bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial disparities in survival of glioblastoma patients not treated with radiation.
Authors: Thakkar Jigisha P. , Dolecek Therese A. , Popa Andra M , Villano John L.
Published: March 2020

2069

Background: Race-based outcomes have been documented for inpatient hospital care for glioblastoma (GBM), however, SEER-based population studies do not replicate the differences in race for outcomes in GBM. Moreover, most advanced cancers demonstrate differences in race based outcomes. We hypothesized that there is a difference in race based outcomes for GBM with advanced clinical involvement preventing an established standard of care such as radiation therapy (RT). Methods: We analyzed survival estimates and procedure frequencies by race for GBM patients (n=4931) 20 years and older, not treated with radiation in the initial round of therapy; from 2000-2008, using the Surveillance, Epidemiology, and End Results (SEER) 17 registries database and listed them by surgery type. Kaplan–Meier relative survival rates were calculated by surgery type and race group (blacks and whites) followed by evaluation of association between race and survival rate. Race comparisons were limited to 1 year because of small numbers in the subgroups. Results: We found no statistically significant support for a racial disparity in survival among GBM patients with different surgical interventions (tumor destruction/biopsy, partial or total resection). However, for those receiving no surgery (and no RT), blacks actually had better one-year survival than whites. By surgery, those receiving gross total resection had higher survival in both blacks and whites. In whites only, any type of surgery (tumor destruction/biopsy, partial or total resection) had better survival than none. Conclusions: Overall, there are no statistically significant differences between blacks and whites in terms of survival in GBM patients not receiving RT in the initial round of therapy. Differences in race based care for GBM have not been found outside of inpatient hospital based care, which is unusual for an aggressive cancer needing specialized multi-modality care. [Table: see text]
Use of axitinib, a new-generation tyrosine kinase inhibitor, to decrease glioblastoma growth despite primary resistance to the VEGF-antibody bevacizumab.
Authors: Kratzsch Tobias , Gruenwald Viktor , Vajkoczy Peter , Kuhn Susanne Antje
Published: March 2020

2077

Background: Targeted therapies are increasingly important in oncology. Axitinib is a novel orally available tyrosine kinase inhibitor which is mainly directed against the VEGFR family. VEGF-antibody bevacizumab is the acting drug of running clinical trials in glioblastoma. Methods: In immunodeficient mice, cell line- and patient-derived glioblastoma xenografts were established and treated with axitinib. Temozolomide, bevacizumab, and phosphate buffered saline served as controls. Tumor size, vascularization (CD31), vascular pericyte coverage (NG-2), apoptosis in tumor and endothelial cells as well as expression of EGFR, VEGFR1, VEGFR2, PDGFRβ, VEGF, and PlGF were determined. Experiments were approved by local ethics committee. Results: Positive control temozolomide always caused growth inhibition whereas primary resistances to bevacizumab as primary drug were observed. As most delighting result, axitinib caused a delay of tumor growth in a glioblastoma xenograft with primary resistance to bevacizumab. Tumor cell proliferation (Ki67) was significantly lower than in controls (p<.05). The number of CD31 positive endothelial cells decreased (p<.001). Numbers of NG2 positive pericytes were reduced (p<.001) and triple immunofluorescence showed a significant reduction of NG2 positive pericyte coverage of CD31 positive endothelial cells (p<.001). Expression of EGFR, PDGFRβ, and VEGFR1 proteins showed no alterations under axitinib treatment, but RT-PCR revealed a significantly decreased mRNA expression of VEGF-A and PlGF. Conclusions: Axitinib had significant effects on glioblastoma xenografts even with primary resistance to bevacizumab in a so far untreated tumor. There are currently two recruiting phase II trials with axitinib in glioblastoma multiforme. Further comparative studies with bevacizumab should urgently define the potential of this substance in glioblastoma therapy.
A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors.
Authors: El-Khoueiry Anthony B. , Ning Yan , Yang Dongyun , Cole Sarah , Kahn Michael , Zoghbi Marwan , Berg Jennifer , Fujimori Masamoto , Inada Tetsuhi , Kouji Hiroyuki , Lenz Heinz-Josef
Published: March 2020

2501

Background: PRI-724 is a first-in-class modulator of Wnt signaling that inhibits the CREB binding protein and β-catenin interaction. In pre-clinical models, PRI-724 (active metabolite C82) increases p300/β-catenin binding and promotes stem cell differentiation thereby eliminating tumor initiating cells and increasing sensitivity to cytotoxic or targeted drugs. Methods: PRI-724 was given as a continuous infusion X 7 days q 2 wks. There was an initial accelerated dose escalation with one pt per dose level and a plan to revert to a 3+3 escalation after 640 mg/m2 unless a dose limiting toxicity (DLT) or 2 moderate toxicities occurred earlier. Eligibility criteria: adequate bone marrow function, AST/ALT <5XULN, total bilirubin<1.5 mg/dL. Survivin/BIRC5 expression was measured by immunomagnetic RT-PCR on circulating tumor cells (CTC). Results: 18 pts treated; median age: 53 years (38-71); 12 (67%) males; median number of prior therapies: 3 (1-5). There was one DLT of grade 3 hyperbilirubinemia. Grade 3 AEs were limited to hyperbilirubinemia in 2 pts, one of which did not meet DLT criteria. Grade 2 AEs were: diarrhea (2pts; 11%), bilirubin elevation (2 pts; 11%), hypophosphatemia (2pts; 11%), nausea (1pt; 6%), fatigue (1pt; 6%), anorexia (1pt; 6%), thrombocytopenia (1 pt; 6%) and alkaline phosphatase elevation (1pt; 6%). There was no MTD at the doses tested. The recommended phase 2 dose was 905 mg/m2 based on the incidence of AEs at 1280 mg/m2 and the plateau in pK parameters. The median Cmax and AUC 0-t for C-82 at 905 mg/m2/day were 887 ng/mL and 262787 h*ng/mL. Median elimination T ½ was 7.35 h. 3 pts with colon cancer had stable disease for 8, 10 and 12 weeks. Survivin expression in CTCs decreased in 72% of pts on C1D8 and 61% on C2D8. There was an inverse relationship between C82 plasma concentration and survivin expression on C1D8 (Spearman correlation coefficient r = -0.72; p=0.001). Conclusions: PRI-724 had an acceptable toxicity profile. Downregulation of survivin expression in CTCs may serve as a pharmacodynamic marker of drug-on-target effect. Studies combining PRI-724 with chemotherapy are ongoing. Clinical trial information: NCT01302405. [Table: see text]
First-in-class, first-in-human phase I trial of KPT-330, a selective inhibitor of nuclear export (SINE) in patients (pts) with advanced solid tumors.
Authors: Razak Albiruni R A , Soerensen Morten Mau , Mahipal Amit , Shacham Sharon , Yau Cindy Y. F. , Lassen Ulrik Niels , McCauley Dilara , Cooksey Jennifer , Tan David Shao Peng , Saint-Martin Jean-Richard , Landesman Yossi , Pond Gregory , Oza Amit M. , Kauffman Michael , Siu Lillian L. , Mirza Mansoor Raza
Published: March 2020

