bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of lapatinib (LPT) and cetuximab (CTX) in patients with CTX-sensitive solid tumors.
Authors: Deeken John F. , Wang Hongkun , Hwang Jimmy J. , Marshall John , Subramaniam Deepa Suresh , He Aiwu Ruth , Weiner Louis M. , Hardesty Rosemarie A. , Steadman Kenneth , Pishvaian Michael J. 
Published: March 2020

2590 Background: Preclinical research has shown that one mechanism of acquired resistance to CTX is via EGFR-ErbB2 heterodimerization, which can reactivate oncogenic pathways. LPT is a dual EGFR and ErbB2 intracellular tyrosine kinase inhibitor. A phase I translational clinical study was performed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and clinical activity of CTX and LPT in patients with EGFR-driven solid tumor malignancies that can be treated with CTX. Methods: Patients (Pts) were enrolled in a 3+3 dose escalation trial. Prior CTX therapy was allowed. CTX was given at 400mg/m2 on Cycle 1, Day 1 (C1D1), then 250 mg/m2 weekly. LPT dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg orally daily. Rash management included daily sunblock, steroid cream, and doxycycline. Cycle length was 21 days, and patients were assessed for toxicity through the end of C2, and for efficacy after every 2 cycles. Fresh tumor biopsies were obtained at baseline and at the end of C1 to compare EGFR and ErbB2 expression levels and EGFR related pathway activation. DNA from blood samples was analyzed for pharmacogenetic (PGx) variations and correlations with toxicity and pharmacokinetics (PK). Results: Between October, 2010 to January 2012, 13 pts were enrolled, with colon (4), lung (3), head and neck (3), and anal cancers (3); 10 were evaluable for toxicity. Treatment-related toxicities of any grade included: rash (67%), diarrhea (42%), fatigue (33%), nausea/vomiting (17%), and dehydration (8%). DLTs included G3 rash in 1 of 6 pts on DL1, and G3 diarrhea despite optimal therapy in 1 of 4 pts on DL2. Enrollment to DL2 continues. Of 7 pts evaluable for response, 1 had an uPR, 3 had SD, including 1 with SD of ≥4 cycles, and 3 had DP. Both patients with uPR and prolonged SD were treated on DL1. Tumor EGFR-ErbB2 and EGFR pathway phosphorylation analyses and PGx results will be presented. Conclusions: The combination of CTX and LPT is well tolerated with expected toxicities. Efficacy was seen even on DL 1. Phase II clinical studies in CTX-sensitive diseases such as colon and head and neck cancer are planned.
Phase I study of docetaxel injection concentrate for nano-dispersion (DICN), a novel polysorbate 80-free formulation of docetaxel.
Authors: Jain Minish Mahendra , Deshmukh Chetan Dilip , Bondarde Shailesh Arjun , Bhatt Niraj , Divekar Ganesh 
Published: March 2020

2592 Background: A polysorbate 80-free formulation of docetaxel may preclude the need for dexamethasone pre-medication and may also reduce toxic effects associated with polysorbate 80. DICN is a novel polysorbate 80-free formulation of docetaxel stabilized with lipid and polymer using NanotectonTM technology. We studied safety, tolerability, and the pharmacokinetics (PK) of DICN in patients with advanced solid malignancies. Methods: Entry criteria included: age 18-65 years, histologically/cytologically confirmed advanced malignancy, performance status ≤ ECOG 2, estimated survival ≥ 12 weeks, and adequate organ function. A standard phase I 3+3 dose escalation schema was employed with an increase of 12.5 to 50% over previous DICN dose level as per safety profile. The infusion was 60 min for 1 cycle and major objectives were to determine maximum tolerated dose (MTD), and PK and safety profiles. Premedication to prevent hypersensitivity was not administered to patients receiving DICN. Three patients were treated with docetaxel 75 mg/m2 to gather PK data. Plasma was analyzed for docetaxel level using a validated assay. Results: Twenty-seven patients treated with DICN had a mean age of 48.8 yrs (range 29-65); 21 were females; and entered with metastatic breast cancer (MBC; n=14), non-small cell lung carcinoma (NSCLC; n=6), ovarian (n=2), and other (n=5). Doses (mg/m2) studied were 60 (n=7), 75 (n=5), 100 (n=3), 125 (n=3), 150 (n=6), and 170 (n=3). Despite lack of dexamethasone premedication, no patient receiving DICN reported a hypersensitivity reaction. Two DLTs (febrile neutropenia) were reported at DICN 170 mg/m2. DICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 60 to 170 mg/m2. Compared with docetaxel 75 mg/m2, Cmax and AUC0-24 of DICN 75 mg/m2 was 1.4 and 1.2 times higher, respectively, and 1.9 and 1.8 times higher, respectively for DICN 150 mg/m2. The median Tmax of DICN 75 mg/m2 and docetaxel 75 mg/m2 were 1.00 and 0.517 hours, respectively. Conclusions: In this study,DICN demonstrated acceptable tolerability and a favorable PK profile. A 150 mg/m2 is the recommended phase II dose for DICN.
Modeling the combined efficacy of rilotumumab (R; AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) for the treatment of locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer.
Authors: Doshi Sameer , Kathman Steven , Tang Rui , Gisleskog Per Olsson , Loh Elwyn , Dubey Sarita , Jiang Yizhou , Oliner Kelly S. , Donehower Ross C. , Iveson Timothy , Zhu Min 
Published: March 2020

