bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST)
Authors: Tolcher A. W. , Yap T. A. , Fearen I. , Taylor A. , Carpenter C. , Brunetto A. T. , Beeram M. , Papadopoulos K. , Yan L. , de Bono J. 
Published: August 2020

3503 Background: Akt facilitates cell proliferation/survival and is a suspected driver of progression in ST. MK-2206, a highly selective non-ATP competitive allosteric Akti, has nM IC50 and broad preclinical antitumor activity. Methods: Safety and tolerability of MK-2206 administered QOD in 28-day cycles (cy) was assessed. Doses evaluated: 30, 60, 90 mg, and 75 mg. Main eligibility criteria: ≥18 yo, evaluable advanced ST, ECOG ≤1, HbA1c ≤8% or fasting glucose ≤110% upper limit of normal. PK and phosphorylated Akt (pAkt) in whole blood by meso-scale ELISA were measured. Sequential tumor biopsies were performed in a subset of pts. Results: Dose escalation occurred in 19 pts (8 female/11 male; median age 57 yo; ECOG 0/1: 5/14) and 37 cy of therapy with no DLTs at 30 and 60 mg. CTCAE G3/4 skin rash and CTCAE G3 mucositis were observed at 90 mg in 4/7 pts. After further accrual at 60 mg confirmed safety at this dose, 75 mg was explored; however, 2/3 pts experienced DLT of rash. Dose escalation is complete; the MTD of MK-2206 is 60 mg QOD. Common drug-related AEs included skin (47.1%), gastrointestinal (41.2%), and general disorders (29.4%). AUC0–48hr and Cmax were dose proportional up to 60 mg. Median Tmax is 6 hrs and mean t1/2 ranged from 63 to 76 hr. MK-2206 concentrations exceeding a preliminary, statistically determined PK target of approximately 50–65 nM for significant pAkti in blood were maintained over the entire dosing interval in all patients in the 60 mg cohort. Evidence of PD activity included decreases in whole blood pAkt at all dose levels, reversible CTCAE G1/2 hyperglycemia and CTCAE G1 insulin c-peptide elevations. RECIST stable disease following 2 cycles of therapy was observed in 1 pt at 30 mg and 5 pts at 60 mg. Observed clinical activity included: central tumor necrosis, decreased ascites and peripheral edema, reduction in index lesions, normalization of LFTs, and decreased CA-125. Conclusions: MK-2206 is generally well tolerated at doses up to 60 mg QOD with plasma concentrations that portend activity in preclinical models. PK/PD data suggest a substantial and maintained target inhibition at 60 mg. [Table: see text]
Ongoing phase I studies of ABT-263: Mitigating Bcl-XL induced thrombocytopenia with lead-in and continuous dosing
Authors: Roberts A. W. , Wilson W. , Gandhi L. , O'Connor O. A. , Rudin C. M. , Brown J. R. , Xiong H. , Chiu Y. , Enschede S. , Krivoshik A. P. 
Published: August 2020

3505 Background: ABT-263, a novel, oral BH3 mimetic, potently inhibits multiple antiapoptotic Bcl-2 family proteins. Ongoing phase 1 studies of ABT-263 show anti-tumor activity in CLL and some lymphomas (Wilson W et al, ASH. 2008). However, thrombocytopenia (TCP) due to on-target Bcl-XL inhibition-induced platelet apoptosis is also observed. Platelet nadir occurred on days 3–5 on 14/21 d dosing with each exposure to drug, was proportional to starting platelet count and recovered during therapy due to compensatory increased megakaryopoiesis. TCP was a dose limiting toxicity (DLT) in 3 patients (pts) in CLL study M06–873 (N = 15) where starting platelet counts tend to be low. We tested 2 strategies to mitigate variability in circulating platelet levels and achieve higher cumulative exposure: introducing a lower lead-in dose and using a continuous dosing (CD) (21/21 d schedule). Methods: CD with a 7 d lead-in dose was explored (150, 150 or 100 mg lead-in doses) with dosing at 200 and 275 mg, 225 and 325 mg, or 125 and 250 mg in studies M06–814 (NHL), M06–822 (SCLC), and M06 873 (CLL), respectively. Results: 22 pts on 21/21 d dosing enrolled to date in the 3 studies. Cmax & AUC at steady-state were comparable between pts at the same dose on 21/21 and 14/21 d schedules. Lead-in followed by CD appears to minimize platelet nadir and cycle variability. At 200 mg and grouping data from 200 and 225 mg doses, median platelet nadir in Cycle 1 was 46% and 42% of baseline on the CD schedule after lead-in vs 33% and 36% on the 14/21 schedule, respectively. For pts receiving 150 mg lead-in, nadir occurred during this phase, and platelet levels remained relatively stable on CD for doses up to 225 mg. 2 DLTs were observed for CD, 1 pt per study M06–814 (275 mg) and M06–873 (200 mg) experienced grade 4 (TCP). While CD enrollment and time on study is still limited, anti-tumor activity includes 1 unconfirmed partial response (68% CT regression) in a SLL pt at 275 mg and 3 CLL pts with ≥50% lymphocyte reduction for ≥2 months. Conclusions: Dosing schedule moderates early platelet nadir. Optimal dosing regimens may vary between tumor types especially where marrow infiltration is a feature. [Table: see text]
First-in-human clinical, pharmacokinetic (PK), and pharmacodynamic (PD) phase I study of the first-in-class spliceosome inhibitor E7107 administered IV (bolus) on days 1, 8, and 15 every 28 days to patients with solid tumors
Authors: Eskens F. A. , Ramos F. J. , Burger H. , de Jonge M. J. , Wanders J. , Lopez-Anaya A. , Baselga J. , Tabernero J. 
Published: August 2020