2505

Background: In cancers, the majority of tumor suppressor proteins (TSP) are transported out of the nucleus exclusively by Exportin 1 (XPO1/CRM1), rendering these TSPs non-functional. KPT-330 is a potent inhibitor of XPO1, and forces the nuclear retention and activation of > 10 TSPs resulting in tumor cell death in vitro, in murine preclinical models and in dogs with spontaneous lymphomas. Methods: KPT-330 was administered orally for 10 doses in a 28-day cycle. Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies were performed. Response evaluation was done every 2 cycles (RECIST 1.1). All pts entering the study had documented progressive disease. Results: 23 pts (10 males; median age 62 yrs; ECOG PS 0/1: 5/18) received KPT-330 across 6 dose levels (3 to 30 mg/m2). There has been no dose limiting toxicity. Nine drug related grade 3/4 adverse events (AEs) post cycle 1 were reported in 6 pts (neutropenia, thrombocytopenia, hyponatremia, increased ALT, fatigue, vomiting [n=2], nausea [n=2]). The most common grade 1/2 AEs were nausea (78%), fatigue (74%) and anorexia (74%). PK analysis demonstrated a fairly proportional increase in Cmax and AUC with increasing dose, with no accumulation and without affecting half-life or clearance of KPT-330. At 30 mg/m2, AUC0-last. (4375 ng*h/mL) was comparable to the anti tumor exposure observed in mice and dogs. Tmax (~3 hrs) and T1/2 (6-7 hrs) were consistent across doses. Significant increase (2-20x) in XPO1 mRNA levels (PDn marker) in circulating leukocytes was observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction. Analysis of tumor biopsies confirmed nuclear localization of TSPs (e.g. p53, FOXO3A, IκB) and apoptosis of cancer cells following KPT-330 administration. RECIST response was evaluable in 13 pts. Stable disease (SD) was noted in 9 pts, with 3 (colon, endocervical & endometrial stromal tumors) remaining with SD at 6+ months (dose levels 3 & 6 mg/m2), as well as one minor response (colon). Conclusions: KPT-330 treatment is generally well tolerated, with favorable PK and PDn properties. Preliminary signals of clinical antitumor activity were observed. Clinical trial information: NCT01607905.
First-in-human phase I study of the liposomal RNAi therapeutic Atu027 in patients with advanced cancer.
Authors: Schultheis Beate , Strumberg Dirk , Santel Ansgar , Gebhardt Frank , Khan Michael , Keil Oliver , Giese Klaus , Kaufmann Jörg
Published: March 2020

2508

Background: Atu027 is a novel vascular stabilising, anti-metastatic, RNAi therapeutic, targeting systemic endothelial cell function and the tumor vasculature. Atu027 comprises a liposomal particle, containing an siRNA, which silences expression of the PKC pathway signalling molecule PKN3. Atu027 was previously shown to restrict tumor growth, local invasion and both, lymph node as well as pulmonary metastasis in mouse xenograft models. Methods: 34 patients with advanced cancer received 10 escalating doses of Atu027 without pre-medication as single and repeated i.v. infusions (qw2x4 per 28-d cycle) with a 3-wks dose intermission. Primary end points were safety, pharmacokinetics and -dynamics (biomarker identification). Response was monitored by CT/MR imaging at baseline, after treatment and at final follow-up (EoS) and was assessed according to RECIST. Results: Atu027 was well tolerated up to 0.336 mg/kg (around twice the predicted effective siRNA plasma levels). An MTD was not achieved. Around 50% of patients experienced disease stabilization according to RECIST. 8 patients had stable disease at EoS and 2 with neuroendocrine cancer had disease stabilization for 9 or 22 months. Partial regression of pulmonary metastasis and a regression of liver metastases were observed in subjects with neuroendocrine and breast cancer, respectively. An improved ECOG performance status was observed in patients of higher dose levels. Most AEs were low grade toxicities (1 or 2), including fatigue and increased lipase. Transient complement system activation was observed for certain factors. Area exposure levels of siRNA strands were dose-proportional and peaks were reached during 4 h-infusion. Of 102 plasma proteins assessed, sFLT1 (sVEGF-R1) was the most promising as a potential biomarker, with decreases from baseline in most pts from dose level 4-10 after treatment. Conclusions: Atu027 was well tolerated and there was suggestion of a clinically meaningful antitumor activity. In view of this further clinical trials can be initiated at a dose of up to 0.336 mg/kg and sFLT1 will be investigated as a potential biomarker. Clinical trial information: NCT00938574.
Phase I study of volasertib (BI 6727) combined with afatinib (BIBW 2992) in advanced solid tumors.
Authors: Peeters Marc , Machiels Jean-Pascal H. , Pilz Korinna , De Smet Marina , Strelkowa Natalja , Liu Dan , Rottey Sylvie
Published: March 2020

