bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of E7389/gemcitabine combination in patients with advanced solid tumors
Authors: Goel R. , Chen E. , Welch S. , Laurie S. , Siu L. , Jonker D. , Srinivasan R. , Wang L. , Ivy P. , Oza A. 
Published: August 2020

e13509 Background: E7389 (E) is a synthetic analogue of halichondrin B, an investigational tubulin-based antimitotic drug. Gemcitabine (G) is a nucleoside analogue clinically active in several human tumours. These two drugs exhibit synergistic cytotoxic effects against the H522 non-small cell lung cancer (NSCLC) xenografts. Methods: A phase I study of these two drugs in combination was initiated in patients with advanced solid tumours. Two prior chemotherapy regimens for metastatic disease were allowed. Results: Patient characteristics: male 11/female 10; median age 59 (range 28–84); performance status 0 /1/2: n=1/13/7; prior chemotherapy 21, prior radiotherapy 7, prior immunotherapy 1; tumour types: ovarian cancer 3, endometrial cancer 3, NSCLC 3, gastric/esophageal adenocarcinoma 3, miscellaneous 9. Total number of cycles given 52, median cycles/patient (range) 2 (1, 8). Cohort (CT) 1: E/G given days 1,8,15 q28 days. Due to DLT, regimen changed in CT 2 with E/G given days 1, 8 q21 days. Cycles (C) given: median 2 range 1–8, total 52. Response: partial response 1 (ovarian cancer), stable 8 [minor response 4 (NSCLC 2, endometrial cancer 1, head and neck cancer 1)], progression 8, inevaluable 4. Conclusions: Further phase II investigation of this regimen should be considered at a dose of E 1.0 g/m2/G 1000 mg/m2 q 3 weeks. [Table: see text] No significant financial relationships to disclose.
A phase Ib dose-escalation study of orally administered MP-470, a multi-kinase inhibitor and supressor of Rad51, in combination with carboplatin doublet containing regimens shows activity in highly refractory solid tumor patients
Authors: Mita M. M. , Tolcher A. , Gordon M. S. , Rosen L. , Mita A. , Fine G. , Choy G. , Berk G. 
Published: August 2020

e13511 Background: MP-470 (MP) is an oral multi-targeted tyrosine kinase inhibitor which inhibits a number of validated tumor targets including c-kit, flt3, and PDGFα. MP470 targets cancer cells by disrupting DNA repair, an important survival pathway in many human cancers. Results presented herein are from two arms of a phase-Ib five arm trial of MP combined with standard of care (SOC) anti- cancer therapies. Methods: MP is administered in combination with SOC in a 21-day cycle. Adults with ECOG PS of 0–2 and malignant disease appropriate for SOC regimens consisting of paclitaxel/carboplatin (PC), carboplatin/etoposide (CE), topotecan, docetaxel, and erlotinib were enrolled. Each arm follows a 3+3 design where MP is escalated based on the modified Fibonacci sequence until the MTD of MP in combination with SOC agents is reached. RECIST and CTCAE are utilized to assess response and safety, respectively. The primary objectives of the study are to determine the MTD, DLTs, and quantify the effects of MP on the PK of SOC agents. Results: Between Dec 2007 and Aug 2008, 26 subjects were enrolled in the PC and CE arms and received a total of 70 cycles (median 2; range, 0–8) of MP at 4 dose levels (100–500 mg/day). Median number of prior therapies was 2 (range, 0–19). Male/Female: 14/12. Median age, 56 years (range, 24–76). Subjects completing ≥ 6 and ≥ 4 cycles were 5 and 7, respectively. Six PRs (2 neuroendocrine, 2 SCLC, 1 NSCLC, 1 small cell of anal canal) and 3 SDs (≥ 4 cycles) was observed. The MTDs have not been reached and DLTs have not been identified. Adverse events occurring in ≥ 15% of patients were myelosuppression, diarrhea, constipation, nausea, reflux, fatigue, alopecia, rash, neuropathy, anorexia, hypokalemia, dyspnea, and myalgias. MP470 did not alter the kinetics of SOC agents. Dose escalation in the PC and CE arms is ongoing. Conclusions: MP470 combined with carboplatin-containing regimens may promote tumor regression and may also sensitize/resensitize tumors to the anticancer effects of such agents. An amendment will be issued to collect tumor tissue biopsy at baseline and during treatment to adequately evaluate DNA damage in tumor tissue. [Table: see text]
Phase I study of pemetrexed (P) and pegylated liposomal doxorubicin (PLD) in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer
Authors: Richards D. A. , Loesch D. , Vukelja S. J. , Wu H. H. , Hyman W. J. , Nieves J. , Wang Y. , Hu S. , Shonukan O. , Tai D. 
Published: August 2020

