bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MLN8237, a novel selective aurora A kinase (AAK) inhibitor, in patients (pts) with advanced solid tumors
Authors: Cervantes-Ruiperez A. , Elez M. E. , Roselló S. , Macarulla T. , Rodríguez-Braun E. , Lee Y. , Ecsedy J. , Liu H. , Fingert H. , Tabernero J. 
Published: August 2020

2565 Background: MLN8237 is a second-generation, selective AAK inhibitor, designed to avoid benzodiazepine-like effects (somnolence) observed with another agent, MLN8054. This phase I trial examines the safety, PK, and PD of MLN8237 administered orally (PO) in pts with advanced solid tumors. Methods: Pts received MLN8237 PO once daily (QD) or twice daily (BID) for 7 days (d) followed by a 14d recovery period. Tumor and skin biopsies were done serially to evaluate bioactivity measured by mitotic index and chromosome and spindle abnormalities in mitotic cells. Doses were increased in cohorts of 3–6 pts until dose-limiting toxicity (DLT) evaluated in the first cycle was seen in ≥2 pts in a cohort. Results: As of 12-Dec-08, 27 pts received MLN8237 (median 2 cycles, range 1–10+); median age was 57 yr (range 31–78). The first cohort received 5mg QD. Higher QD doses were safe in another Phase 1 study (Infante et al, EJC Suppl 2008;6[12]:90), so subsequent cohorts in this study started at 80mg QD (Table). DLTs at 60–100mg PO BID included neutropenia, pancytopenia, stomatitis, and somnolence. Somnolence (of any grade) was seen with QD dosing, but was reduced with divided doses each <100 mg. Antitumor activity was seen in a pt in cohort 4 with a large treatment-resistant pleomorphic liposarcoma. Preliminary PK analyses showed dose-dependent increases in AUC0–24 and Cmax. Consistent with Aurora A inhibition, increased mitotic index in skin and tumor biopsies after MLN8237 dosing was coupled with decreased bipolar spindles and aligned chromosomes in mitotic cells from tumor biopsies. Conclusions: At the doses and schedule evaluated, MLN8237 is tolerable with BID dosing x7d and exhibits favorable PK, PD, and clinical antitumor activity. Additional planned cohorts include extended dosing for 14–21d in 28–35d cycles. The results support future phase 2 development. [Table: see text] [Table: see text]
A phase I study of AT9283, an aurora kinase inhibitor, in patients with refractory solid tumors
Authors: Kristeleit R. , Calvert H. , Arkenau H. , Olmos D. , Adam J. , Plummer E. R. , Lock V. , Squires M. , Fazal L. , Judson I. 
Published: August 2020

2566 Background: AT9283, a multitargeted kinase inhibitor, inhibits several closely related tyrosine and serine/threonine kinases with an IC50 of <10 nM including Aurora A and B, JAK and ABL. Exposure of solid tumour cell lines to AT9283 in vitro induces an “aurora inhibitory” phenotype. Cell survival decreases with increased duration of exposure. Methods: A phase I dose escalation study was performed using a 72 hour continuous intravenous (iv) infusion schedule repeated three weekly according to a stand ard “3+3” design. Results: Thirty-three patients have been treated with a median age of 61 (range 33 to 76 years). The maximum tolerated dose (MTD) was 9 mg/m2/day. Treatment was well tolerated with febrile neutropenia the only dose limiting toxicity. Other adverse events considered possibly related to AT9283 were reversible and included gastrointestinal disturbance and fatigue. Biological evidence of aurora B inhibition manifest as a reduction in histone H3 phosphorylation in skin biopsies during the infusion was observed at all dose levels. A plateau steady state plasma concentration of AT9283 was achieved within 24 hours of initiating drug infusion at all dose levels and exposure increased linearly with dose. Seven patients received an initial oral dose of AT9283 as an aqueous solution in a fasting state at a dose of 0.9 mg mg/m2 one week prior to starting iv treatment. Interim pharmacokinetic analysis indicated that the median oral bioavailability was 27% (range 17 to 45%) The best response to treatment was a partial response in one patient with NSCLC (ongoing). An additional 4 patients received at least six cycles of therapy (squamous cell carcinoma of the lung, adenocarcinoma of the esophagus and colorectal carcinoma [2]) with a best response of stable disease. Conclusions: The MTD of AT9283 when administered as a 72 hour continuous iv infusion was 9mg/m2/day. Febrile neutropenia is the dose limiting toxicity and evidence of anticancer activity was seen in heavily pre-treated patients. [Table: see text] [Table: see text]
Phase I study of the novel anticancer drug PM00104 as a 24-hour IV infusion every 3 weeks (q3w) in patients (pts) with advanced solid tumors or lymphoma
Authors: Capdevila J. , Clive S. , Tabernero J. , Lardelli P. , Soto-Matos A. , Baselga J. , Piera A. , Pardos I. , Rye R. , Smyth J. F. 