2521

Background: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases (Plk). Volasertib and afatinib, an irreversible ErbB family blocker, have shown single agent anti-tumor activity and manageable safety profiles in patients (pts) with advanced solid tumors. This dose escalation study was designed to determine the maximum tolerated dose (MTD) of two combination schedules of volasertib and afatinib in pts with advanced solid tumors refractory to or not amenable to standard therapy. Methods: In a 3 + 3 design, cohorts of 3–6 pts received volasertib 150–300 mg IV d1 Q3W + afatinib 30–50 mg PO QD d2–21 Q3W (Schedule A) or afatinib 50–90 mg d2–6 Q3W (Schedule B). Up to 12 additional pts were enrolled at the MTD. Primary endpoint was the MTD per schedule. Secondary endpoints included pharmacokinetics (PK), safety and efficacy (RECIST). Results: 57 pts (median 58 yr; ECOG PS 0/1/2: 35%/60%/5%) were treated (n=29, Schedule A; n=28, Schedule B). MTD was volasertib 300 mg/afatinib 30 mg (Schedule A) and volasertib 300 mg/afatinib 70 mg (Schedule B). Cycle 1 dose limiting toxicities (DLTs) were experienced by 5 (Schedule A) and 7 (Schedule B) pts. Most common DLTs were diarrhea (n=5), neutropenia (n=3), fatigue (n=2) and decreased ejection fraction (n=2) in Schedule A, and thrombocytopenia (n=6), neutropenia (n=5), diarrhea (n=4) and febrile neutropenia (n=3) in Schedule B. Most common grade 3/4 adverse events were neutropenia (n=8), thrombocytopenia (n=6), diarrhea (n=3) and febrile neutropenia (n=3). Volasertib exhibited multi-exponential PK behavior with a long half-life (130 hr), moderate clearance (900 mL/min) and large volume of distribution (Vss >6000 L). Co-administration of volasertib and afatinib had no effect on the PK profile of either drug. Two pts in Schedule A (volasertib 300 mg/afatinib 30 mg) achieved partial responses (tumor types: NSCLC, head and neck). Conclusions: MTD of volasertib was 300 mg Q3W combined with afatinib 30 mg d2-21 (Schedule A) or afatinib 70 mg d2-6 (Schedule B). Both agents could be combined at previously shown active single agent doses. At the MTD, treatment was manageable and showed preliminary anti-tumor activity. Clinical trial information: NCT01206816.
Phase I study of everolimus (E, RAD001) and ganitumab (G, AMG 479) in patients (pts) with advanced solid tumors.
Authors: Jalal Shadia Ibrahim , Strother Robert Matthew , Sandusky George , Prasad Nagendra K , Berry William , Jones David R , Younger Anne , Funke Jennifer M. , Detty Tammi , Althouse Sandra , Perkins Susan M. , Chiorean E. Gabriela
Published: March 2020

2529

Background: Synergism between IGF and mTOR inhibitors has been documented preclinically. We conducted a phase I study to determine the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor efficacy of E with G. Methods: Eligible pts had good organ function, ECOG PS 0-1. The study had a standard “3+3” design, using E 5 or 10 mg orally daily (QD), and G 12 mg/kg IV every 2 wks (Q2W) in 28 day cycles (C); an expansion cohort was added at MTD for further efficacy analysis. E was given as single agent during C1D1-7 with PKs on C1D1 and D7, and continuously after C1D16. G was started on C1D15 with single agent PK. PKs for both drugs at steady state were performed on C3D1. PDs (blood and serial tumor biopsies) for IGF and PI3K/Akt/mTOR pathways were performed at baseline, C1D7, C3D1 and time of progression. Results: 20 ptswere enrolled to date, M/F: 8/12, median age 55 yrs (24-70); PS: 0/1= 13/7. The table summarizes dose levels and DLTs. The most common toxicities were fatigue (5), diarrhea, mucositis, dysgeusia, anemia and thrombocytopenia (4 each), and rigors (3). Grade (Gr) 3 toxicities were: mucositis (3), anemia (2), thrombocytopenia (2), and diarrhea (1). Pts received a median of 3 cycles (0-9). One pt discontinued study on C1D9 due to intracerebral bleed and 1 pt withdrew consent on C1D15. Among 18 evaluable pts, none responded and 9 pts (50%) had SD with a median duration of 20 wks (range 11-35). Prolonged clinical benefit (SD ≥ 20 wks) was noted in refractory fibrolamellar HCC, neuroendocrine, GIST and urachal cancers. PKs showed no significant interaction between E and G. Baseline IGF-1R and PTEN expression, and IGF1 levels did not affect clinical benefit. pS6 downregulation and pAkt upregulation in paired tumor biopsies occurred in all (7/7) or most (6/7) samples evaluated, and did not correlate with efficacy. IGF1 and IGFBP3 levels increased on-treatment in 80-90% of pts. Conclusions: E+G is safe and the RP2D is E 10 mg QD + G 12 mg/kg Q2W. While on target pS6 reduction occured, the IGF1-R inhibition did not affect pAkt upregulation from mTOR blockade. Clinical trial information: NCT01122199. [Table: see text]
A pilot study of sirolimus (S) in subjects with Cowden syndrome (CS) with germ-line mutations in PTEN.
Authors: Komiya Takefumi , Blumenthal Gideon Michael , Ballas Marc S. , Dechowdhury Roopa , Manu Michell , Fioravanti Suzanne , Hornyak Thomas J , Wank Stephen , Weinstein Douglas , Morris Jennifer , Hewitt Stephen M. , Memmott Regan , Dennis Phillip A. , Morrow Betsy
Published: March 2020

