluate the maximal tolerated dose (MTD), dose-limiting toxicity (DLT), and secondarily, any tumor response for this novel combination. Methods: Patients with advanced solid tumors with adequate organ function were eligible. Lenalidomide was given orally days 1–14, and docetaxel was administered intravenously on day 1 of each 21-day cycle. DLT was defined as grade 3 or higher non-hematologic toxicity, grade 4 neutropenia with fever, and grade 4 anemia or thrombocytopenia. Results: Nineteen patients, 14 male and 5 female, with tumor types including prostate (7), sarcoma (3), head and neck (2), pancreatic, colon, melanoma, adenocarcinoma of unknown primary, gastric, bladder, and GIST have been enrolled. ECOG performance status was zero (10 patients) or one (9 patients). The median age was 59 years (range 35 to 86). Fourteen patients had zero or one prior treatment regimens (range 0 to 6). A total of 64 cycles have been administered (range 1 to 12). In the first nine evaluable patients, eight (89%) had grade 3 or 4 neutropenia. Docetaxel 75 mg/m2 given every 3 weeks with lenalidomide 5 mg on days 1–14 exceeded the MTD due to one grade 3 nausea/vomiting and one grade 4 neutropenia with fever. After the addition of pegfilgrastim on day 2, there has not been any neutropenia in the subsequent seven evaluable patients. Other grade 3 and 4 toxicities included leukopenia (31%), lymphopenia (19%), as well as nausea, vomiting, fatigue, anemia, infection, hyponatremia, and hypokalemia (6% each). Seven patients (44%) have had stable disease (range 3 to 12 cycles). One prostate cancer patient experienced a >95% reduction of PSA. Enrollment is ongoing and the current dose level is docetaxel 75 mg/m2, lenalidomide 10 mg days 1–14, and pegfilgrastim on day 2. Conclusions: The toxicity evaluation is ongoing. This trial will provide the MTD of docetaxel 75 mg/m2 given every 3 weeks with lenalidomide on days 1–14 in combination with pegfilgrastim support to avoid neutropenia. No significant financial relationships to disclose.
Identification of predictive and surrogate molecular markers for dasatinib in prostate cancer: Rationale for patient selection and efficacy monitoring
Authors: Wang X. , Reeves K. , Luo R. , Wu S. , Xu L. , Ayers M. , Lee F. , Clark E. , Huang F. 
Published: March 2020

3579 Background: Dasatinib is a potent, multi-targeted kinase inhibitor that was recently approved for treatment of chronic myelogenous leukemia resistant to imatinib. To aid its clinical development in prostate cancer, we used a panel of prostate cancer cell lines to identify molecular markers that could be used to predict sensitivity to dasatinib and to monitor its activity. Methods: Baseline gene expression profiles of 16 cell lines were used to identify predictive biomarkers based on the correlation of gene expression with in vitro sensitivity of cells to dasatinib. Selected cell lines were treated with dasatinib to identify surrogate biomarkers based upon changes in gene expression following dasatinib treatment. Results: We identified 174 genes whose baseline expression levels were highly correlated with sensitivity or resistance to dasatinib. These include cell lineage markers cytokeratin 5 (CK5), androgen receptor (AR), and prostate specific antigen (PSA). Our results indicate that “basal type” cell lines (those with high expression of CK5 and low expression of AR and PSA) are sensitive to dasatinib. Dasatinib treatment studies further identified genes whose expression levels were significantly modulated by the drug. Ten genes, including urokinase-type plasminogen activator (uPA), were not only significantly correlated with sensitivity to dasatinib but also reduced in their expression upon drug treatment. In addition, the down-regulation of uPA was specific to dasatinib and the effect was not seen in taxol-treated cells. The extent of down-regulation was correlated with the sensitivity of cell lines to dasatinib. EphA2, a specific kinase target of dasatinib, was identified as a biomarker common to prostate and breast cancers. Finally, the expression of 5 genes including CK5, AR, PSA, uPA and EphA2 in prostate tumors was examined and the dasatinib sensitivity signature was validated using a published data set derived from a clinical population. Conclusions: Candidate markers correlated with dasatinib sensitivity were identified. A five-gene model consisting of predictive markers as well as potential surrogate markers has been formulated and will be evaluated in ongoing dasatinib prostate cancer trials. No significant financial relationships to disclose.
Treatment of metastatic colorectal cancer with aimpila, a glycoside/alpha-fetoprotein complex
Authors: Pak V. , Molchanov O. , Vincent M. 
Published: March 2020

3589 Background: Aimpila is a non-covalent complex of two natural compounds: porcine alpha-fetoprotein (PAFP) and a glycosidic apoptosis inducer (AI). PAFP is able to bind selectively to the AFP receptor-positive cancer cells and deliver the AI intracellularly due to AFP receptor-mediated endocytosis. The AI opens mitochondrial permeability transition pores, resulting in apoptosis. Preclinically, the complex is cytotoxic. We investigated the single agent activity of aimpila in patients (pts) with liver metastatic colorectal cancer (mCRC). Methods: Eligibility Criteria: Age >18 yrs, mCRC, any prior treatment, having documented progressive metastatic liver disease. Treatment consisted of oral capsules at a fixed sub-maximal dose (0.3 mg of active substance in an oral capsule, twice a day for 8 weeks). 12 pts were accrued, 6 chemonaïve; median ECOG performance status was 0, median age 56 years (range 45–65), and median time from previous treatment failure was 9.0 months (range 1–20). CT scans were performed before and after. Results: Of the 12 patients, 9 are evaluable for response by RECIST. Two achieved a complete response (CR), 1 a partial response (PR); subsequent confirmatory CT scans are pending. Three achieved stabilization (SD), in 2 cases = 2 months; 3 experienced disease progression. Of 3 non-evaluable pts, 1 experienced clinical deterioration without a CT scan, 1 experienced stable disease >2 months but with both lesions <10 mm in diameter, and a third developed nausea and vomiting leading to interruption of treatment, the only recorded significant adverse event. CEA estimations before and after treatment are available from 2 pts; 1 pt (radiological CR) going from 816 ng/ml to 268 ng/ml; the other (radiological SD) going from 1,243 ng/ml to 638 ng/ml. In this latter patient, one of the liver lesions disappeared, radiologically. The PR pt and 1 of the SD pts had progressed after previous oxaliplatin-based chemotherapy. Median survival has not yet been reached, with a median follow-up of 4 months. Conclusion: Single agent aimpila was well-tolerated in this patient population and produced major objective responses in some patients with liver mCRC. Further study is warranted. [Table: see text]
A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies
Authors: Chia S. K. , Chi K. N. , Kollmannsberger C. , Paton K. , Bhagat K. , D’Aloisio S. , Das-Gupta A. , Kletzl H. , Zwanziger E. , Gelmon K. 
Published: March 2020

