bluuebunny/crossref_metadata_2025 huggingface dataset:
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.

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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.

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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

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No significant financial relationships to disclose.
Effect of IGF-1R inhibitor BMS-754807 on tumor glucose metabolism and proliferation in Sal-IGF xenografts by FDG and FLT- PET imaging
Authors: Chow P. L. , Ho C. P. , Kan D. , Attar R. M. , Graf Finckenstein F. , Carboni J. M. , Galbraith S. M. , Lee F. Y. , Gottardis M. M. , Krishnan B. S.
Published: August 2020

e14501

Background: The type 1 insulin-like growth factor receptor (IGF-1R) plays a critical role in mitogenesis and survival in a variety of human tumor cells. IGF-1R is also closely related to the insulin receptor (IR). It is becoming increasingly evident that stimulation of IR or IR/IGF-1R hybrid receptors by insulin or IGF-1/2 may contribute to cancer growth, suggesting that both IGF-1R and IR may be targets for cancer therapy. BMS-754807 (‘807) is an oral IGF-1R tyrosine kinase antagonist under development that also blocks IR activity. This study explores the feasibility of fluorodeoxyglucose (FDG) and fluorothymidine (FLT) positron emission tomography (PET) as pharmacodynamic imaging biomarkers in a xenograft model. Methods: Mice were implanted with fragments of Sal-IGF, a transgenic salivary gland tumor expressing constitutively active IGF-1R. Once tumors reached desired size, the mice were divided into 3 treatment groups (vehicle, 6.25 mg/kg ‘807, & 50 mg/kg ‘807 on days 1–4). FDG-PET scans were performed on day -2 (prior to treatment), days 1 & 2 (max/min concentrations post day 1 dose), and days 4 & 5 (max/min day 4 dose). FLT-PET scans were performed on days -2, 2 (min day 1 dose), & 5 (min day 4 dose). Results: With FDG-PET imaging, a 66% reduction (P<0.05, paired t-test) in tumor SUVmean was observed at the end of the 50 mg/kg therapy (day 4) and sustained for 24h (day 5) with a concomitant reduction of 37% in tumor burden by day 5 (P<0.05). FLT-PET studies demonstrated a 45% reduction (P<0.05) in tumor SUVmean observed 24h after the end of 50 mg/kg therapy (day 5) with a concomitant reduction of 50% in tumor burden (day 5, P<0.05). Conclusions: Correlation with tumor growth inhibition suggests feasibility of FDG- PET despite IR blockade. These results support the use of both FDG and FLT PET imaging in clinical trials with ‘807.

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Tolerability and safety of oral neratinib (HKI-272) in Japanese patients with advanced solid tumors
Authors: Ito Y. , Hatake K. , Takahashi S. , Yokoyama M. , Suenaga M. , Ota M. , Onozawa Y. , Yamazaki K. , Hironaka S. , Boku N.
Published: August 2020

e14505

Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. In non-Japanese pts, neratinib was found to have clinical activity against solid tumors and dose-limiting toxicity (DLT) of diarrhea. The maximum tolerated dose (MTD) was 320 mg daily and the recommended dose (RD) was 240 mg because of the diarrhea. In this phase 1 study, the MTD was determined and safety and preliminary efficacy were assessed in Japanese pts with advanced solid tumors. Methods: Pts (3- 6/cohort) received 80, 160, 240, or 320 mg oral neratinib. Each pt participated in only 1 dose group and received single doses of neratinib followed by 1 wk of observation; pts then received daily continuous administration at the same dose. DLTs were assessed from the first single dose to the end of 14 days of continuous treatment. Pharmacokinetics (PK) will be analysed via a noncompartmental method. Tumor measurements were made at screening and at the end of every 8 weeks (2 cycles) by RECIST. Results: Preliminary data for 21 pts as of 30 Oct 2008 are presented. Pts had a median age [range] of 61 yrs [39–78], were 62% male, and had all received ≥2 prior chemotherapy regimens. Tumor types at primary diagnosis were advanced colorectal (81%), breast (14%), and gastric (5%) cancer. Median duration of neratinib treatment [range] was 10 wks [3–29].Two patients at the 320-mg dose had DLTs of diarrhea plus anorexia. Therefore the MTD was determined to be 240 mg. Neratinib-related AEs, any grade in ≥25% of pts included diarrhea (95%), fatigue (67%), anorexia (43%), nausea (43%), abdominal pain (38%), decreased hemoglobin (38%), increased AST (33%), and rash (29%). Neratinib-related AEs, grade ≥3 in ≥1 pts were anorexia (3 pts) and diarrhea (2 pts). Two pts had partial response (PR), 8 pts had stable disease (SD) ≥8 wks, 2 had SD≥16 wks, 9 had progressive disease. The 2 pts with PR had ErbB-2+ advanced breast cancer. PK analysis is still ongoing. Conclusions: In Japanese pts, the MTD for neratinb was determined to be 240 mg and the RD will be confirmed as 240 mg. Neratinib is tolerable and demonstrates preliminary antitumor activity in pts with solid tumors.