2532

Background: CS is characterized by germline PTEN mutations. Because tumors from CS patients show increased activation of the PI3K/Akt/mTOR pathway, mTOR inhibitor such as S might have activity in such patients. Methods: Eligibility: subjects with germline PTEN mutation who meet international diagnostic criteria for CS, age 18, ECOG PS 0-2, and adequate organ function. Subjects were treated with a 56-day course of daily oral S (2 mg). Objective: Inhibition of the mTOR pathway in benign skin/GI lesion, as assessed by IHC (P-AKT, Total S6, P-S6, P-4E-BP1, score 0-4), changes in benign or malignant tumor by CT/MRI/PET, digital dermoscopy/endoscopy, and changes in cerebellar testing by modified SARA (Neurology 2006). Protocol was amended to allow up to 20 subjects. Results: A total of 18 pts/16 families were enrolled. Median age 42 (range 19-69). Male/Female: 9/9. Involvement in skin, thyroid, GI polyps, breast, CNS, and all of the five organs was observed in 18, 15, 13, 8, 18, 5 subjects, respectively. 7 had h/o malignancies: 3 renal cell, 4 breast, 3 thyroid, 4 others. 3 cerebellar gangliocytomas and 2 others were measurable by CT or MRI. PTEN mutations: 6 families in Exon 1-2, 1 in Exon 4, 9 in Exon 5-8. All but one (D24H) were truncating mutations. 11 of 16 pts who completed a 56-day course reported subjective improvement in energy, mood, focus or skin lesion. Pts with Ex6-8 mutation (n=4) had a median SUV decrease of 29.4%. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Cerebellar evaluation showed a significant improvement in a total SARA score at 1 month (n=9, p=0.034). 3 pts were treated for only 28 days due to voluntary withdrawal. IHC analysis in skin and GI benign lesions showed a decrease in average P-S6K, P-S6, Total S6, P-S6/Total S6 in response to S. P-S6K/Total S6 ratios at d14 and d56 were significantly lower than at baseline (p=0.0026, 0.0391, respectively). The most common AEs (all grades >25%) were LFTs/Hb (39%), fatigue/hypercholesterolemia (28%). Grade 3 AEs: 1 pt hypophosphatemia/lymphopenia. Conclusions: A 56-day course of S was well tolerated in subjects with CS and was associated with improvement in symptoms, skin/GI lesions, cerebellar function and decreased mTOR signaling. Clinical trial information: NCT00971789.
Pharmacodynamic study using FLT PET/CT in patients treated with axitinib.
Authors: Liu Glenn , Scully Peter , Kolesar Jill , Bruce Justine Yang , Eickhoff Jens C. , Perlman Scott , Carmichael Lakeesha , Heideman Jennifer , Jeraj Robert
Published: March 2020

2537

Background: Axitinib (AX) is a potent VEGFR2 TKI. The objective of this study was to characterize tumor vascular and proliferative changes in patients treated with AX. Methods: Thirty pts with solid malignancies with at least one target lesion appropriate for FLT PET/CT imaging were enrolled. Pts were treated in Cycle #1 (C1) with AX at 5 mg BID x 2 wks, followed by a 1 wk drug holiday. Subsequent cycles continued the AX BID on a continuous basis until progression or unacceptable toxicity. In cohort A, FLT PET/CT was obtained at baseline, C1D14 (during AX) and C1D21 (AX withdrawal). Cohort B used the same treatment schedule, but FLT PET/CT was obtained on C1D14, C1D16 and C1D21. At each imaging time, peak FLT Standardized Uptake Values (SUVpeak), AX pharmacokinetics and plasma VEGF levels were obtained. Results: Of the 30 total pts, 28 had at least 1 PET/CT scan with 24 completing all planned PET/CT scans (13 in Cohort A; 11 in Cohort B). Strong proliferative flare (36% increase in SUVpeak from C1D14 to C1D21) was observed in majority of pts with most of the flare occurred within two days after AX withdrawal (25% increase in SUVpeak from C1D14 by C1D16). A robust vascular flare paralleled proliferative flare (R=0.57). A trend linking short progression free survival with high withdrawal flare was seen (44% increase in SUVpeak for PFS ≤ 6mo vs 11% increase in SUVpeak for PFS > 6 mo; p=0.14). VEGF levels and AX PK levels increased during treatment, followed by decrease during withdrawal. Conclusions: The observed AX pharmacodynamics is consistent with our prior observation with another VEGFR TKI and suggests that acute AX withdrawal results in a robust withdrawal flare. This information suggests that the timing of cytotoxic chemotherapy during the flare may increase the therapeutic index, as opposed to concurrent administration which may be antagonistic. This study also shows the power of quantitative molecular imaging, which can simultaneous evaluate treatment response heterogeneity, as well as compensatory effects that may lead to early treatment failure. Clinical trial information: NCT00859118.
Phase I dose escalation study of the protein kinase C iota inhibitor aurothiomalate for advanced non-small cell lung cancer, ovarian cancer, and pancreatic cancer.
Authors: Mansfield Aaron Scott , Fields Alan P. , Jatoi Aminah , Qi Yingwei , Adjei Alex A. , Erlichman Charles , Molina Julian R.
Published: March 2020