Published: August 2020

2568 Background: PM00104 is a novel synthetic alkaloid related to the marine compounds jorumycin and renieramycins. Preliminary preclinical studies suggest changes in cell cycle and DNA binding properties and transcriptional inhibition as main mechanisms of action. PM00104 has shown broad in vitro and in vivo anti-tumor activity (IC50 ≤ 10-8 M) with an acceptable toxicology profile. Methods: The aim of this phase I study was to assess the safety profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), relationship between PK and pharmacodynamics (PD) and anti-tumor activity of PM00104 administered as a 24-hour i.v. infusion q3w. Sequential cohorts of 3–6 pts were treated at 133, 266, 400, 800, 900, 1600, 3200, 4000 and 5000 μg/m2. Results: Twenty nine pts have been treated (18 male, 11 female; median age: 59, range: 44–78; ECOG PS ≤2). Five pts developed DLTs: 2 pts at 5000 μg/m2 (grade 4 thrombocytopenia/neutropenia and grade 3 nausea/vomiting in 1 pt; and grade 3 nausea in 1 pt); 1 at 4000 μg/m2 (grade 4 neutropenia/thrombocytopenia and grade 3 asthenia); 1 at 3200 μg/m2 (grade 3 tumor pain) and 1 at 266 μg/m2 (grade 3 transaminase increase). The MTD was reached at 5000 μg/m2 and the RD at 4000 μg/m2. At the RD 6 more pts have been included in order to further evaluate the safety profile and anti-tumor activity. Other adverse events included nausea and vomiting (more frequent at doses ≥800 μg/m2), fatigue, anorexia and diarrhea; most of them being of ≤grade 2 severity. No objective responses were seen but 3 pts with pancreatic adenocarcinoma, hepatocarcinoma and lower esophagus adenocarcinoma presented stable disease lasting >3 months. PM00104 shows a dose-proportional PK profile, the half-life being 20–30 hours and the volume of distribution around 1000 L. Conclusions: PM00104 has shown an acceptable safety profile with signs of anti-tumor activity in pts with advanced malignancies when administered as a 24-hour i.v. infusion q3w. PM00104 is also being evaluated with other administration schedules as monotherapy and in combination with other anti-tumor agents. [Table: see text]
A phase I study of flavopiridol using an alternative schedule in patients (pts) with advanced solid tumors
Authors: Ramaswamy B. , Phelps M. , Baiocchi R. , Bekaii-Saab T. , Wilkins D. , Arbogast D. , Campbell A. , Doyle A. L. , Grever M. , Shah M. 