3508 Background: E7107 is a potent first-in-class inhibitor of the spliceosome, most likely by interacting with spliceosome-associated protein-130 (SAP 130). Splicing removes intron sequences from pre-mRNA and exons are fused resulting in the formation of mature mRNA. Alternative splicing frequently encodes oncoproteins. E7107 interferes the maturation process of pre-mRNA to mRNA, with consequent changes in protein expression profiles. Methods: Objectives of this study were to explore (1) tolerability and safety profile, (2) PK, (3) PD effects on pre-mRNA splicing, and (4) anti tumor activity of E7107 administered as bolus infusion on days 1, 8, 15 of a 28-day schedule Results: 36 patients (21M/15F, median age 61yrs (45–79)) received E7107 doses of 0.6 mg/m2 (n=4), 0.9 mg/m2 (n=3), 1.3 mg/m2 (n=3), 2.0 mg/m2 (n=3), 3.0 mg/m2 (n=4), 4.5 mg/m2 (n=3) and 4.0 mg/m2 (n=16). At 4.5 mg/m2 two episodes of DLT (grade 3 and 4 diarrhea) and at 4.0 mg/m2 one episode of DLT (a combination of grade 3 nausea, vomiting and abdominal cramps) were observed. Other frequently occurring side effects were mainly gastrointestinal. The maximum tolerable dose (MTD) is 4.0 mg/m2. No complete or partial responses were observed. Pharmacokinetic analysis revealed large volume of distribution (Vss: 279 to 1369 L), high systemic clearance (CL: 111 to 253 L/hr), and moderate elimination half-life (t1/2: 5.3 to 15.1 hr). Systemic exposure on Days 1 and 15 (Cmax, AUC0-∞) increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes (TRAPPC4, SLC25A19, GTF2H1), monitored in PBMC's, showed a 15–25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a 10–25-fold increase. Notably, at days 1 and 15, modulations generally peaked at 2–6 hr after end of the infusion and almost completely recovered to base-line levels at 24–48 hr. Conclusions: The MTD for E7107 using this schedule is 4.0 mg/m2. PK is dose-dependent and reproducible within subjects. PD analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107. [Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of HDM-2 antagonist JNJ-26854165 in patients with advanced refractory solid tumors
Authors: Tabernero J. , Dirix L. , Schoffski P. , Cervantes A. , Capdevila J. , Baselga J. , van Beijsterveldt L. , Winkler H. , Kraljevic S. , Zhuang S. H. 
Published: August 2020