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Sunitinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors: Updated phase I study results
Authors: Heath E. I. , Blumenschein G. R. , Cohen R. B. , LoRusso P. M. , LoConte N. , Kim S. T. , Chao R. , Wilding G.
Published: August 2020

e14509

Background: Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, and RET, approved for the treatment of advanced RCC and imatinib-resistant/intolerant GIST. Safety and antitumor activity of SU in combination with paclitaxel (P) and carboplatin (C) were evaluated. Methods: Successive pt cohorts with advanced solid tumors (STs) received oral SU at 25, 37.5, or 50 mg for 2 wks during 3-wk cycles (Schedule 2/1) or for continuous 3 wk cycles (CDD schedule) with P (175–200 mg/m2) plus C (AUC=6 mg·min/mL) on day 1 of each of 4 cycles. Dose limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the maximum tolerated dose (MTD). Response was evaluated for pts with measurable disease. Pts with clinical benefit continued on SU after 4 cycles under a continuation protocol. Results: Forty-three pts were enrolled (25 in Schedule 2/1 and 18 in CDD schedule). Median age was 58 yrs (range: 32–76), and 74% of pts had ECOG PS of 1. Tumor types included NSCLC (n=10), SCLC, esophageal, and pancreatic (n=4 of each), and other (n=21). In initial dose escalation cohorts, 4 DLTs were observed out of 23 pts (Heath et al. ASCO 2008). Based on overall tolerability, additional pts were enrolled on both schedules at SU 37.5 mg with P 175 mg/m2 plus C. In these expanded cohorts, 2 more DLTs were observed in Schedule 2/1 (Gr 4 thrombocytopenia) out of 7 pts; dose escalation and further enrollment was stopped (Table). Gr 3/4 AEs (all cohorts) included neutropenia (63%), thrombocytopenia (47%), and leukopenia (35%). Of 35 pts evaluable for response, there were 4 confirmed partial responses and 3 additional patients with unconfirmed PRs. Conclusions: SU in combination with P/C may represent a clinically useful treatment option in pts with advanced STs. The determination of MTD based on observed DLTs/tolerability is ongoing.

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A phase I clinical trial of FOLFIRI in combination with the pancyclin–dependentkinase (CDK) inhibitor flavopiridol
Authors: Dickson M. A. , Carvajal R. D. , Shah M. , Tse A. N. , Dials H. , Cane L. M. , Schwartz G. K.
Published: August 2020