e13515 Background: P and PLD are clinically active as single agents and synergistic in preclinical models. This phase I, open-label trial determined the maximum tolerated dose (MTD) and safety profile of P followed by PLD in patients (pts) with breast or gynecologic cancers. Methods: Using standard phase I (3+3 dose escalation) study design, cohorts of 3–9 pts received escalating doses of P followed by PLD in 28-day cycles: P 400–500 mg/m2 on Days 1 and 15 and PLD 30–45 mg/m2 on Day 1. All pts received folic acid (350–1000 μg daily) and vitamin B12 (1000 μg) until 21 days after last dose of P. Pts continued until dose-limiting toxicity (DLT) or disease progression (PD) occurred. Results: From 11/05 to 1/08, 29 pts were registered/treated. Median age: 60.6 years (range, 47.5–80.1); ECOG performance status 0/1: 28%/72%; primary disease sites: ovarian (55%), breast (35%), peritoneal (10%); prior therapies: chemotherapy (100%), surgery (72%), hormones/biologics (35%), radiation (21%). Dosing results are shown below. At dose level (L) 2 and L3, 1 pt/cohort had DLTs; L5 was added and 3/3 pts had DLTs; 4 more pts were treated at L4 (1 pt replaced). Most frequent drug-related Grade 3–4 hematologic toxicities: neutropenia (86%), leukopenia (59%), thrombocytopenia (48%), anemia (41%). Most frequent drug-related Grade 3–4 nonhematologic toxicities: hand-foot syndrome (14%), hypokalaemia (10%). Major reasons for discontinuation: PD (48%), toxicity (28%), pt request (14%). Overall best responses (n=24): 5 pts (21%) had partial response (PR), 14 pts (58%) had stable disease (SD), 2 pts (8%) had PD, 3 pts (13%) were not evaluable. All 5 PR and 8 SD pts were ovarian; 5 SD and both PD pts were breast. Conclusions: P followed by PLD was reasonably tolerated in this heavily-pretreated population. The MTD was P 500 mg/m2 and PLD 40 mg/m2. These dose levels may be carried forward to phase II studies in more specific patient populations. [Table: see text] [Table: see text]
Phase I safety and pharmacokinetic (PK) study of sunitinib (S) in combination with ifosfamide (I) in patients (pts) with advanced solid tumors (STs)
Authors: Hamberg P. , Steeghs N. , Loos W. J. , van der Biessen D. J. , den Hollander M. A. , Tascilar M. , Verweij J. , Gelderblom H. , Sleijfer S. 
Published: August 2020

e13520 Background: S is a tyrosine kinase inhibitor (TKI) of PDGFR, VEGFR and KIT. As combinations of VEGFR-TKI with cytotoxic therapy are promising, this phase I study aimed to determine the recommended phase II dose (RP2D) of S in combination with 2 different I schedules. Methods: Pts with progressive STs, good PS, organ function, and no standard therapy available, were eligible. I (3 g/m2/day, 72h CIV (I*3), every 3 wks) was combined with continuous S. S was started at 12.5 mg/day and to be escalated in serial cohorts of 3–6 pts. RP2D was exceeded if ≥ 1/3 pts experienced dose-limiting toxicity (DLT) within the 1st cycle. After establishing the RP2D of S with I*3, feasibility of this S dose with I at 1.2 g/m2/day for 5 days CIV (I*5) every 3 wks was assessed without further scheduled dose-escalation. At RP2D, additional patients were enrolled to assess PK. Circulating endothelial cells (CECs) were measured prior to the 1st, 3rd and 6th cycle. Results: 26 pts (36–68 yrs) were accrued. 12.5 mg S was not feasible with I*3 due to neutropenia > 7 days in 2/6 pts. After protocol amendment, pegfilgrastim 6 mg (P) was given to all subsequent patients after each I-cycle. Using P, the RP2D was I*3 plus 12.5 mg S (in 1/9 pts DLT: febrile neutropenia), while I*3 plus 25 mg S was not feasible due to febrile neutropenia in 2/5 pts and hypertension & cardiac chest pain in 1/5 pts. 12.5 mg S was also feasible using I*5 as 1/6 pts had a DLT: encephalopathy. Most frequent drug related adverse events (all grades/grade 3–4) were: neutropenia (77%/62%), thrombocytopenia (73%/31%), elevated transaminases (65%/0%), renal (42%/4%), nausea (77%/0%), vomiting (58%/0%) and alopecia (62%/0%). 4/22 pts evaluable for response had PR: 1 CUP, 1 small cell carcinoma (SCC) and 2 sarcoma pts. 7 pts had SD for ≥ 3 months: 1 CUP, 1 uveal melanoma, 1 SCC, and 4 sarcoma pts. The AUC ratio of I and its metabolites in cycles I*3 without versus with S ranged from 0.72 to 1.36. No consistent change in the number of CECs during treatment was observed. Conclusions: S at 12.5 mg/day with I*3 or I*5 every 3 weeks supported by P is tolerable in pts with advanced STs. S does not affect I-PK. Antitumor activity was observed in pts with diverse tumor entities including sarcoma. No significant financial relationships to disclose.
Cancer-related TTP: Role of plasma exchange
Authors: Farhat M. H. , de Souza B. , Hanbali A. 
Published: August 2020