3514 Background: JNJ-26854165 is a novel first-in-clinic oral Human Double Minute-2 (HDM-2) ubiquitin ligase antagonist. It increases the level of HDM-2 client proteins (e.g. p53) by inhibiting the association of HDM-2-client protein complex with the proteosome. Preclinical studies have demonstrated potent anti-proliferative and apoptosis-inducing activity of JNJ-26854165 in a broad range of p53 wild type and mutant tumor models. Methods: A 3+3 dose escalation study with the primary objectives to determine the adverse event (AE) profile, dose limiting toxicities (DLT) and maximum tolerated dose of JNJ-26854165 is ongoing. Secondary objectives include evaluation of PK and PD activity. Eligible patients have ECOG PS≤2 and adequate hematological, renal and hepatic function. JNJ-26854165 is administered orally once daily on a continuous schedule (21-day cycles). Sequential skin and tumor biopsies are taken, and evaluations for HDM-2, p53 and other pathway related markers are performed, including further molecular analyses for HDM-2 activity. Results: 37 pts have been treated at 9 dose levels (DL), 4–300 mg qd. AEs included nausea, vomiting, fatigue, anorexia, insomnia, electrolyte disturbances, liver function tests and creatinine elevations, and asymptomatic QTc prolongation, mostly grade 1–2. A DLT, grade 3 QTcF prolongation, was observed in one patient at DL 9. The patient was asymptomatic and the QTc prolongation recovered after treatment discontinuation. PK data showed dose-proportionality. After dosing at 300 mg, steady state Cmax and AUC0–24h were 2–3 μg/mL and ≈50 μg.h/mL, respectively, well exceeding the expected effective exposure modeled by preclinical studies. PD data showed engagement of the targeted pathway such as dose-dependent p53 upregulation in skin, upregulation of HDM-2 levels in tumors after treatment, and an increase in plasma MIC-1 levels. No objective responses have been observed so far. Conclusions: JNJ-26854165 was well tolerated at doses beyond the expected effective exposure modeled by preclinical studies. PD activity was observed at the 150–300 mg dose levels. The trial continues with cohort expansion at 300 mg. Updated results will be presented. [Table: see text]
An open-label, dose escalation, safety, and pharmacokinetic study of ENMD-2076 administered orally to patients with advanced cancer
Authors: Bastos B. R. , Diamond J. , Hansen R. , Gustafson D. , Arnott J. , Bray M. , Sidor C. , Messersmith W. , Shapiro G. 
Published: August 2020

3520 Background: ENMD-2076, a novel, orally-active antimitotic and antiangiogenic molecule inhibits Aurora A as well as tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and the FGF receptors. This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of ENMD-2076 administered once daily to patients (pts) with advanced cancer. Methods: The dose escalation scheme utilizes 3 (or 4) + 3 (or 2) design. Pts receive ENMD-2076 once daily in 28-day cycles (followed by 7–14 days of rest between cycles 1 and cycle 2 only). Results: 14 pts have been enrolled in 3 dose cohorts (range 60 to 120 mg/m2/d). Median age/performance status is 62/1. The total number of treatment cycles to date is 45, with a median of 3 cycles (range <1 to 9 cycles). Most frequent, related toxicities (all grades, n=14) were hypertension (29%), fatigue (21%), proteinuria and diarrhea (both 14%). One pt experienced dose limiting toxicity of Grade 4 hypertension and Grade 3 cholecystitis in the first dose cohort of 60 mg/m2/d. Following drug interruption, the pt restarted at 30 mg/m2/d and continued for 4 additional cycles before being removed for progressive disease. Noncompartmental PK analysis of the first two dose levels shows that the plasma concentration of ENMD-981693 (the active free base of ENMD-2076) is dose- linear, as reflected in AUC and Cmax. The estimated terminal half-life (t1/2) is unaltered regardless of dose; however, t1/2 is approximately 50% greater at steady state than following single dose administration. Four ovarian cancer and 2 colon cancer pts have achieved decreases ranging from 11–61% in either CA125 or CEA, respectively (4 are associated with stable disease at Cycle 2 by modified RECIST criteria). Serum KDR concentrations assayed by ELISA decreased from baseline in all patients on treatment from a mean of 9153 pg/mL (SEM 464.2) at D1 to 6987 pg/mL (SEM 460.0) at D28 (p <0.05). Conclusions: ENMD-2076 is a small molecule kinase inhibitor with acceptable toxicity and preliminary evidence of antitumor activity in pts with ovarian and colorectal cancers. [Table: see text]
Phase I study of vandetanib (V) and bevacizumab (B) combination therapy evaluating the VEGF and EGF signal transduction pathways in adults with solid tumors and NHL
Authors: Gutierrez M. , Murgo A. J. , Allen D. , Turkbey I. , Gardner E. R. , Trepel J. , Chen H. , Giaccone G. , Doroshow J. H. , Kummar S. 
Published: August 2020