Published: August 2020

2580 Background: A phase I study of flavopiridol, a cyclin-dependent kinase inhibitor, using an alternative schedule was conducted in pts with solid tumors given its promising activity in pts with chronic lymphocytic leukemia (CLL). Methods: Using standard 3x3 ph I dose escalation design, NCI-sponsored trial was performed to determine the safety and dose-limiting toxicity (DLT) of flavopiridol given as a 30-min IV loading dose followed by a 4-hr infusion weekly for 4 wks repeated every 6 wks. DLT was defined as Gr 4 hematologic toxicity (HT) for > 7 days, > Gr 3 non-HT except Gr 3 fatigue or diarrhea resolving <4 days and cytokine release syndrome (CRS) > Gr 3 despite steroids. Blood samples were obtained at pre-dose and 0.5, 1, 3, 4.5, 6, 8, 24, and 48-hr after start of first bolus dose for pharmacokinetics (PK). Results: 26 pts with advanced solid tumors with a median age of 63 (44–75) yrs were enrolled. Median no. of doses was 7.5 (1–24). Table 1 outlines the PK parameters, DLTs and CRS. Due to a grade 5 CRS/death in cohort 3, the protocol was amended to include 20 mg IV dexamethasone prior to flavopiridol to prevent CRS (cohorts 2B, 1B). Of the 20 evaluable pts, 35% had stable- and 65% had progressive-disease. Results of serum cytokines (IL-2, IL-4, IL-6, TNF-a, IFN-g, IL-10) levels will be presented. Conclusions: There was a higher frequency of CRS, despite prophylactic steroids seen our pts with solid tumors compared to previous studies with CLL and this correlated with AUC. PK and toxicity profile in our pt population differs from pts with hematologic malignancies administered flavopiridol on the same schedule. Protein binding and serum albumin levels are under evaluation as potential contributors. This work is supported by NCI U01-CA76576. [Table: see text] [Table: see text]
A phase I study of nelfinavir, an FDA approved HIV protease inhibitor, in adults with refractory solid tumors
Authors: Dennis P. A. , Blumenthal G. , Ballas M. , Gardner E. , Kawabata S. , LoPiccolo J. , Helsabeck C. , Root H. , Figg W. D. , Bernstein W. 
Published: August 2020

2583 Background: Preclinical studies show that HIV protease inhibitors such as nelfinavir (N) have dose- dependent, pleiotropic anti-cancer activities. However, the maximum tolerated dose (MTD) of N has not been established in humans. Methods: Pts were treated on a modified Fibonacci dose-escalation scheme with a twice daily oral dose of N starting at the FDA approved dose of 1250 mg bid on a 21-day cycle. Patients with refractory solid tumors, ECOG PS < 2, and adequate organ function were eligible. Therapy continued until MTD or disease progression. PBMCs as well as optional tumor biopsies were collected for Akt inhibition and expression of markers of ER stress (ERS). Results: 14 patients have been enrolled. Of the 11 evaluable for toxicity, there were 10 men, 10 Caucasians, and 1 African American (median age 63 years (range 24 - 77)). Tumor types included NSCLC (3), SCLC (2), thyroid (3), pancreatic (1), colorectal (1), and renal cell (1). Median number of prior systemic therapies was 2 (range, 1 - 6). There have been no grade 4 or 5 toxicities. We observed 12 grade 3 toxicities that were asymptomatic laboratory abnormalities. The most prevalent toxicities were ALT transaminitis (5 events in 8 subjects in dose level ((DL) 2, 3, 4), AST transaminitis (4 events in 8 subjects in DL 2, 4), diarrhea (8 events in 5 subjects in DL 2, 3, 4), and hyperglycemia (5 events in 5 subjects in DL 1, 2, 3). Enrollment continues at DL 4 (3125 mg twice daily). There have been no responses. Two subjects with lung cancer had stable disease for 9 weeks. Pharmacokinetic data revealed median Cmax of 2,461.5 ng/ml (DL1), 11,809 ng/ml (DL2), 11,576 ng/ml (DL3), and 11,986 ng/ml (DL4), occurring 4 hours after an oral dose. There was no relationship between the drug levels and albumin levels. Akt inhibition and increased expression of markers of ERS and apoptosis have been observed in PBMCs from week 1 in the majority of patients at every dose level, but there was no correlation with clinical response. Conclusions: N appears to be well tolerated in subjects with advanced solid tumors at 2.5 times the FDA approved dose. AUC data suggest that there may be only minimal increases in plasma drug concentrations with doses above 1875 mg twice daily. No significant financial relationships to disclose.