e13527 Background: Thrombotic thrombocytopenic purpura (TTP) is a multisystemic disease classically described by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic manifestations and renal dysfunction. It is considered a hematologic emergency for which, the treatment of choice is plasma exchange therapy. However, its diagnosis and treatment can be particularly challenging in the setting of disseminated malignancy, as the misdiagnosis of TTP in a patient with cancer-associated thrombotic microangiopathy (TMA) will lead to ineffective use of plasma exchange and delay the timely delivery of chemotherapy. Moreover, patients with disseminated malignancy respond less often to plasma exchange and have a higher mortality rate. Methods: Three patients with disseminated malignancy who presented as TTP are discussed. Two of the three patients were given plasma exchange and had fatal outcomes, while the third patient received chemotherapy as the initial therapy and survived hospitalization. The three patients had prolonged PT with normal aPTT; LDH levels (>1,000 IU/L); and presence of schistocytes in the peripheral blood smear. Results: TMA associated with disseminated malignancy remains a challenging and underdiagnosed condition with very poor prognosis. Plasma exchange has no clinical use is potentially even life-threatening especially when it delays the administration of the appropriate chemotherapy which is the ultimate treatment for the underlying malignancy that resulted in TMA. We propose that the following criteria be used for diagnostic consideration of disseminated malignancy-associated TMA: evidence of hemolysis; leukoerythroblastic picture on the peripheral blood; coagulopathy consisting of elevated d-dimer, prolonged PT with normal aPTT; extreme elevations in the LDH levels (>1,000 IU/L); and presence of schistocytes in the peripheral blood smear. Such patients should be immediately considered for a bone marrow biopsy as chemotherapy should be initiated as soon as possible. Conclusions: See Table. [Table: see text] No significant financial relationships to disclose.
Reversion of physiological drug resistance of weakly basic drugs: The discovery of a new mechanism of PEG-PCL nanoparticles
Authors: Li R. , Xie L. , Li X. , Liu Q. , Qian X. , Jiang X. , Yu L. , Ding Y. , Liu B. 
Published: August 2020

e13528 Background: A number of studies have reported the superior antitumor effect of nanoparticles loading chemotherapeutics than the free agents, yet the underlying mechanism has not attract enough attention. The extracellular pH of cancer cells is lower than that of the intracellular pH. Due to this pH gradient, weakly basic drug will protonated extracellularly and display decreased intracellular concentration. In this study, we aimed to reveal a new mechanism of PEG-PCL nanoparticles, namely the reversion of physiological drug resistance. Methods: Tetradrine (Tet), an alkaloid isolated from traditional Chinese medicine, was incorporated into the diblock copolymer methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL). In vitro cytotoxicity of free Tet and Tet-loaded nanoparticles at pH7.4 and pH6.8 was compared on four different cancer cell lines. Fluorescent particle cellular uptake study was also used. To evaluate the antitumor effect of the nanoparticles in a more complex model rather than monolayer cell culture, we used Histoculture Drug Resistance Assay (HDRA). The in vivo antitumor effect of the nanoparticles was also studied in ICR mice bearing H22 tumor with different in vivo pH values. Results: In vitro cytotoxicity study in four tumor cell lines showed that the cytotoxicity of free Tet decreased significantly (P<0.05) when the extracellular pH decreased from 7.4 to 6.8, while the cytotoxicity of Tet-loaded nanoparticles increased or didn’t change significantly. The possible mechanism may mainly be the endocytosis of nanoparticles, which was proven by fluorescent particle cellular uptake study. HDRA indicated better tissue penetration of nanoparticles over free Tet. As to in vivo study, the mice with in vivo tumor pH 6.8 and treated with Tet-loaded nanoparticles exhibited best tumor inhibit rate and mildest side effect, suggesting that the use of nanoparticles was more preferable than the manipulation of tumor pH by the use of basic water. Conclusions: Our study clearly demonstrated that the mPEG-PCL nanoparticles could overcome the drug resistance caused by low extracellular pH and enhance drug penetration in the tumor tissue, thus increasing the antitumor efficacy of weakly basic agents. No significant financial relationships to disclose.
A phase I study of brostallicin (B) combined with either bevacizumab (BV) or irinotecan (I) in patients (pts) with advanced solid malignancies
Authors: MacArthur R. B. , Singer J. , Becerra C. , Weitman S. , Von Hoff D. 
Published: August 2020