3522 Background: (V), a small molecule tyrosine kinase inhibitor, has strong inhibitory activity against VEGFR-2 and the EGF RTK. (B), a humanized anti-VEGF monoclonal antibody, blocks the binding of human VEGF to its receptors. We proposed that dual blockade of the VEGF pathway provides an added therapeutic effect compared with either agent alone. Methods: A standard 3–6 pt/cohort design, dose-escalation Phase I study was performed. (V) was self-administered PO, days 1–21 of each 21-day cycle. (B) was administered by IV infusion Q 3 wks. Objectives: Determine the toxicity profile and the MTD of the combination of (V+B); evaluate (V) pharmacokinetics, changes in tumor vascularity by dynamic contrast enhanced MRI (DCE-MRI) and effects of (V+B) treatment on circulating endothelial progenitors and mature circulating endothelial cells. Eligibility: ECOG ≤ 2, adequate organ function. The MTD is the dose level at which no more than 1 of 6 patients experience DLT during the first 2 cycles of treatment, and the dose below at which at least 2 (of ≤6) patients have DLT due to drug treatment. Results: 9 pts have been accrued to date. Diagnosis: pancreatic-1, NSCLC-1, colorectal-3, peritoneal mesothelioma-1, melanoma-1, NHL-1, jejunal adenocarcinoma (JAC)-1. 1 DLT (gr 3 Allergic reaction) was observed at DL 2. HTN was the most common toxicity at DL 2. Other gr 2–3 toxicities seen beyond 2 cycles included: diarrhea, elevated creatinine, leucopenia, anemia, thrombocytopenia, hemorrhage, prolonged QTc interval, proteinuria, rash (hand-foot syndrome / acneiform). Partial Response (PR) was achieved in 2 pts (pancreatic 14 mos + and JAC 6 mos); disease stabilization in 5 pts (4 mos +). DCE-MRI results showed a reduction in the parameters of permeability, (ktrans and kep), associated with one PR. Conclusions: We decided not to escalate beyond DL 2 due to the gr 2–3 toxicities observed with chronic therapy. We recommend (V): 200mg daily and (B): 5mg/kg IV q3 weeks as the Phase II dose. [Table: see text] No significant financial relationships to disclose.
Phase II trial of pharmacodynamically (PDally)-guided optimal biologic dose titration (OBDT) of sorafenib (S) in combination with metronomic cyclophosphamide (mC) in advanced neuroendocrine tumors (aNET)
Authors: Quintela-Fandino M. A. , Young A. , Webster S. , Grewal M. , Wang L. , Moore M. J. , Krzyzanowska M. , Mak T. W. , Siu L. L. 
Published: August 2020

3526 Background: There is a paucity of reliable PD assays for guiding individual OBDT. PD effects of kinase inhibitors have been previously measured in static tissues. We developed a dynamic flow-cytometric PD assay that quantitates RAF signal transduction capacity (STC) based on the differential MEK´s phosphor-status in stimulated vs. basal conditions (phosphor-shift [PS]) in PBMCs. In a pilot study of 7 patients (pt) with advanced solid tumors in a phase I trial (unpublished data) the % of PS inhibition (I) 7 days after starting S at 400 mg BID showed a 10-fold interpatient variation and correlation with TTP. PDGFR-B/VEGFR2 blockade plus mC showed synergistic effect in the RIP1-Tag2 mouse NET model (J Clin Oncol. 23:939) In this phase II trial of aNET a double antiagniogenic strategy is undertaken: PD-guided OBDT of S + mC. Methods: Eligibility criteria included: unresectable NET with documented PD within 6 months prior to entry; ECOG 0–2; unlimited prior therapy but S; octreotide allowed. Therapy: pt start run-in phase with S at 200mg bid + 50 mg QD fixed dose of mC. After 7 d they escalate to 400 mg BID of S regardless of RAF STC assay results. RAF STC and toxicity are then assessed Q14d, escalating S at 200 mg BID increments until any of the following is achieved: a) 90% RAF STC I; b) maximum S dose of 800 mg BID; or c) intolerable Gr 2 or G3+ toxicity. Once S dose is determined based on these criteria, cycle 1 begins. Design: Simon 2-stage optimal; P0 = 0.05 P1 = 0.2; α =0.05 β = 0.1. Results: Accrual: 10 pt M:F = 6:4, islet cell:carcinoid = 5:5, age median 56 (40–79), ECOG 0:1 = 5:5. S doses (mg BID) at cycle 1 were 200 (2 pt)/400 (5)/600 (2)/800 (1); corresponding cycle 1 day 1RAF STC I (%) were 5, 53/94, 100, 95, 16, 65/25, 41/71, respectively (R2 = 0.13 p = 0.72) Most frequent Gr 3 non-hematologic possibly related adverse events in 30 cycles: hand-foot (2 pt), hypertension, abdominal pain, diarrhea, vomiting, lipase, ileal perforation (1 each). Disease control rate (9 evaluable pt): 78% (95% CI: 52–100%) (1PR, 6 SD). Conclusions: This approach appears feasible/safe. Large interpatient S dose differences are needed to achieve RAF SCT I/toxicity balance. No S dose-RAF SCT I relation is shown. Disease control rate is promising. No significant financial relationships to disclose.
Phase I study of intravenous decitabine in combination with oral vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas (NHL)
Authors: Stathis A. , Hotte S. , Hirte H. , Chen E. X. , Webster S. , Iacobucci A. , McGill S. , Wang L. , Espinoza-Delgado I. , Siu L. L. 
Published: August 2020