Phase II study of bavituximab plus docetaxel in patients with locally advanced or metastatic breast cancer
Authors: Tabagari D. , Nemsadze G. , Jincharadze M. , Janjalia M. , Shan J. S. 
Published: August 2020

3005 Background: Phosphatidylserine (PS) is an anionic phospholipid normally present on the inside surface of cell membranes. PS becomes exposed on the outside surface of tumor endolethial cells. Bavituximab (B) is a novel anti-PS monoclonal antibody and has demonstrated preclinical synergistic antitumor activity when used in combination with docetaxel. Methods: This Simon 2-stage trial is designed to determine the overall response rate (CR+PR) in patients with locally advanced or metastatic breast cancer to a combination of weekly bavituximab (3 mg/kg) plus docetaxel (35 mg/m2) on days 1, 8, 15 of a 28-day cycle for up to 6 cycles. Following completion of docetaxel, weekly bavituximab is continued until progression or toxicity. If ≥ 6 responses are observed in the 15 pt enrolled to Stage A, an additional 31 pts will be enrolled to Stage B. Secondary objectives include time to tumor progression, duration of response, overall survival, and safety. Results: Data are available for the 15 female pts enrolled in Stage A of the trial. Median age was 49 years;13 had stage IV and 2 had recurrent/progressive stage III breast cancer at study entry. All patients received prior chemotherapy, 13 had surgery, 7 had hormone therapy and 5 had prior radiotherapy. Patients received a median of 6 cycles of treatment. All patients reported at least one AE, to date. The most common AEs (regardless of severity or causality) were alopecia, epistaxis, fatigue, back pain, diarrhea, nasal dryness, infusion related reaction, arthralgia, pyrexia, stomatitis and nail bed bleeding. Grade 3 drug-related AEs were back pain, headache, DVT (discontinued study treatment at week 3) and chest pain (SAE) starting during a docetaxel infusion, which recurred after completion of bavituximab, reported in one patient each. Using RECIST, the overall response rate in these 15 pt is 67% (95% confidence interval, 38–88%) for the intent-to-treat group and 71% (95% CI, 42–92%) for the 14 evaluable patients. All responses were confirmed at least 4 weeks later. Conclusions: Bavituximab plus docetaxel achieved an encouraging response rate in advanced/metastatic breast cancer in Stage A of this study. Enrollment in Stage B of the trial is expected to be completed with preliminary results available by the annual meeting. [Table: see text]
Results from the first phase I clinical study of the novel Ii-Key/HER2/neu(776–790) hybrid peptide vaccine in patients with prostate cancer
Authors: Perez S. A. , Bisias S. , Kallinteris N. L. , Ardavanis A. , Georgakopoulou K. G. , Apostolikas N. , Thanos A. , Papamichail M. , von Hofe E. , Baxevanis C. N. 
Published: August 2020

3011 Background: HER-2/neu(776–790) represents an immunogenic epitope from the HER-2/neu oncoprotein whose immunogenicity is highly potentiated upon linkage with the Ii-Key moiety (LRMK) from the MHC class II invariant chain. Herein, we present the results of the first phase I clinical trial of the Ii-Key/HER-2/neu(776–790) (AE37) vaccine in patients (pts) with prostate cancer. Methods: Androgen-dependent (AD) and androgen-independent (AI) pts with HER-2/neu+ (IHC: 1–3) prostate adenocarcinomas were eligible. Concomitant medication with bicatulamide and LHRH or docitaxel was allowed. All pts received 6 monthly vaccinations with the AE37 vaccine (500 μg of AE37 plus 125 μg of GM-CSF) administered in two doses intradermally 5cm apart in the same extremity for each vaccination cycle. Immunologic responses were measured monthly in vitro by the