2551

Background: Protein kinase C iota (PKCi) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers and promotes tumorigenesis. The gold compound aurothiomalate (ATM) inhibits downstream activation of Rac1 by PKCi. We sought to determine the maximum tolerated dose (MTD) of ATM. Methods: We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. In the dose escalation cohort patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Up to 9 subjects were allowed to enroll in the expansion cohort at the MTD. Blood samples were analyzed for elemental gold levels. Patients were evaluated for response every eight weeks with computed tomography using modified response evaluation criteria in solid tumors. Results: Fifteen patients, all pretreated, enrolled in this study. There were ten patients with NSCLC, four with ovarian cancer and one with pancreatic cancer. Six patients were treated at the 25 mg dose, 6 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity (DLT) at 25 mg (hypokalemia), 1 DLT at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities in the dose escalation cohort. The recommended MTD of ATM is 50 mg, and 1 subject was treated in the expansion cohort at 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). The best response observed was stable disease in 2 subjects. There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold with concentrations exceeding 20 µM after one month of therapy with 75 mg of ATM and after 2 months of therapy with 50 mg of ATM, consistent with linear pharmacokinetics. Conclusions: In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. In this heavily pre-treated group of patients in who we observed at best stable disease, it remains unclear whether future investigations that target PKCi should focus on single agent ATM, combination therapy with ATM, or other PKCi inhibitors that are currently in development. Clinical trial information: NCT00575393.
PHI-55: (NCI#7427): A phase I study of halichondrin B analog (E7389) in combination with cisplatin (CDDP) in advanced solid tumors: A CCC, NCI/CTEP-sponsored trial (grant U01 CA 062505).
Authors: Koczywas Marianna , Lenz Heinz-Josef , Mortimer Joanne E. , El-Khoueiry Anthony B. , Frankel Paul Henry , Gandara David R. , Cristea Mihaela C. , Chung Vincent M. , Lim Dean , Reckamp Karen L. , Lau Derick H. M. , Ye Wei , Doyle L. Austin , Carroll Mary I. , Newman Edward M.
Published: March 2020

2564

Background: E7389 is a structurally simplified synthetic macrocyclic ketone analog of the marine sponge natural product Halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. Methods: The goals of this trial were to determine the DLT, the MTD, and PK of E7389 (administered on days 1, 8 and 15 every 28 days) in combination with CDDP (administered on day 1 every 28 days) in patients (pts) with advanced solid tumors. The protocol was amended after dose level 4 (E7389 1.4 mg/m2, CDDP 60 mg/m2) when it was not feasible to administer E7389 on day 15 due to neutropenia; the treatment schedule was changed to E7389 days 1 and 8 and CDDP day 1 every 21 days. Eligibility criteria included normal organ function and < 2 prior chemotherapy regimens. Results: To date, 36 pts have been treated (E7389 0.7-1.4 mg/m2 and CDDP 60-75 mg/m2). Median age 61 years; 19 males; the most common tumor types were lung (8), pancreatic (5), head and neck (6). 36% ECOG 0, 56% ECOG 1, 8% ECOG 2; Median number of cycles was 3 (1 – 8). There were 3 pts with DLT’s on the 28-day cycle: gr 4 febrile neutropenia (1.0/60); gr 3 anorexia/fatigue/hypokalemia (1.2/60); and gr 3 stomatitis/fatigue (1.4/60). There were 3 pts with DLTs treated on the 21-day schedule: gr 3 hypokalemia/hyponatremia (1.4/60); gr 4 mucositis (1.4/60); and gr 3 hypokalemia (1.2/75). With 2 DLTs out of 6 pts at E7389 1.4 mg/m2 and CDDP 60 mg/m2, E7389 was reduced, CDDP was escalated, and the MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2(1 patient out of 6 with a DLT). At the MTD, protocol defined dose modifications or delays were required in 2 of the 6 patients by cycle 2. Notably, all DLTs were observed in patients exposed to at least 2 prior lines of chemotherapy. Two pts had an unconfirmed PR (pancreatic, breast) and 2 had a PR (esophagus, transitional bladder). Conclusions: On a 21 day schedule,E7389 in combination with CDDP appears well tolerated and showed preliminary activity. The MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2. Clinical trial information: 00400829.
A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors.
Authors: Calvert Alan Hilary , Gonzalez Michael , Ganguli Sushila , Ng Matthew , Benafif Sarah , Capelan Marta , Goldstein Robert , Shah Krunal , Jarvis Claire , Flynn Michael , Forster Martin , Anderson Stephanie , Schmitt-Hoffman Anne , Lane Heidi , Engelhardt Marc , Hannah Alison L. , Tzankov Alexandar , Bachmann Felix , Molife L Rhoda , Kristeleit Rebecca
Published: March 2020