3528 Background: Decitabine (D), a hypomethylating agent, and vorinostat (V), a histone deacetylase inhibitor, belong to two different classes of drugs with an epigenetic effect. The ideal dose scheduling of these drugs remains controversial. This phase I study aims to determine the recommended phase II dose (RPTD) of the combination, their toxicity profile, pharmacokinetic (PK) interaction and preliminary clinical activity. Methods: Patients (pts) with advanced solid tumors or relapsed/refractory NHL are eligible. Two different schedules of D and V are being evaluated: sequential administration of D followed by V and concurrent administration of D and V. Dose escalation of D and V on the sequential schedule is described in Table. Results: To date, 27 pts have been entered into dose levels 1, -1, 1a, 1b, -1b, -2b of the sequential schedule. Demographics: median age 61 (range 31–76), F:M = 13:14, ECOG 0:1:2 = 8:16:3, tumor types: 24 solid tumor and 3 NHL. Pts received a total of 77 cycles with a median of 2 cycles (range 1–8). Adverse events (AE) of grade 3 or higher of at least possible attribution to the study treatment were neutropenia (16 pts), thrombocytopenia (4), febrile neutropenia (2), fatigue (2), and 1 pt each for constipation, dehydration, nasal bleeding, elevated alanine aminotransferase, and hyponatremia. Dose limiting toxicities (DLT) consisted mainly of myelosuppression, constitutional and gastrointestinal symptoms occurred in 7/27 (26%) of pts so far. Disease stabilization for 4 or more cycles was observed in 7 out of 22 (31.8%) evaluable pts (two with breast and one each of thymus, colon, pancreatic, appendix and non-small cell lung cancers). Conclusions: The sequential combination of D and V seems to be tolerable after some adjustments in the doses and duration of drug administration. Prolonged disease stabilization has been observed in multiple tumor types. Accrual is ongoing and RPTD will likely be dose level -1b or -2b. ( Supported by NCI Grant No. U01CA132123.) [Table: see text] No significant financial relationships to disclose.
A first-in-human phase I study of 4SC-201, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors
Authors: Brunetto A. T. , Ang J. E. , Lal R. , Olmos D. , Frentzas S. , Mais A. , Hauns B. , Mollenhauer M. , Lahu G. , de Bono J. S. 
Published: August 2020

3530 Background: 4SC-201 (former code BYK408740) is a specific, potent, pan-HDAC inhibitor with improved ADME properties. Methods: Patients (pts) with advanced refractory solid tumors were dosed once daily (QD) d1–5 in a 14-day cycle in sequential cohorts of 3–6 pts with 50 or 100% dose increments. Primary objectives were to determine safety, tolerability, pharmacokinetics (PK) and maximum tolerated dose (MTD) of 4SC-201. Pharmacodynamic assessment (histone acetylation and HDAC enzyme activity) and anti-tumor efficacy were secondary objectives. Blood samples for PK and PD were taken on days 1, 5 and 47 of treatment. Results: 18 pts (9M/9F) with a median age of 58.5 yrs (range 40–70) were treated at five dose levels: 3 pts each at 100mg, 200mg, 400mg and 600mg and 6 pts at 800mg. All pts were evaluable for toxicity and received at least 2 treatment cycles. Grade 3 DLT of nausea and vomiting occurred in 1 pt dosed at 800mg. Most common adverse events included nausea, vomiting and fatigue. 8 of 9 pts treated in the 600mg and 800mg cohorts had stable disease during the main phase of the study (4 treatment cycles). A patient with liposarcoma and another with thymoma (marginal response) continued treatment beyond 6 months. PK parameters were dose-proportional with a low inter-individual variability and indicated good bioavailability. The apparent t1/2 of oral 4SC-201 ranged from 2.3 to 4.4 hours. The degree of HDAC inhibition measured in a peripheral blood mononuclear cell functional assay was dose- dependent and increased from 50 to 100 %, although histone H4 acetylation accumulation after dosing did not differ significantly between dose levels. Conclusions: Oral 4SC-201 has favorable disposition and can be safely administered; 600mg QD d1–5 in a 14-day cycle is recommended for phase II evaluation. Safely administered doses modulate target with antitumor activity. [Table: see text]