e13531 Background: B is a DNA minor groove binding (MGB) agent with single agent cytotoxic activity. B has shown synergy with BV and I. The combinations were studied using a “complete” phase I design. Methods: The primary objective was to determine the maximally tolerated dose (MTD) and dose limiting toxicities (DLT) of B+BV and B+I. For B+BV cohort 1 both drugs were infused on day 1 of a 21 day cycle. BV was dosed at 15mg/kg, B was dosed at 6 mg/m2. For cohort 2, the BV dose was unchanged, and B dose reduced to 4 mg/m2. For B+I cohort 1 both drugs were also infused on cycle day 1. I was dosed at 200 mg/m2 with B at 4 mg/m2. For cohort 2, I was reduced to 125 mg/m2 and B reduced to 2 mg/m2. Cycle 1 DLT was defined: grade 4 neutropenia lasting ≥ 5 days, grade 3 or higher febrile neutropenia, grade 4 thrombocytopenia or grade 3 or 4 thrombocytopenia with bleeding, grade 3 or higher diarrhea, nausea or vomiting despite optimal management, grade 3 or higher for all other non-hematologic toxicities. For pts receiving BV, grade 2 or higher proteinuria. Eligible pts had treatment refractory metastatic/unresectable solid tumors, acceptable performance status, and adequate hematologic parameters and organ function. Results: 19 pts were enrolled. 11 pts received B+BV and 8 received B+I. Median age was 58 years. For B+BV 5 patients were treated in cohort 1, 6 in cohort 2. For B+I, 2 patients were treated in cohort 1, 6 in cohort 2. The MTD has not been defined for either treatment combination. In the current preliminary dataset 18/19 pts (93.3%) experienced one or more adverse events (AEs). In the B+BV group, grade 4 neutropenia was reported in 2/11 patients, both in cohort 1, and grade 3 neutropenia in one additional patient, also in cohort 1. In the B+I group, grade 4 AEs included neutropenia (DLT), febrile neutropenia (DLT), severe abdominal pain, and thrombocytopenia. Of the evaluable pts, no complete or partial responses were seen. For B+BV 5/11 pts have received 4 or more cycles, and for B+I 2/8. Conclusions: The combination of B+BV and B+I show manageable toxicity in advanced solid tumors at the doses reached in cohort 2. Additional data will be provided at the time of presentation. [Table: see text]
Pulmonary toxicity in patients receiving docetaxel chemotherapy
Authors: Kefeli U. , Yumuk P. F. , Ceyhan B. , Dane F. , Eroglu B. , Cabuk D. , Basaran G. , Teomete M. , Turhal N. S. 
Published: August 2020

e13532 Background: Docetaxel is used widely as monotherapy or in combination for the treatment of various types of cancers. Although rarely observed, pulmonary toxicity can be seen with docetaxel. This side effect had been reported mostly in non-small cell lung cancer patients receiving docetaxel. We aimed to investigate the pulmonary toxicity in patients receiving docetaxel chemotherapy other than lung cancer. Methods: 34 patients were investigated prospectively to demonstrate the pulmonary toxicity of docetaxel. Pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans were applied to all patients before chemotherapy and 14 - 21 days after completion of treatment. We used a HRCT scoring system that was based on the previous studies. All HRCT images were reviewed by two different observers. Results: We have seen no pulmonary symptoms that may reflect pulmonary toxicity in 34 patients. There were statistically significant differences between pre- and post-treatment values of FEV1 (L/sec) (p<0.05), FEV1/FVC (%) (p<0.05), FEF25–75 (L/sec) (p<0.01), FEF25–75 (%) (p<0,01), DLCO (mL/mmHg/min) (p<0.001), DLCO (%) (p<0.001), DLCO/VA (DLCO/L) (p<0.05), and DLCO/VA (%) (p<0.05). Also, there was a statistically significant difference between the pre- and post-treatment HRCT scores. The differences between pre- and post- treatment values of pulmonary function tests were not correlated with the number of docetaxel cycles and cumulative dose. There was a statistical relationship between number of docetaxel cycles (r =0.468, p<0.0001), docetaxel cumulative dose (r=0,596, p<0.0001) and HRCT scores after completion of docetaxel treatment. Conclusions: Although we have shown that docetaxel treatment causes a decline in PFTs and worsens HRCT scores, the symptoms of patients were not consistent with these differences. Therefore, it should be noted that the negative effects of docetaxel on PFTs and HRCT scores should be investigated by increasing the number of patients. No significant financial relationships to disclose.
Pharmacokinetics (PK) and safety of tesetaxel, an orally administered taxane, in a study examining a range of doses including the active phase II dose
Authors: Beeram M. , Qureshi A. , Patnaik A. , Papadopoulos K. , Tolcher A. W. 
Published: August 2020