2566

Background: BAL101553, a pro-drug of the small molecule BAL27862, is a novel microtubule targeting agent (MTA) with cytotoxic and vascular disrupting properties. Pre-clinical data showed anti-proliferative activity in several in vitro and xenograft tumour models, including tumours refractory to conventional MTAs through diverse resistance mechanisms. Primary objectives of this FIH study were determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included the evaluation of PK, PD and anti-tumour activity. Methods: An accelerated titration dose-escalation design was used. Eligible patients (pts) with advanced solid tumours, who had failed standard therapy, received BAL101553 as a 2-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Adverse events (AEs) were assessed according to CTCAEv4. Disease response was assessed by RECIST 1.1 every 2 cycles. Results: 16 pts (7 male; median age 52 years; range 29-80) with solid tumours were treated at 4 dose levels (15, 30, 45 and 60 mg/m2). DLTs were observed at 60 mg/m2 and included rapidly reversible grade (G) 3 hypertension (HTN) and G3 reduced mobility/ dizziness. DLT criteria for HTN were subsequently modified. Frequent drug-related AEs were injection site reactions, nausea, vomiting (all G1-2), and G2-3 HTN (transient during the infusion; responding to nifedipine). One pt experienced G2 peripheral neuropathy at 60 mg/m2. PK analyses indicated conversion of BAL101553 to the active BAL27862, dose proportional exposure for both compounds and a half-life of BAL27862 in a range of 11 to 27 h. Preliminary tumour PD data comparing pre/post biopsies showed loss of CD34+ capillaries and focally decreased proliferation. A confirmed partial response was demonstrated in 1 pt with ampullary (pancreaticobiliary) cancer maintained on treatment for >16 cycles with intra-pt dose escalation. 2 pts (laryngeal and rectal cancer) demonstrated stable disease >16 weeks. Conclusions: BAL101553 is well tolerated up to 60 mg/m2 with evidence of anti-tumour activity. Dose escalation continues to determine the MTD. Clinical trial information: NCT01397929.
A genotype-directed study to optimize dosing of irinotecan according to the UGT1A1 genotype.
Authors: Innocenti Federico , Salgia Ravi , Ramirez Jacqueline , Janisch Linda A. , Undevia Samir D. , House Larry , Das Soma , Wu Kehua , Turcich Michelle , Marsh Robert de Wilton , Karrison Theodore , Maitland Michael L. , Schilsky Richard L. , Ratain Mark J.
Published: March 2020

2570

Background: The risk of severe neutropenia from irinotecan (I) is in part related to UGT1A1*28, a polymorphism that reduces the elimination of SN-38, the active metabolite of I. We aimed to identify the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of I in advanced solid tumor patients (pts) stratified by*1/*1, *1/*28, and *28/*28 genotypes. We hypothesized that *1/*1 pts would tolerate a higher MTD than the standard 350 mg/m2 dose and that *28/*28 pts would require dose reduction. Methods: 68 pts (30 lung, 30 gastrointestinal, 8 other cancers) received q3w, flat-dose I. Genotype frequencies were 46% (*1/*1), 41% (*1/*28), and 13% (*28/*28). Pts (66% males, median age 68 years) had 0-1 PS (only one pt had PS 2). 82% were Caucasians, 13% African Americans, and 4% Hispanics. The I starting dose was 700 mg in *1/*1 and *1/*28 pts, and 500 mg in *28/*28 pts. Pharmacokinetics was obtained at cycle 1. DLT at cycle 1 was defined as grade (G) 4 neutropenia (N) for ≥4 days, G≥3N on a treatment day, G≥3 febrile N, G4 anemia or thrombocytopenia, or G≥3 non-hematological toxicity. Results: In *1/*1 pts, the MTD was 850 mg (4 DLTs/16 pts), and 1000 mg was not tolerated (2 DLTs/6). In *1/*28 pts, the MTD was 700 mg (5 DLTs/22) and 850 mg was not tolerated (4 DLTs/6). In *28/*28 pts, the MTD was 400 mg (1 DLT/6) and 500 mg was not tolerated (3 DLTs/3). DLTs were mainly G4N, G≥3 febrile N, and G3 diarrhea. I clearance followed linear kinetics. I and SN-38 AUCs were associated with decreased log10ANC nadir (r2 0.27 and 0.30, respectively, p<0.0001). At the MTD, I AUC in *28/*28 pts was 50% and 62% lower than that of *1/*28 and *1/*1 pts (16.8±4.4, 33.4±11.9, 44.2±11.3 h*ug/ml [mean±SD], respectively). At the MTD, SN-38 AUC in *28/*28 pts was 30% and 26% lower than that of *1/*28 and *1/*1 pts (620±407, 881±715, 841±888 h*ng/ml). 3 PRs were observed (NSCLC-700 mg-*1/*28, gastric-850 mg-*1/*1, small bowel-850 mg-*1/*28). Conclusions: In a heavily pretreated population, UGT1A1*28 information can be used to individualize dosing of I. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in pts receiving I. Clinical trial information: NCT00708773.
Phase I study of inotuzumab ozogamicin (INO) combined with R-GDP for relapsed CD22+ B-cell non-Hodgkin lymphoma (B-NHL).
Authors: Sangha Randeep S. , Davies Andrew John , Dang Nam H. , Ogura Michinori , Paccagnella M. Luisa , Ananthakrishnan Revathi , Vandendries Erik , Tee Goh Yeow
Published: March 2020