IFNγ-based ELISPOT assay using pts’ PBMC and in vivo at the beginning and end of immunizations using DTH. Local dermal reactions were also measured after each vaccination. Results: Eligible pts [AD (n=18), AI (n=10)] were at stages T1–3N0M0, GS: 3–7 (n=18); T1–3N+M0, GS: 6–7 (n=2); T1–3N0M+, GS: 6–9 (n=4) and T1–3N+M+, GS: 6–9 (n=4). All pts had standard treatment prior to vaccinations, including surgery (S) (n=9); hormonal treatment (HT) (n=4); S+HT (n=6); S+HT+radiotherapy (RT); (n=2); S+chemotherapy (CH) (n=2); HT+RT (n=2); CH (n=3) and S+HT+CH (n=2). During vaccinations, 11 pts were free of any treatment, while 5 pts who had progressive disease received additional chemotherapy; the remainder received HT alone or combined with RT. 25 pts completed all vaccinations. Toxicity and side effects beyond grade-2 were not observed. GM-CSF was reduced by 50% for subsequent vaccinations when a local reaction of 100mm or greater was observed. DTH reactions to the parent HER-2/neu(776–790) peptide were increased (compared to pre-vaccination) for all pts, while approximately half the pts responded with significantly increased IFNγ responses to AE37 and/or parent HER-2/neu(776–790) peptide in at least 2 sequential vaccination cycles. Conclusions: The AE37 vaccine is safe and well tolerated. AE37 is also capable of eliciting potent and specific immunologic responses in prostate cancer pts. [Table: see text]
Correlation of immune responses and survival in a phase II study of belagenpumatucel-L in non-small cell lung cancer
Authors: Fakhrai H. , Tong A. , Nemunaitis J. , Shawler D. L. 
Published: August 2020

3013 Background: Belagenpumatucel-L (Lucanix), a therapeutic vaccine comprised of 4 TGF-β2 antisense gene-modified allogeneic non-small cell lung cancer (NSCLC) cell lines, was tested in a phase II trial in which subjects with stage IIIB/IV NSCLC received intradermal injections of the vaccine every 4–8 weeks. Methods: We performed 2 cellular immunity assays and 2 humoral immunity assays on subjects in the trial. To measure the overall immune status, pretreatment peripheral blood mononuclear cells (PBMC) were stimulated by PMA/ionomycin and assessed by formation of IFN-γ ELISPOT. We also measured in vitro IFN-γ ELISPOT formation by subjects’ PBMC following vaccination. The two humoral assays looked at the induction of anti-belagenpumatucel-L antibodies and anti-HLA antibodies. Results: Subjects were classified as immune response positive (IR+) if they were positive for 3 or 4 of the assays described above. The remaining subjects were classified as immune response negative (IR-). There were 11 subjects who were IR+ and 24 who were IR-negative. The IR+ subjects had a median survival of 32.5 months (95% CI, 25.2 to 39.8) compared to 11.6 months (95% CI, 5.6 to 17.6) for IR- subjects (p=0.011, log-rank test). Subjects were also classified as clinical responders or nonresponders based on their tumor assessment after 4 months on trial. 10/19 subjects classified as clinical responders were IR+ compared to only 1/16 nonresponders (p=0.004, Fisher's exact test). Conclusions: These data demonstrate a strong correlation between the achievement of a combination of cellular and humoral immune responses and a significant increase in overall survival in the subjects treated with belagenpumatucel-L and suggest that both components of the immune system are important for the induction of clinically significant antitumor immunity by the vaccine. [Table: see text]
A phase I study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma (MM) or renal cell carcinoma (RCC)
Authors: Spicer J. F. , Jameson M. B. , Savage P. , Jodrell D. , Rudman S. M. , Erlandsson F. , Acton G. , McKeage M. 