e14511

Background: Preclinical data indicate that sequential treatment with flavopiridol (F) increases irinotecan- and 5-FU-induced apoptosis. Clinically, F showed promising activity when combined with irinotecan (Shah et al CCR 2005). Methods: We conducted a phase I trial of FOLFIRI + F every 2 weeks in patients (pts) with advanced solid tumors. Based on sequence- dependent inhibition, F was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses (MTD) were determined: MTD1 (F over 1 h) and MTD2 (F 30-min bolus + 4 h infusion). F pharmacokinetics (PK) were determined. Results: Of 74 pts treated, 63 were evaluable for toxicity and 56 for response. Pt characteristics: median age 60 (range 19–83), KPS 90 (70–90), prior regimens 3 (1–10). 39 pts received prior irinotecan. Tumor types: colorectal, gastric, HCC, GE junction, small bowel, pancreas, bile duct, breast, bladder, ovarian, sarcoma, melanoma, anal, urethral, thymic, head & neck, unknown primary. MTD1: F 80mg/ m2 with irinotecan 180mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus + 2400mg/m2 over 48 h. Dose-limiting toxicities (DLT) were diarrhea, fatigue, neutropenia, neuropathy. MTD2: F 35mg/m2 bolus + 35mg/m2 over 4 h with the same FOLFIRI dose. DLTs were diarrhea, neutropenia, and fatigue. Clinical activity included 2 partial responses (small bowel cancer, 10.3 m; bladder cancer, 10 m) and 1 complete response (mucosal melanoma 10.3 m). 22 pts had stable disease (median 5.9 m; range 1.5–25.7 m). Clinical benefit rate (CR + PR + SD for > 3 m) was 39% (22/56). Of 25 pts with colorectal cancer, 11 had as best response SD for > 3m (median 6 m, range 4.2–15.4 m), despite failing ≥ 1 irinotecan-containing regimen. 6 of those had significant decreases (36–78%) in CEA. F PK showed interpatient variability with no significant interaction between FOLFIRI dose and F Cmax. F Cmax increased with increasing F dose. At MTDs, there was higher Cmax in pts who experienced DLT (3.48μM) vs those who did not (2.21μM). Conclusions: F can be safely given as a bolus (80mg/m2) or split dose (35mg/m2 bolus + 35mg/ m2 over 4 h) in combination with irinotecan 180mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus + 2400mg/m2 over 48 h. Promising clinical activity is seen in mucosal melanoma and irinotecan-refractory colon cancer. (Supported by NCI R01CA67819)

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Phase I, pharmacokinetic, and pharmacodynamic evaluation of BNC105P, a novel anticancer agent that is both a vascular disrupting agent (VDA) and an inhibitor of cancer cell proliferation
Authors: Desai J. , Wong S. , Chong G. , Bibby D. , Leske A. , Kremmidiotis G. , Rosen M. , Rischin D.
Published: August 2020

e14512

Background: BNC105P is a novel anticancer agent that inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly becomes the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells compared to quiescent endothelial cells. Methods: BNC105P (2.1 to 18.9 mg/m2) was given IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors (ECOG 0–2) and adequate organ function. The objectives were to determine safety, tolerability, MTD and pharmacokinetics (PK). A pharmacodynamic response was evaluated using DCE-MRI with two baseline and two post dose assessments (3–6, 24 h). DLTs were determined during the first 21 days. Results: 9 pts (7 M; 2 F), median age 60 years have been enrolled with one pt each at 2.1 and 4.2 mg/m2. At 8.4 mg/m2, one pt experienced Grade 2 (Gr 2) mucositis and a switch to a ‘3+3’ design occurred. No DLTs have been observed in 3 pts at 12.6 mg/m2 and 1 pt at 18.9 mg/m2. Notable toxicity includes one episode of Gr 1 febrile episode possibly related to infusion, two episodes of Gr 1 fatigue and one Gr 1 rash. PK data of BNC105 indicates a linear increase in plasma AUC levels (Table) and plasma half life of < 0.5 h. Best observed responses were SD in 2/9 pts including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2). At doses ≥ 8.4 mg/m2, DCE-MRI images indicate changes in tumor perfusion post-dose. Two pts at 12.6 mg/m2 had a decrease in Ktrans values of 6 and 15 % compared to baseline. Conclusions: Pharmacodynamically active doses have been achieved with plasma drug levels correlating with active preclinical plasma exposure. To date, no excess toxicity has been observed at doses up to 18.9 mg/m2.

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Results of a phase II study to evaluate the biological effects of intratumoral (ITu) reolysin in combination with low dose radiotherapy (RT) in patients (Pts) with advanced cancers
Authors: Saunders M. , Anthoney A. , Coffey M. , Mettinger K. , Thompson B. , Melcher A. , Nutting C. M. , Harrington K.
Published: August 2020