2574

Background: CD22 is expressed on most B-NHL. INO, an anti-CD22 antibody linked to calicheamicin, has activity in refractory B-NHL. This study hypothesized that INO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for relapsed CD22+ B-NHL was safe and tolerable. Methods: Patients (pts) with relapsed CD22+ B-NHL treated with ≥1 prior R-chemo regimen were enrolled using an up-and-down independent dose-escalation schema for G and P. INO (0.8 mg/m2 day 2) was combined with R-GDP (R 375 mg/m2, G, and P day 1; oral D 40 mg days 1-4) on a 21-d cycle for up to 6 cycles. Dose-limiting toxicity (DLT) included febrile neutropenia, grade (Gr) 4 ANC lasting ≥7 d, Gr 4 platelets ≥7 d, Gr ≥3 platelets with bleeding and transfusion support, Gr ≥3 QTc prolongation, Gr 4 AST/ALT, Gr 2 bilirubin ≥7 d, G-CSF during cycle 1, Gr ≥3 clinically significant or drug-related nonhematologic toxicity ≥7 d, and Gr ≥2 drug-related nonhematologic toxicity causing dose delay of ≥7 d. Results: Thirty-seven pts were treated: 15 DLBCL, 11 FL, 7 MCL, 1 MZL, 1 SLL, and 2 indolent B-NHL. Characteristics: aged 33 to 81 y (median 65 y); 34 with ECOG PS £1; median of 2 prior chemo regimens (range 1-6); 5 refractory to prior therapy. No DLTs were observed at the starting dose of G 500 mg/m2, P 37.5 mg/m2 (n = 6); 2 DLTs (febrile neutropenia, Gr 2 platelets) at G 1000 mg/m2, P 37.5 mg/m2 (n = 3); no DLTs at G 1000 mg/m2, P 0 mg/m2 (n = 6); 2 DLTs (febrile neutropenia; Gr 4 ANC ≥7 d) at G 500 mg/m2, P 50 mg/m2 (n = 8); and 2 DLTs (Gr 3 hypokalemia, Gr 4 neutropenic sepsis) at G 500 mg/m2, P 75 mg/m2 (n = 4). In a maximum tolerated dose (MTD) confirmation cohort of 10 additional pts, 3 pts had DLTs (2 with Gr 4 platelets, 1 with febrile neutropenia); thus MTD was determined to be INO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2, D 40 mg, P 50 mg/m2. Gr ≥3 adverse events included thrombocytopenia (68%), neutropenia (54%), lymphopenia (32%), anemia (27%), leukopenia (24%), hypokalemia (22%), fatigue (11%), and febrile neutropenia (11%). Median treatment cycle was 4 (range 1-6). There were 8 complete and 9 partial responses. Conclusions: INO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2) and P (50 mg/m2). Preliminary efficacy is being explored in the ongoing MTD expansion cohort. Clinical trial information: NCT01055496.
A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Ciprotti Marika , Tebbutt Niall C. , Lee Fook Thean , Lee Sze Ting , McKee Dave C. , O'Keefe Graeme J. , Gong Sylvia J. , Chong Geoffrey , Gan Hui Kong , Hopkins Wendie , Chappell Bridget , Scott Fiona Elizabeth , Brechbiel Martin W. , Tse Archie N. , Jansen Mendel , Matsumura Manabu , Watanabe Rira , Beckman Robert A. , Greenberg Jonathan , Scott Andrew Mark
Published: March 2020

2583

Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody (Ab) to human DR5 created by CDR grafting of the murine Ab TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in pts with mCRC. Methods: Pts with mCRC were treated with weekly IV CS-1008 in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (0.2 to 6 mg/kg), followed by a weekly dose of 2 mg/kg. D1 and D36 doses were trace-labeled with 111In, followed by whole-body planar and regional SPECT imaging over 10 days. Primary endpoints: initial biodistribution, pharmacokinetic (PK) and tumor uptake following single infusion; changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints: tumor response; changes in tumor metabolism by FDG-PET; serum apoptosis biomarkers and tumor response markers. Results: 19 pts (median age 64 yrs; M:F 11:8; 2-6 prior chemotherapy regimens) were enrolled as follows: Co 1, n=2; Co 2, n=4; Co 3, n=5; Co 4, n=3; and Co 5, n=5. Tumor uptake was variable: 7 pts had no uptake, 11 pts had uptake in all sites of disease but liver, 1 pt showed liver uptake. Tumor uptake and PK were not affected by dose or repeated drug administration. No anti-CS-1008 Ab responses were detected. DR5 expression in archived samples did not correlate with uptake or response. 111In‐CS‐1008 biodistribution showed gradual blood pool clearance and no abnormal uptake in normal tissue. Mean % change in SUVmax from baseline in lesions with uptake was higher than in those with no uptake. There were 8 SD, 1 PR and 10 PD. Duration of PR was 3.7 months (mo). Mean duration of SD was 4 mo. Disease control rate (SD + PR) in pts with uptake was 58% vs 28% of pts with no uptake. Lesions with no uptake were more likely to progress, with a PD risk of 3.4 times higher than those lesions with uptake. Conclusions: Tumor DR5 expression, assessed by 111In-CS-1008 imaging, revealed real-time heterogeneous DR5 expression and appeared to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Clinical trial information: NCT01220999.
Phase I study of the HDAC inhibitor vorinostat in combination with capecitabine in a biweekly schedule in advanced breast cancer.
Authors: James Edward Samuel , Chung Gina G. , DiGiovanna Michael , Sanft Tara Beth , Hofstatter Erin Wysong , Sowers Noelle , Clark Mary Beth , Lilian Rebecca , Chmael Susan , Cappiello Michelle , Abraham Gineesha , Israel Gary M , Pusztai Lajos , Harris Lyndsay , Abu-Khalaf Maysa M.
Published: March 2020