2594 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF) that inhibits signaling though the MET receptor. In a double-blind, placebo-controlled, phase 2 trial of 121 patients with G/EGJ cancer, R (7.5 or 15 mg/kg) + ECX showed trends for improved progression-free survival (PFS) and overall survival compared to ECX alone. The combined effects of R and ECX on tumor reduction and PFS were modeled using the phase 2 data. Methods: A population pharmacokinetic (PK) model was used to estimate R PK parameters and individual R concentrations (C) over time. A tumor dynamic model was developed to characterize the combined effects of R with ECX on tumor growth and cell death and to evaluate the impact of baseline patient characteristics and lab values on model parameters. A discrete time-survival model was developed with PFS and C data to evaluate the effect of R, ECX, and the interaction between R and ECX on PFS within a given time interval. Results: R exhibited linear PKs with an estimated mean clearance of 0.216 L/d/70 kg. The tumor dynamic model suggested that R and ECX worked jointly to reduce tumor size from baseline via inhibition of the tumor growth rate constant (Kgrowth) and stimulation of the death rate of tumor cells (Kdeath). Assuming the maximal inhibition of Kgrowth is 100%, the estimated mean C that provided 50% maximal Kgrowth inhibition (EC50) was 6.71 µg/mL. The mean (SD) estimated effect of 7.5 and 15 mg/kg R on Kgrowth was 90.1% (3.8%) and 95.5% (1.9%) inhibition, respectively. None of the tested baseline factors appeared to significantly affect tumor reduction by R + ECX. In the discrete time-survival model, the R and ECX combination significantly improved PFS, and the model suggests that the magnitude of the effect of one treatment was dependent on the other. Conclusions: R and ECX appeared to work in combination to decrease tumor size and to improve PFS.
The role of phase I clinical trials in advanced malignant melanoma: Retrospective analysis of CTEP-sponsored trials 1995-2011.
Authors: Luke Jason John , Rubinstein Larry , Smith Gary L , Ivy S. Percy , Harris Pamela Jo 
Published: March 2020

2606 Background: Standard chemotherapy for melanoma is DTIC (RR ~10%). Many physicians do not refer to phase I due to perceived limited clinical benefit (CB=CR+PR+SD) and increased toxicity. To understand the actual experience of melanoma patients (pts) in phase I trials, we analyzed the outcomes of melanoma pts treated on CTEP phase 1 trials (1995-2011) and compared them to DTIC. Methods: We queried the CTMS of CTEP for phase I trials in which advanced melanoma pts were treated. Trials were separated into targeted (T), chemo (C) and immunotherapy (I). Pt characteristics, response and toxicity data were collected. Chemotherapy included chemo with targeted or immunotherapy. Toxicity was drug related if attributed possibly, probably or definitely to drug. Fisher’s Exact Test (2-sided p) was used to compare groups. DTIC data was pooled from 6 modern phase III clinical trials (1999-2011). Results: 937 pts (M595:F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2 (majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and toxicity data are shown in the Table. Targeted therapy was associated with lower RR (p=.01), immuno with lower CB rate (p<.001) and chemo with higher incidence of G4 toxicity (p<.001) relative to the other groups. Comparing phase 1 to DTIC, RR and CB were not clinically different (phase I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was significantly higher (54% vs. 28%) in phase I (p<.0001). Conclusions: Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had similar therapeutic benefit but more toxicity compared to DTIC naïve pts in modern clinical trials. [Table: see text]
Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hematologic cancers.
Authors: Shih Kent C. , Bendell Johanna C. , Reinert Anne , Jones Suzanne , Kelley Robin Katie , Infante Jeffrey R. , Korn Michael , Hege Kristen , Chopra Rajesh , Xu Shuichan , Wong Lilly , Liu Yong , Mortensen Deborah , Munster Pamela N. 
Published: March 2020