e14514

Background: Reolysin, a wild type reovirus serotype 3 Dearing strain, replicates preferentially in Ras-activated cancer cells. In vitro and in vivo data have shown that combining reolysin and radiation (RT) significantly increases RT-induced cytotoxicity. A completed phase I trial of ITu reolysin and RT demonstrated that the combination was well tolerated and resulted in local and systemic responses. Methods: This open-label, single-arm, multicenter Phase 2 study combined ITu reolysin with low-dose fractionated RT. 20 Gy was given in 5 consecutive daily 4 Gy fractions combined with 2 ITu injections of reolysin (1x1010 TCID50) on days 2 & 4. The primary endpoint was objective tumor response rate in treated lesions. Secondary endpoints were to evaluate: viral replication, immune response and safety. Pts with ECOG performance status ≤2, with refractory advanced or metastatic cancers were eligible. Results: 16 heavily pre-treated pts (9 male, median age 66 yrs, ECOG 0:4pts; 1:12pts) with advanced cancer: melanoma (5), colorectal (4), gastric (1), ovarian (1), pancreas (1), lung (1), cholangiocarcinoma (1), sinus (1), and thyroid (1) were enrolled since Dec 2006. Most pts had received prior chemotherapy (13 pts) or RT (5 pts). No related serious adverse effects were observed during the study. Toxicities related to treatment were Grade 1 or 2: chills, pyrexia, headache, lethargy, anorexia, vomiting, shivering, nausea, and mild injection site pain. Of 14 pts evaluable for response, 13 pts had stable disease or better in the treated target lesion. Of these, partial responses were observed in 4 pts (lung, melanoma x 2, gastric) and minor responses were observed in 2 pts (thyroid, ovarian). Antibody responses to reolysin were delayed compared to previous results with intravenous administration. Conclusions: The combination of ITu reolysin and low dose RT was well tolerated and resulted in marked responses or stabilization in the treated target lesions for most of the pts evaluated to date. Further study in the radical setting is warranted.

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Phase I study of MGCD265 administered intermittently to patients with advanced malignancies (Study 265–102)
Authors: Hong D. , LoRusso P. , Kurzrock R. , Maroun C. , Mehran M. , Drouin M. , Martell R. , Wheler J.
Published: August 2020

e14516

Background: MGCD265 is an orally-available small molecule designed to inhibit c-Met, VEGFR-1, -2, -3, Tie-2 and Ron kinases. These targets are potentially relevant for the treatment of a variety of cancers. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of MGCD265 using an intermittent schedule of administration in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered on days 1–7 and 15–21 (1 week on, 1 week off schedule) of each 28-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Eleven patients with advanced solid tumors have been treated. Characteristics: age range 40–72; gender: 3 M/8F; ECOG: 1 (7 patients); 2 (4 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs have been reported during cycle 1. Six patients received treatment for 2 or more cycles. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax (Table below) with an approximate mean half-life of 30 hours and an approximate mean Tmax of 7 hours. At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Intermittent administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Treatment of patients at 192 mg/m2 is underway.

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Bevacizumab-related hypertension: Search for underlying mechanisms
Authors: Steeghs N. , Rabelink T. J. , op ’t Roodt J. , de Koning E. , Gelderblom H.
Published: August 2020

e14520

Background: Hypertension is a commonly observed side effect of inhibitors of VEGF/VEGFR-2 signaling such as bevacizumab. The mechanisms leading to this increase in blood pressure during anti-angiogenic therapy have not been elucidated. Recent studies suggest that functional rarefaction (a decrease in perfused microvessels) or anatomic rarefaction (a reduction in capillary density) may play an important role. The purpose of this study was to search for possible mechanisms that cause hypertension in patients treated with anti-angiogenic therapy and to confirm our hypothesis that systemic inhibition of VEGF inhibits vascular function and causes rarefaction. Methods: Patients treated with bevacizumab for any type of cancer were eligible. Measurements of blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), aortic pulse wave velocity (PWV), and capillary density and diameter with sidestream dark field (SDF) imaging of the mucosal microcirculation of the lip were performed at baseline, after 6 weeks of treatment, and 3 months after discontinuation of bevacizumab treatment. Results: Fourteen patients were included in this study. During bevacizumab treatment the mean systolic and diastolic blood pressure values increased, +3.4 mmHg (p=0.406), and +5.6 mmHg (p=0.023) resp. Mean FMD showed a statistically significant decrease of -3.1% (p=0.006). Mean NMD was unchanged. After 6 weeks treatment mean PWV increased significantly +0.7 m/s (p=0.0.027). A significant reduction in capillary density was seen from 18.0 capillary loops per image at baseline to 12.7 after 6 weeks (p=0.000007). Also a significant reduction in capillary diameter was seen, from 6.9 to 5.6 μm (p=0.002). Results after discontinuation of bevacizumab treatment were not yet available. Conclusions: Rarefaction (reduction in capillary density) and endothelial dysfunction observed in this study provide a plausible mechanism for the increase in blood pressure which results from treatment with bevacizumab.