2587

Background: Synergy between histone deacetylase inhibitors and 5-fluorouracil is thought to be due to down regulation of thymidylate synthase. Study objectives are to assess maximum tolerated dose (MTD), dose limiting toxicities (DLT) and objective response rate of vorinostat (V) in combination with capecitabine (C). Secondary aims are pharmacodynamics of V. Methods: Cohorts of 3-6 patients (pts) were enrolled on a 3+3 dose-escalation phase to assess MTD of escalating doses of oral C (1500/1800/2000mg) with V 200 mg BID on days 1-7 and 15-21 of a 28 d cycle. 10 pts enrolled on dose expansion phase and treated at MTD. Pts received a “run in” treatment of V for 5 d and pre/post V biopsy (bx) collected when feasible. DLT was defined as ≥ grade 3 non hematological toxicity, grade 4 thrombocytopenia, grade 4 neutropenia > 5 d, grade 4 febrile neutropenia requiring hospitalization, QTc >500ms,or treatment delay > 2 weeks from toxicity. Microarray analysis was performed using Illumina HT-12 gene arrays on pre/post bx from 4 pts. Results: 23 ptswith median age 51 (range 33-69) were treated: 8 pts at 1500/200mg, 5 pts at 1800/200mg, and 10 pts treated on dose expansion phase at 1500/200mg. Median # of prior lines of chemotherapy was 2 (range 0-7). 3 pts are still on study. Median # of cycles on study were 2 (range 1-42). Cycle 1 DLT was grade 3 fatigue in 2 pts treated on 1800/200mg, and in 1 pt treated on 1500/200mg. Other grade 3/4 toxicities are summarized in the Table. 14 pts are evaluable for response (12 pts at 1500/200mg and 2 pts at 1800/200mg). No objective responses were seen, 3 pts had stable disease > 6 months (1 pt completed 42 cycles). Changes in pathways involved in extracellular matrix and TGFb pathway were noted. Conclusions: DLT of C concomitant with V was fatigue. MTD was 1500 mg C combined with 200 mg V BID. Combination has modest clinical activity. Consistent modulation of pathways involved in extracellular matrix and TGFb pathway, suggesting biomarkers of response to V. Clinical trial information: NCT00719875. [Table: see text]
Involvement of compensatory CD44+ stem cells following BCL-2 suppression by antisense oligonucleotides.
Authors: Rubenstein Marvin , Hollowell Courtney M.P. , Guinan Patrick
Published: March 2020

2590

Background: Gene therapy is in theory specific but encounters difficulties in practice. Suitable targets are found in many pathways and tumors do express altered patterns of expression. However the actual activity of most regulatory genes are similar to normal. Resistance develops because biochemical pathways are complex, regulated by stimulatory and inhibitory factors, each possibly affected by therapy. It’s suggested that tumors alter dependence on targeted gene products for growth by relying upon others, through compensation. Antisense oligos have targeted regulatory proteins in both in vivo and in vitro prostate cancer models. Cells treated with antisense directed against bcl-2 compensated by suppressing caspase-3 (an apoptosis promoter) and enhancing androgen receptor (AR), (co-activating) p300 and IL-6 expression. This suggests that in LNCaP a progression to increased androgen sensitivity accompanies bcl-2 suppression with a pattern of co-activation associated with more advanced prostate tumors. Methods: We evaluated mono- and bispecific oligos which targeted and equally suppressed bcl-2 expression in LNCaP cells. To further evaluate compensatory mechanisms related to tumor resistance we evaluated the level of CD44 expression employing RT-PCR and agarose gel quantification. Bands representing pcr product were photographed, converted to black and white and assessed by MIPAV software. Results: Comparable amounts of RNA from LNCaP cells treated with either mono- or bispecific oligos directed against bcl-2 (and EGFR in the bispecifics) were evaluated by RT-PCR using primers directed against CD44. When background intensity was subtracted, the relative intensity of the bands corresponding to CD44, and representing cells treated with MR4, MR24 and MR42 (compared to controls) were respectively increased 3.0% ± 33.6 (NS), suppressed 16.4% ± 49.1 (NS) and suppressed 9.2% ± 26.5 (NS). These results were pooled from both duplicate PCR runs and gels, and indicate no significant changes in CD44 expression was produced by any oligo type. Conclusions: Stem cells expressing this marker were unaffected by treatment, suggesting this population is not altered by suppressive bcl-2 therapy.
Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results.
Authors: Bernadou Guillemette , Rezai Keyvan , Merlin Jean-Louis , Campone Mario , Lokiec Francois , Bachelot Thomas Denis , Delaloge Suzette , Dieras Veronique , Jimenez Marta , Ternant David , Paintaud Gilles
Published: March 2020

2599

Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.
Phase I clinical trials attrition related to central molecular prescreening.
Authors: Boni Valentina , Garralda Elena , Cubillo Antonio , Diaz-Padilla Ivan , Calles Antonio , Gomez-Martin Carlos , Cerdá Sara , Puerta Sonia , Ordonez Esther , López-Ríos Fernando , Olmos David , Hidalgo Manuel , Calvo Emiliano
Published: March 2020

2600

Background: The increasing trend to incorporate molecular assays as part of selection assessment in Ph1 trials is based on the potential to observe early antitumor activity. Nonetheless, its impact has been almost negligible to date and might affect time to achieve a recommended dose. We assessed the impact on recruitment of pursuing central mandatory molecular assessment of tumor samples on a state-of-the-art Ph1 unit. Methods: Two first-in-human Ph1 studies, requiring central laboratory biomarker assessment as inclusion criterion (DS6 IHC and FGFR mut/ampl, respectively), and a consecutive series of pts in our program for central tumor mutation screening (OncoCarta Panel v1.0) to participate in molecularly-driven Ph1 studies, were reviewed. Results: 13 (4.8%) out of 267 pre-screened pts were able to receive treatment within a targeted Ph1 trial. Conclusions: A vast majority of pts trying to participate in molecularly-driven trial central biomarker screening are not included due to negative results. Still 71.1% pts who were initially eligible and were positive in the central review fail to participate due to clinical and/or analytical deterioration during the time of central molecular assessment. New strategies including local sample pre-screening allowance, as well as anticipated massive molecular profiling in the conventional setting, are needed to reduce this time and improve feasibility of these trials. The derived current “impoverishment” of studies with non-targeted drugs (that lack patients with tumors with “hot” mutations) and of those with targeted drugs (that miss patients with nonmutated tumors) within the same Ph1 Programs, and the need of a joint approach to co-finance for wide-spectrum molecular profiling for different studies, would be discussed as well. [Table: see text]