e13535 Background: Tesetaxel is an orally active taxane with potent cytotoxic activity against various cancer cell lines in vitro, including cell lines and xenografts of human tumors that over-express P-glycoprotein. Tesetaxel displays markedly lower neurotoxicity than docetaxel in preclinical models. In Phase 2 studies, 2nd-line therapy with tesetaxel (27–35 mg/m2 every 3 weeks) was associated with overall response rates of 20% and 38% in patients (pts) with gastric and breast cancer, respectively. Neutropenia was the most common serious adverse event. We are conducting a dose-ranging study to examine the PK and safety of tesetaxel at doses including and just below the previously established MTD of 27 mg/m2. Methods: Eligibility criteria include advanced solid tumors, ECOG PS ≤ 2, and adequate organ function. The starting dose is 18 mg/m2, which is being escalated in increments of 3 mg/m2 to a maximum of 27 mg/m2. Tesetaxel is given for a minimum of 2 cycles; pts with response or stable disease may receive up to 2 more cycles. Plasma is assayed at various times to determine concentrations of parent drug and metabolites. A total of 12 patients will be entered into the dose-escalation phase, with sample expansion to 12 pts at the MTD. Results: Ongoing enrollment is expected to be completed in Q1 2009. Our group's prior study of tesetaxel 18 mg/m2 and 27 to 40 mg/m2 has shown that tesetaxel displays dose-proportional absorption and has a long terminal plasma half-life (mean approximately 180 hrs). We expect to confirm these data over a narrow dose range and to examine the data for correlations between PK and the duration and severity of neutropenia. Conclusions: Tesetaxel is an orally active taxane that eliminates infusion reactions and the associated need for premedication. It may overcome inherent or clinically acquired resistance to prototype taxanes and may prove to have reduced taxane-associated peripheral neuropathy in the clinical setting. Essential to future tesetaxel studies, this study will determine whether correlations between key PK parameters and dose-limiting reactions exist. [Table: see text]
Effects of zoledronic acid (ZOL) on proliferation of nasopharyngeal carcinoma (NPC) cell lines and synergistic effects of ZOL and cisplatin on NPC cell lines
Authors: Ghimire B. R. 
Published: August 2020

e13536 Background: Recent evidence suggests that zoledronic acid (ZOL) inhibits cancer cell proliferation and exerts synergistic antitumor activity at clinically achievable concentrations and have shown the potential to become attractive agents for cancer therapy. This study is the first to report the effects of ZOL on NPC cell lines. Methods: Cell proliferations were determined by MTT assay on four NPC cell lines CNE-1, CNE-2, SUNE-1 and 5–8F. NPC cell lines were seeded in a flat-bottomed 96well plate at 10+4 in 200μl of medium per well and incubated with various concentrations of ZOL for 72 hours. IC50 values for each cell lines were obtained using the non-linear regression program CalcuSyn. IC10 values for ZOL and Cisplatin were calculated from the IC50 curve of each four cell lines. For displaying the synergistic activity concentration equivalent to IC10 of ZOL alone, Cisplatin alone and in combination were added. The entire specimen was incubated for a total of 72 hours and the absorbance was measured at a wavelength of 540nm in a multiwell spectrophotometer. Results: IC5O values (μM) of ZOL on NPC cell lines SUNE-1, CNE-1, CNE-2, 5–8F were 4.56±0.09, 11.96±0.50, 16.73±0.28, 11.01±0.64 respectively. Conclusions: The experiment establishes synergistic effects of ZOL and cisplatin in anti proliferation of NPC cell lines. Thus, ZOL in combination with other cytotoxic agents may be promising therapeutic strategies for NPC with bone metastasis. The efficacy and safety of ZOL for NPC should be verified in early phase clinical trials [Table: see text] No significant financial relationships to disclose.