No significant financial relationships to disclose.
Interest of DCE-US with quantification to demonstrate the VDA effect on vascularization in patients with advanced solid tumors treated with AVE8062
Authors: Chebil M. , Soria J. , Chami L. , Massard C. , Benatsou B. , Roche A. , Armand J. , Lassau N.
Published: August 2020

e14522

Background: To determine the optimal time for the assessment of the perfusion in patients receiving AVE8062 (Vascular Disrupting Agent) at different doses combined with a fixed dose of cisplatin and then to correlate these results with the tumor response. Methods: Patients (pts) with advanced solid tumors, treated with AVE8062 (from 11.5 to 30 mg/m2) in combination with 75 mg/m2 cisplatin given every 3 weeks, were prospectively followed by DCE-US. DCE-US was performed before treatment, at 3 time points (0, 6 and 24 hours (h)) on Day 1 of the first (C1) and second cycle (C2), then every 2 cycles thereafter. Contrast uptake was acquired using VRI perfusion software after SonoVue bolus injection. Time-Intensity Curves (TIC) were determined using linear raw- data from CHI-Q (Toshiba) software. Peak Intensity (PI) representing the blood volume was calculated from automatic modeling of TIC. CT-scans performed before treatment and every 2 cycles were reviewed and tumor response assessed (RECIST). Results: A total of 96 DCE-US were performed in 13 pts, 11 of whom had data for both cycle 1 and cycle 2. Among these 11 patients, 8 presented with a dramatic decrease of PI and 3 with an increase of PI. At cycle 1, mean change from baseline in PI was -36% at 6h and -47% at 24h after AVE8062 infusion. Greater decreases were observed at cycle 2, -70% at 6 h and 78% at 24 h. No pt had a clinical response, but by cycle 2, the 8 pts with a decrease in PI at 24h went on to have stable disease as best response; 3 pts with increased PI 24h after their second treatment all had disease progression as best response. Conclusions: The best timing to observe the effect of AVE8062 on the PI seems to be 24 hours after drug administration at cycle 2. These preliminary results suggest that 24 hr PI at cycle 2 could be useful for determining pts who are more likely to have disease progression as best response to AVE8062. If confirmed, the assessment of PI variation may predict the clinical response to AVE8062. Further studies are needed to assess the possible predictive value of DCE-US on duration of progression-free survival.

No significant financial relationships to disclose.
Plasma biomarkers predictive for disease control duration in the phase I study of E7080, a multitarget kinase inhibitor
Authors: Yamamoto N. , Yamada Y. , Nokihara H. , Goto Y. , Tanioka M. , Yamada K. , Koizumi F. , Koyama N. , Tamura T.
Published: August 2020

e14524

Background: E7080 is an oral multi-targeted kinase inhibitor of VEGFRs, PDGFRs, FGFRs and c-kit. In the phase I study for advanced solid tumors, E7080 was repeated every 3 weeks (twice daily by 2 wks-on/ 1 wk-off). The toxicities were manageable and the preliminary antitumor activity including one partial response was observed at doses up to MTD [ASCO 2008; abstract 3527]. This study was conducted to evaluate whether the change of plasma biomarkers in the E7080 phase I study could predict the antitumor activity or the disease control duration. Methods: The treatment duration was determined as a period from the first dosing to treatment failure. Plasma angiogenic proteins and circulating endothelial cells (CEC)/ progenitor cells (CEP) were measured in blood samples collected on Days 1 (pre-dose), 8 and 15 of Cycles 1 and 2. CEC and CEP population with (+) or (-) c-kit expression were analyzed by FACS. Correlation was determined by Spearman's rank correlation coefficient (r) and test for non-correlation (p). Results: 19 (76%) out of 25 evaluable patients had PR/SD including 6 (24%) patients with the treatment duration of ≥180 days. VEGF increase and sVEGFR1 and -R2 decreases in plasma were seen with the increased dose of E7080. But these changes had no correlations with disease control. E7080 decreased c-kit(+) CEC and CEP, but not c-kit(-) population. Importantly, patients showing the decrease of c-kit(+) CEC in Cycle 1 had received E7080 treatment for significantly longer duration (r=-0.468, p=0.018). The decrease of c- kit(+) CEC diminished during treatment-off for final 7 days in Cycle 1 and repeatedly decreased in Cycle 2 treatment. The decrease of c- kit(+) ratio in CEP correlated with the increase of plasma SCF (r=-0.457, p=0.021) and SDF1 (r=-0.466, p=0.018), but not with VEGF or thrombopoietin. Conclusions: The change of c-kit(+) CEC correlated with the disease control duration in the phase I study of E7080. SCF and SDF1 may play a role in c-kit(+) CEP accumulation. C-kit(+)-selective changes of CEC could be a candidate biomarker to predict the disease control duration in anti-angiogenic therapy of E7080.