3594 Background: Erlotinib is a potent oral TKI of the epidermal growth factor receptor (EGFR). At the current recommended daily dose of 150 mg/day there is activity in advanced stage NSCLC, but with frequent grade 1/2 rash and diarrhea. We performed a phase I dose escalation study of erlotinib with a once and twice weekly schedule to assess the PKs, PDs, and to determine if toxicities would be less on an intermittent but high dose schedule. Methods: A standard dose escalation schedule starting at 1,400 mg once/week and 600 mg twice/week with increments of 200 mg to 4 dose cohorts/schedule was utilized with three patients per cohort. A cycle consisted of 3 weeks of therapy. PKs were performed on cycle 1 and 2. PDs on normal skin punch biopsies were performed at baseline and after cycle 1. Tumour evaluation was done following every 2nd cycle. Subjects were treated until progression or unacceptable toxicity. Results: 32 patients were enrolled from Oct 2004-April 2006. Median age 58 years (28–74 years); median PS 1 (0–2); and median prior palliative systemic regimens 2 (0–6). In the once weekly schedule the maximum tolerated dose (MTD) was not reached with the top dose of 2,000 mg/week. A median of 2 cycles were delivered (1–14), with 3/13 patients achieving stable disease = 3 months. 4/13 patients had G1 rash and 6/13 patients G1 diarrhea during the first 2 cycles. In the twice weekly schedule the MTD was reached at 1,200 mg twice/week with 2/6 subjects experiencing G3 rash. The recommended dose level is 1,000 mg twice/week. A median of 4 cycles were delivered (1–28) with 2 partial responses, 1 minor response and 6 stable disease = 3 months out of 19 patients in total. G1/2 rash or diarrhea occurred in 13 and 9 patients respectively. No corneal toxicity was seen. The PK data demonstrated a variable but linear pattern. At 1,000 mg twice/week the median Cmax, Tmax and AUC0–24 hr was 6.28 μg/ml, 2 hours and 135 μg.h/ml respectively. PD analysis is ongoing. Conclusions: A once weekly and twice weekly high dose schedule of erlotinib is feasible, with MTD not reached in the once weekly schedule. A recommended dose of 1,000 mg twice/week has clinical activity, is generally well tolerated, and results in significantly higher systemic exposure than the 150 mg once daily dose. No significant financial relationships to disclose.
Preliminary results of a phase I clinical trial of CYT-6091: A pegylated colloidal gold-TNF nanomedicine
Authors: Libutti S. K. , Paciotti G. F. , Myer L. , Haynes R. , Gannon W. E. , Eugeni M. , Seidel G. , Shutack Y. , Yuldasheva N. , Tamarkin L. 
Published: March 2020

3603 Background: CYT-6091, a nanotherapeutic manufactured by covalently linking tumor necrosis factor-a (TNF) onto the surface of 30 nm particles of pegylated colloidal gold, avoids uptake by the reticuloendothelial system (RES) and distributes primarily to solid tumors. In tumor bearing mice, CYT-6091 shows little to no uptake by the RES and increases intra-tumor TNF levels 10-fold. Electron micrographs show the accumulation of gold nanoparticles in tumors, with few particles in healthy tissue. In dogs with naturally occurring cancers and healthy rabbits, CYT-6091 caused fever but no hypotension, the known DLT for TNF. Methods: CYT-6091 is being tested in a phase I open label trial in solid tumor, advanced stage disease patients. Patients (n=3/dose), admitted to the NIH Clinical Center ICU, receive two IV injections of CYT-6091 on day 0 and 14. Doses start at 50 μg/m2 of TNF and increase by 50 μg/m2 increments to 300 μg/m2. Vital signs are monitored and blood samples are drawn over 48 hours. The primary endpoint of the study is to determine the MTD for CYT-6091. Secondary endpoints include PK, disease response (staged 45 days post treatment), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Seven patients have been treated to date. The three treated with the lowest dose (50 μg/m2) exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the seven patients treated with 50, 100 or 150 μg/m2 showed a DLT hypotensive response, and blood chemistries and urinalysis were not significantly different following treatment. PK estimates for the TNF T1/2, administered as CYT-6091, are 117, 145 and 127 minutes for 50, 100 and 150 μg/m2, respectively. Electron micrographs of tumor biopsies and adjacent healthy tissue show as much as a 10-fold increase in the number of gold nanoparticles in tumors from 5 of 6 patients compared to adjacent healthy tissue. Conclusion: These observations are the first definitive demonstration in man of the tumor targeting of a systemically administered, colloidal gold-based nanomedicine. No significant financial relationships to disclose.