Published: August 2020

3024 Background: AS1409 (huBC1-huIL-12) is a fusion protein combining a humanized antibody specific for the ED-B splice variant of fibronectin with human IL-12. ED-B-fibronectin is expressed in tumor vasculature. IL-12 stimulates T and NK cell activity. Responses to IL12 occur in MM and RCC, but with high systemic toxicity. AS1409 is designed to target IL-12 to tumor vasculature. Methods: Patients with MM or RCC were treated in a dose-escalating trial of weekly i.v. AS1409 for 6 weeks with a starting dose of 15mcg/kg. Patients without unacceptable toxicity or disease progression could continue therapy. IFN-gamma and IP-10 were measured as biomarkers of activation of cellular immunity. Results: 13 patients (9 males; median age 53 years; 11 MM, 2 RCC) were treated (7 at 15mcg/kg, 6 at 25mcg/kg). DLTs observed at 25 mcg/kg were transaminase elevation and fatigue. Other toxicities included flu-like syndrome, fever, myalgia, and mucositis. Three patients continued to receive AS1409 beyond 6 weeks and 1 patient remained on treatment beyond 30 weeks. All patients showed elevation of IFN-gamma and IP10 following the first dose, although subsequently attenuated; prominent anti-drug antibody (ADA) responses were seen. A partial response was seen in a patient with MM metastatic to lymph nodes treated at 15mcg/kg, and a best response of stable disease was seen in 4 patients. Mean AS1409 half-life was 19.3 ±5.3h, mean distribution volume was 0.25 ± 0.098L/kg and clearance was 9.8 ± 6.5mL/hr/kg. Conclusions: At 15mcg/kg AS1409 was well tolerated. Biomarker activation and objective radiological evidence of anticancer activity was observed at this dose. Further study of AS1409 is focussed on optimizing dosing and scheduling, characterizing the ADA response, and antibody biodistribution. [Table: see text]
Novel monoclonal antibody that enhances natural killer (NK) cell cytotoxicity against multiple myeloma (MM): Preclinical data and interim phase I clinical trial results
Authors: Benson D. M. , Romagne F. , Squiban P. , Wagtmann N. , Farag S. , Mita A. , Hofmeister C. , Smith M. , Bakan C. , Caligiuri M. 
Published: August 2020

3032 Background: MM is increasing in incidence and remains incurable. NK cells have modest killing activity against MM cells in part because of inhibitory signals from HLA class 1 antigens which act via the KIR receptors on NK cells. A novel anti-KIR blocking antibody (1–7F9 named IPH 2101) enhances patient NK cell cytotoxicity against autologous MM tumor cells in vitro and appears safe in an ongoing phase 1 clinical trial. Methods: NK cells from healthy controls or patients were pre-treated with IPH 2101 or IgG4 isotype control and co-cultured with MM cell lines or autologous MM tumor targets. NK cell production of interferon-gamma (IFN-γ) or granzyme B (GrB) were measured by ELISPOT. An open-label, single-agent, phase 1 dose escalation study of IPH 2101 is being conducted in patients with relapsed/refractory MM. KIR binding, pharmacokinetics, pharmacodynamics, effects on NK cell maturation, and biological effects of IPH 2101 are being monitored in all patients. Results: At an effector to target (E:T) ratio of 1:1, IPH 2101 significantly enhances NK cell IFN-γ release against MM targets (mean 33 spots/well ± 12, SEM vs. 11 ± 0.3, p = 0.005). At an E:T ratio of 10:1, IPH 2101 enhances NK cell cytotoxicity, by GrB release, of patient NK cells against autologous MM tumor cells (mean 111 spots/well ± 14, SEM vs 56 ± 10, p = 0.002). By Western blot, IPH 2101 may reduce levels of src, a kinase known to be involved in inhibitory KIR signaling. Dose escalation in the phase 1 study has been completed from 0.0003 mg/kg to 0.075 mg/kg in 14 evaluable patients. At the highest dose tested, KIR occupancy has been detected at a mean 95% ± 1.4 at 2 hours post dose, lasting up to 56% ± 18 during 2 weeks post dose. At this dose level, PK data show good correspondence with previous modeling activity. No deleterious effect on NK cell maturation has been seen. IPH 2101 has been well tolerated to date. Conclusions: IPH 2101 improves autologous NK cell killing of MM tumor cells by blocking inhibitory KIR. In the ongoing clinical trial, the antibody appears safe and well tolerated at the doses tested. This immunotherapeutic approach may hold promise as treatment for MM and further study is warranted. [Table: see text]