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Phase I study of daily administration of MGCD265 to patients with advanced malignancies (Study 265–101)
Authors: Kollmannsberger C. K. , Hurwitz H. , Vlahovic G. , Maroun C. , Dumouchel J. , Reid G. , Martell R. , Shapiro G.
Published: August 2020

e14525

Background: MGCD265 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor that targets the mesenchymal epithelial transition (c-Met) and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3). Additional RTK targets include Tie-2, and Ron. Those kinases are known to be involved in tumor development and angiogenesis. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of daily administration of MGCD265 in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered as a continuous 21-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Ten patients with advanced solid tumors have been treated. Characteristics: age range 25–75; gender: 8 M/2F; ECOG: 0 (1 patient); 1 (9 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs during cycle 1 have been reported. Eight patients received treatment for 2 cycles or more. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax with an approximate mean half-life of 23 hours (see Table below). At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Daily oral administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Further dose escalation is underway.

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Phase I study of everolimus (E; RAD001) + low-dose weekly cisplatin (C) for patients with advanced solid tumors: Preliminary results
Authors: Fury M. G. , Sherman E. , Stambuk H. , Haque S. , Lisa D. , Shen R. , Carlson D. , Pfister D. G.
Published: August 2020

e14527

Background: Preclinical studies demonstrate synergistic anti-tumor activity with the combination of E + C. Methods: Patients received E per oral for days 1–21 of a 28 day cycle. E was dose escalated though 4 planned dose levels (DLs): 2.5 mg/day, 5 mg/day, 7.5 mg/day, and 10 mg/day. Cisplatin dose was fixed at 20 mg/m2 intravenously on days 1, 8, 15. A standard 3 + 3 dose escalation scheme was used. Blood samples for pharmacokinetics were collected on Day 1 and Day 8 of Cycle 1. Response was assessed by RECIST after 2 cycles. Results: 24 patients enrolled: 13 M, 11F; median age 62 (32–77); median number of prior cytotoxic chemotherapy regimens 1 (0–3; 75% with prior RT). At DL1, 3 patients were inevaluable (1 withdrawal of consent prior to treatment, 1 disease progression during cycle 1, 1 recurrent diverticulitis during cycle 1) and were replaced. DL 1 was expanded after a patient with melanoma metastatic to liver had sudden death of unclear cause, and the protocol was amended to exclude patients with hepatic dysfunction. At DL2, one patient experienced grade 3 small bowel obstruction of uncertain etiology, and the dose level was expanded to 6 evaluable patients without additional DLT. No DLTs occurred at DL3. No DLTs have occurred to date among 6 patients enrolled at DL 4. Adverse events per cycle (total n = 63 cycles; 20 patients evaluable for toxicity) include: lymphopenia G3 (19%), AST G3 (3.2%), alkaline phosphatase G3 (3.2%), ALT G3 (1.6%), hyponatremia (1.6%). Median cycles per patient, 2 (range <1 to 10+). Minor response seen in pulmonary carcinoid (n = 1); prolonged SD ≥ 6 cycles seen in pulmonary carcinoid (n=2), basal cell carcinoma (n=1), and esthesioneuroblastoma (n=1). Conclusions: Pending safety analysis at the final planned dose level, the phase II recommended dose is E 10 mg/day (days 1 - 21) + C 20 mg/m2 (days 1, 8, and 15) on a 28-day cycle.