3006^ Background: The mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in cancer. The mTOR kinase exists in two multi-protein complexes, TORC1 and TORC2, which drive key cellular metabolic and proliferative functions. TORC1-selective inhibitors can induce feedback upregulation of TORC2 and treatment resistance. CC-223 is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and TORC2, selected to address this escape mechanism. Methods: Subjects with advanced solid and hematologic cancers were enrolled using an accelerated (1+5) dose escalation design. CC-223 was administered orally once daily (QD) in 28 day cycles until disease progression. Safety, pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated. Results: 28 subjects were treated across 5 dose levels: 7.5 (n=1), 15 (n=2), 30 (n=9), 45 (n=7) and 60 mg (n=8). The most common (> 20%) related adverse events (all grades) were fatigue (64%), nausea (50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia and vomiting (32% each) and rash (29%). Dose-limiting toxicity (all grade 3) occurred in 4 subjects: hyperglycemia (30 mg), rash (45 mg), fatigue (60mg), and mucositis (60 mg). The maximum tolerated dose (MTD) was 45 mg QD. Dose proportional exposure was observed with a terminal half life of 4 to 8 hrs (mean steady state Cmax 485 ng/mL, AUC0-24 2371 ngxhr/mL at 45 mg). Inhibition of TORC1 (pS6, p4EBP1) and TORC2 (pAKT) biomarkers in blood cells was characterized to be exposure-dependent and described by an Emax model. Near maximal inhibition of both TORC1 and TORC2 biomarkers was achieved at the peak concentrations of 30 or 45mg QD. Target inhibition was predicted to last 8 to 20 hours at 45mg QD. Tumor responses included: 1 partial response lasting 9 months (ER+ breast) and 7 subjects with stable disease (SD) lasting 8+ weeks (range 8 to 23.3). Conclusions: CC-223 was well tolerated with toxicities comparable to other drugs in this class. Evidence of TORC1/TORC2 pathway inhibition was observed as well as preliminary signals of anti-tumor activity, including one durable PR. Expansion cohorts in selected hematologic and solid tumors will evaluate CC-223 at the MTD of 45 mg QD.
First-in-human study of AMG 900, an oral pan-Aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors.
Authors: Carducci Michael Anthony , Shaheen Montaser F. , Paller Channing Judith , Bauman Julie E. , Azad Nilofer Saba , Shubhakar Poornima , Tang Rui , Stroh Mark , Friberg Gregory R. , Verschraegen Claire F. 
Published: March 2020

3009 Background: Aurora kinases A, B, and, C play essential roles in regulating cell division. Overexpression of aurora A and B in human tumors is associated with high proliferation rates and poor prognosis. AMG 900 is an investigational, orally administered, highly selective inhibitor of aurora A, B, and C that demonstrated activity in drug-resistant cell lines and human tumor xenografts. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AMG 900. Methods: Key eligibility criteria: ≥ 18 years old, advanced solid tumors, measurable disease, ECOG ≤ 2, and adequate organ function. AMG 900 was administered orally daily for 4 consecutive days (D) every 2 weeks (Q2W). In the dose-escalation phase, the starting dose was 1 mg and was escalated by 100% in subsequent cohorts (1 pt/cohort) until dose limiting toxicity (DLT) or grade 2 (G2) AMG 900-related toxicity occurred in the first 28 D. Dose escalation continued in a standard 3+3 design at ≤ 25% if DLT occurred or ≤ 50% if G2 related toxicity occurred. The maximum tolerated dose (MTD) was determined without prophylactic G-CSF support. Results: As of OCT 2011, 19 pts (1 pt at 1, 2, 4, and 8 mg; 3 pts at 16 mg; and 6 pts at 24 and 30 mg) had received ≥ 1 dose of AMG 900. Demographics were 58% women, median age 60 (32-77) years, and ECOG 0/1, 63%/37%. There were 4 DLTs: G4 neutropenia > 7 days at 24 mg (n=1) and 30 mg (n=1); G4 neutropenia > 7 days + G4 thrombocytopenia at 30 mg (n=1); and febrile neutropenia (FN) at 30 mg (n=1). MTD without G-CSF support was 24 mg. 89% of pts had treatment-related adverse events (AEs). G≥3 treatment-related AEs were neutropenia, 8 (42%); leukopenia, 4 (21%); anemia, 2 (11%); thrombocytopenia, 1 (5%); and FN, 1 (5%). Preliminary PK showed no obvious departures from dose-proportionality with a half-life of ~16 h. Tumor-response data were available for 17 pts: stable disease, 13 pts (range 0.4 to 43.7 wks); progressive disease, 4 pts. One pt (16 mg cohort) with recurrent ovarian cancer had 16% tumor shrinkage and 45% decrease in CA-125 (SD > 6 months). Conclusions: AMG 900 administered at 24 mg daily for 4D Q2W is the recommended dose for phase 2 trials. Dose escalation is now ongoing to determine the MTD with prophylactic G-CSF.
A first-in-human phase I study of MORAb-004 (M4), a humanized monoclonal antibody recognizing endosialin (TEM-1), in patients with solid tumors.
Authors: Diaz Luis A. , Azad Nilofer Saba , Gounder Mrinal M. , Coughlin Christina Marie , Fishel Jean , O'Shannessy Daniel , Grasso Luigi , Wustner Jason , Aluri Jagadeesh , Parno Jeff , Carvajal Richard D. 
Published: March 2020