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Bevacizumab (BEV) and continuous low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid tumors: final results of a prospective clinical trial
Authors: Kurbacher C. M. , Schmidt M. , Kurbacher J. A. , Schäfer S. , Arenz P. N. , Nagel W. J. , Reinhold U.
Published: August 2020

e14544

Background: BEV is potent inhibitor of VEGF-mediated tumor angiogenesis. VEGF is also crucial in antineoplastic immunortolerance by blocking the generation of dendritic cells (DC). VEGF inhibition may thus result in an improved anti-cancer immune response which may be further augmented by GM-CSF, a powerful stimulator of DC generation. In a previous study, GM-CSF was able to produce clinical responses in patients (pts) suffering from refractory carcinomas (Kurbacher et al., Oncology 2005). In this trial, we investigated BEV+GM-CSF in pts with advanced solid neoplasms. Methods: 26 pts have been enrolled: epithelial ovarian cancer, n=12; breast cancer, n= 6; primary peritoneal carcinoma, n=3; hormone-refractory prostate cancer, n=2; miscellaneous, n=3. All pts have been considered refractory to or non-treatable by chemotherapy due to their baseline bone marrow and/or organ functions. Fourteen pts had previously received BEV as part of other antineoplastic regimens. BEV was applied at a fixed dose of 6 mg/kg q2w. The starting dose of GM-CSF (sargramostim) was 125 μg/d. In cases not responding and/or not achieving moderate leukocytosis (< 20 G/L), GM-CSF was increased every 4 weeks at 25 μg increments up to a maximum of 250 μg/d. Toxicity was documented according to the NCI-CTC score, responses were recorded according to the RECIST or Rustin criteria. Results: Grade (G) 3–4 hypertension was seen in 3 pts, with 1 pt experiencing cerebral stroke 6 weeks after cessation of BEV+GM-CSF. Other G3–4 toxicities were fatigue in two pts, and fever, pain, myalgia, and central nervous symptoms in either one pt. Other side-effects like injection-site reactions, proteinuria, anemia, thrombocytopenia, and constipation did not exceed G1–2. The objective response rate was 31% (1 CR, 7 PR, 10 SD, and 8 PD); the rate of pts benefiting was 69%. Eight pts failing prior BEV benefited from BEV+GM-CSF. Until today, 13 pts have died. The median time to progression is 92 days and the median overall survival is 302 days. Conclusions: BEV+GM-CSF is an active and generally well tolerated non-cytotoxic regimen in pts with advanced solid tumors. Thus, large-scaled studies of this promising treatment are warranted.

No significant financial relationships to disclose.
Incidence of thromboembolism in patients receiving vorinostat: Clinical trial and post-marketing data from more than 1,800 patients
Authors: Rizvi S. , Lis J. , Boileau K. , Garcia-Vargas J.
Published: August 2020

e14547

Background: Thromboembolic events (TEEs) occur in approximately 10–15% of advanced cancer patients. Risk factors include cancer therapy and extent and type of malignancy. Vorinostat, a histone deacetylase inhibitor, has been licensed in the USA for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. TEEs were observed in 6/86 patients (7.0%) enrolled in vorinostat CTCL clinical trials at licensure. To gain further insight into the association between TEEs and vorinostat treatment, we analyzed data from vorinostat clinical trials and post-marketing surveillance (PMS) reports. Methods: Serious adverse events (SAEs) reported through November 3, 2008, among patients receiving vorinostat in completed and ongoing clinical trials, PMS reports, and published literature were reviewed for terms consistent with TEEs. A committee of independent (non-Merck employees) academic experts evaluated these reports. Although no safety signals were observed, the committee recommended that d-dimer and/or plasmin-antiplasmin assays should be conducted. This recommendation has been implemented in three ongoing studies ( NCT00486720 , NCT00632931 , NCT006429542) and will provide further information on clotting parameters among patients being treated with vorinostat. Results: During the reporting period, data from >1,845 cancer patients who received vorinostat were reviewed. Irrespective of causality, 107 patients (<5.8%) reported TEE SAEs (Table). Of these, 47 (<2.6%) had TEE SAEs that were rated as related to vorinostat, four of which were fatal. As of the data cut off, review of the special assays in the three studies did not result in any conclusive correlation. Conclusions: The incidence rate of TEEs observed in vorinostat studies is similar to reported rates of TEEs for advanced cancer patients.

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Non-invasive bioluminescence imaging of caspase-3 activity in Breast Cancer
Authors: Olsen C. C. , Li F. , He Z. , Li W. , Li C.
Published: August 2020

e14557

Background: Apoptosis is a major form of tumor cells death during cytotoxic therapy. Understanding the kinetics of apoptosis would greatly facilitate development of more effective therapeutic approaches. In order to monitor apoptosis activities in vivo, we developed a novel bioluminescence-based reporter gene to detect caspase 3 activities, which are elevated at the execution phase of apoptosis. Methods: A caspase-3 reporter system was constructed by combining two different reporter proteins; green fluorescent protein (GFP) and firefly luciferase (FL) linked through multiple polyubiquitin domains with a caspase-3 recognition site. Under normal circumstances, the reporter proteins are rapidly degraded by the proteasome system.. During apoptosis, activated caspse 3 cleaves off the multi-ubiquitin domain from the reporter protein. This enable the GFP and luciferase fusion reporter to be stabilized and achieve a significant gain in GFP protein and luciferase activities, which in turn could be monitored both in vitro and in vivo. 4T1 cells transduced with CMV-luc or Caspase-3 reporter xenografts were treated with both chemotherapy and radiation therapy and monitored for apoptosis activity. Results: In vitro experiments demonstrated increased luciferase with increasing radiation dose reflective of apoptosis with background levels nearly undetectable. Taxol was associated with a time-dependent increase from 24 to 72hrs after drug exposure, indicating that apoptosis is a gradual, heterogeneous process. EGFP signal increased from 1.85% in controls to 80.6% in cells treated with 1uM Taxol. Xenografts showed nearly undetectable luciferase background with Cytoxan therapy resulting in a 90-fold increase, 10 Gy a 24 fold increase and fractionated RT (5Gy x3) with a 46-fold increase. Conclusions: We developed a novel in vivo caspase reporter based on the ubiquitous proteosome system of protein degradation and bioluminsecence imaging. This allowed us to assess activation of apoptosis in response to chemoradiation therapy in tissue culture and breast cancer xenografts over the course of 2–3 weeks, which has not been possible with other technologies.

No significant financial relationships to disclose.
In vitro and in vivo anti-leukemia activity of CHR-2845, a cell-targeted HDAC inhibitor for use in monocytic leukemia
Authors: Tong W. , Stevenson W. , Cortes J. , Needham L. , Brotherton D. , Davidson A. , Drummond A. , Garcia-Manero G.
Published: August 2020

e14579

Background: Histone deacetylase inhibitors alter gene expression and induce apoptosis in a wide range of cancer cells including those derived from human leukemias. CHR-2845 is a novel hydroxamic acid derivative histone deacetylase inhibitor (HDACi) which is a selective substrate for the intracellular carboxylesterase hCE-1, whose expression is restricted to cells of the monocyte- macrophage lineage. Methods: We studied the in vitro and in vivo anti-leukemia activity of CHR-2845 using cell proliferation assay, annexin V binding assay, cell cycle analysis, western blot and in vitro primary leukemia cell culture. Results: Both U937 and THP1 cells express high levels of hCE-1 whereas the myeloid cell line, HL60, does not. In comparison to vorinostat, CHR-2845 showed increased anti-proliferative potency (IC50) against monocytic cell lines (THP1, 30 nM vs 700 nM and U937, 30 nM vs 475 nM), compared to a myeloid cell line (HL60, 700nM vs 470 nM). In a broad panel of leukemic cell lines, the potency of CHR-2845 over vorinostat correlated completely with hCE-1 expression. In monocytic cell lines, CHR-2845 induced more apoptosis than vorinostat (THP1: 45±5% vs 11±1% and U937: 23±14% vs 6±1%), as measured by flow cytometry using Annexin V. Biochemical assessment of histone H3 and H4 protein acetylation by Western blot also indicateed that CHR-2845 is at least 10 times more potent than vorinostat in monocytic cell lines but not in HL-60 cells. This increase in histone acetylation was associated with increased phosphohistone H2AX, indicating formation of double-strand DNA breaks induced by this compound. These data for CHR-2845 and vorinostat on apoptosis and histone acetylation in THP1 and U937 versus HL60 cells, confirmed the selectivity of this novel compound for cells of the monocytic lineage. We also studied the anti-leukemia activity of CHR-2845 in primary leukemia cells from 8 patients with acute or chronic myelomonocytic leukemia. CHR-2845 decreased proliferation and induced apoptosis more than an equivalent dose of vorinostat in some of the patients we studied. Conclusions: These results indicated that CHR-2845 has potential to be efficacious in the treatment of patients with monocytic leukemia.

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