3016 Background: Endosialin (TEM-1) is a membrane glycoprotein on the cell surface of activated mesenchymal cells (e.g. pericytes, fibroblasts and mesenchymal tumor cells) and on a subset of human cancers. It is involved in the development of tumor vasculature, stromal/tumor organization and PDGFRb signaling. M4 is a humanized IgG monoclonal antibody which targets TEM-1. Preclinical studies suggest that M4 may have single agent activity via inhibition of the tumor microenvironment and by direct effects on tumors expressing this target. Methods: A phase I dose escalation study in patients (pts) with advanced solid tumors was conducted to evaluate the safety, pharmacokinetic profile and preliminary efficacy of M4 administered intravenously on a weekly schedule; final results are presented. Results: 36 pts refractory to therapy were treated at 10 dose levels (0.0625 to 16 mg/kg administered i.v. on a weekly schedule). Drug-related adverse events (AE) observed were primarily infusion toxicity (grade 1 and 2 fever, chills, headache, myalgia). The MTD was determined to be 12 mg/kg. DLT of grade 3 vomiting was observed at 16 mg/kg. Preliminary pharmacokinetic (PK) analyses demonstrate M4 accumulation beginning at 4 mg/kg, and that elimination mechanisms are saturable beginning at 0.25 mg/kg. Exposure (AUC) increases in a greater than dose-proportional manner, with the apparent t1/2 increasing proportionally with dose. Tumor shrinkage (Minor/mixed tumor responses, mR) were seen in four pts (soft tissue sarcoma (2), hepatocellular carcinoma, pancreatic neuroendocrine tumor). Each mR was associated with prolonged disease stabilization in these pts (6-14 months). A cohort (n=4) of pts with refractory colorectal carcinoma demonstrated disease stabilization (15-24 weeks). Analysis of archival tumor revealed TEM-1 stromal staining in all cases with tumor cell expression noted on a subset of tumors of mesenchymal origin. Conclusions: In this phase I study, M4 was tolerated up to 12 mg/kg (MTD) and early signs of potential activity were observed. Expanded cohorts of 1-12 mg/kg are ongoing to further define an optimal dose.
Clinical pharmacokinetics of the Smac-mimetic birinapant (TL32711) as a single agent and in combination with multiple chemotherapy regimens.
Authors: Fetterly Gerald J. , Liu Biao , Senzer Neil N. , Amaravadi Ravi K. , Schilder Russell J. , Martin Lainie P. , LoRusso Patricia , Papadopoulos Kyriakos P. , Adjei Alex A. , Zagst Patricia D. , McKinlay Mark A , Weng David Edward , Graham Martin 
Published: March 2020

3029 Background: Birinapant is a novel small molecule Smac-mimetic that targets members of the inhibitor of apoptosis proteins (cIAP1, cIAP2 and XIAP) involved in the blockade of apoptosis. A population PK model was developed to characterize the interpatient variability in birinapant PK and to evaluate the effect of multiple combination regimens on birinapant disposition and safety. Methods: Birinapant was administered alone or in combination to 114 patients (55M/59F; 89% Caucasian) with advanced malignancies. Birinapant was administrated by a 30 min IV infusion QW alone (30 pats), or approx. 30 min. after chemotherapy with irinotecan (19 pats), docetaxel (20 pats), gemcitabine (17 pats), liposomal doxorubicin (13 pats), or paclitaxel/carboplatin (15 pats). Birinapant dose levels ranged from 0.18 to 35 mg/m2. Population PK modeling was performed to investigate the effect of the following patient covariates: [BW (38.5-127.5 kg), age (27.5-86.0 yrs), CrCL (36.4-219.2 ml/min), ALT (6-121 IU/L), and TBIL (0.1-1.7 mg/dL)]. Results: A 3-compartment PK model described the time course of birinapant disposition with predicted values for T1/2, CL, and Vd of 40 h, 21 L/h and 10.2 L, respectively. Birinapant displayed linear PK across the dose range with no significant accumulation in plasma following weekly dosing. Goodness of fit plots supported the model fit, with residual variability of 23%. The PK of birinapant remained unchanged when combined with irinotecan, docetaxel, gemcitabine and liposomal doxorubicin. Concomitant administration with paclitaxel/carboplatin resulted in a 2-fold increase in birinapant AUC possibly due to reduced OATP1B3 mediated tissue uptake. Conclusions: These data show that birinapant possesses an excellent PK profile with dose proportional kinetics, a long terminal half-life for target coverage, low/moderate interpatient variability in CL and no significant accumulation following weekly dosing. Importantly, the PK of birinapant remained unchanged when combined with multiple chemotherapy regimens and the increased exposure with paclitaxel/carboplatin was not associated with any change in birinapant tolerability.
Proof of mechanism (POM) in the first-in-human trial of two novel indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors.
Authors: Doroshow James H. , Ji Jiuping Jay , Chen Alice , Allen Deborah , Zhang Yiping , Lawrence Scott M , Pfister Thomas D. , Wang Lihua , Redon Christophe E. , Bonner William , Speranza Giovanna , Weil Marcie K. , Eiseman Julie , Holleran Julianne L. , Kinders Robert J. , Beumer Jan Hendrik , Parchment Ralph E. , Pommier Yves , Tomaszewski Joseph E. , Kummar Shivaani 
Published: March 2020

3031 Background: Indenoisoquinolines LMP 400 and LMP 776 form stable DNA-top1 cleavage complexes, have a preference for unique DNA cleavage sites, and are not substrates for ABC transporters compared to camptothecins. We conducted a randomized phase I trial of LMP 400 and LMP 776 in patients (pts) with refractory tumors to establish safety and MTD of LMP 400 and LMP 776 administered IV daily x 5 d, q 28d; determine PK; evaluate TOP1 and γH2AX levels in tumor biopsies (bx); and compare pharmacodynamic responses of LMP400 and LMP776. Methods: Pts had refractory malignancies; ≥ 18 yrs old; KPS > 70%; adequate organ function. DLT: drug-related gr ≥ 3 non-hem or gr 4 hem toxicities during C1. Pts assigned to receive either LMP 400 or LMP 776. Dose level (DL) in mg/m2/day for LMP 776: 1, 2, 3, 4.5 mg; LMP 400: 2.5, 5, 10, 20, 40, 80. Accelerated titration design with one pt per dose level (DL), 100% dose escalation until one DLT or 2 gr 2 toxicities, then 3+3 design. Tumor bx and circulating tumor cells (CTCs) were obtained at baseline and C1D3. Results: Twenty pts accrued to date [LMP 400 (11 pts); LMP 776 (9 pts)]; M/F 7/13; median age 59 (range 32-71 yrs); diagnosis (# of pts): colorectal (10), vaginal adenocarcinoma (1), head and neck (2), bladder (1), melanoma (1), pancreas (1), thyroid (1), small cell lung (1), sarcoma (1), lymphoma (1). DLTs: LMP 400- gr 4 myelosuppression, gr 3 fatigue at DL 6; DL 5 expanded to establish MTD; LMP 776 (DL2)- gr 4 hypercalcemia, no other DLTs, dose escalation continuing. One pt with irinotecan-refractory colon cancer had shrinkage of lung nodules post one cycle of LMP 400. Relative to baseline, 5 of 6 tumor bx demonstrated 20-50% reduction in TOP1 levels (LMP 776); an increase in γH2AX foci in tumor was observed in 2/6 LMP 776 and 1/1 LMP 400 pts. An increase in γH2AX was also observed in hair bulbs (3/3 pts) and CTCs (9/20 pts). PK for LMP 400 and LMP 776: mean T1/2 48 and 36 h; Cl 1.5 and 2.0 L/h/m2; Vc 30 and 31 L/m2, respectively. Conclusions: POM, as assessed by reduction in TOP 1 levels and increase in γH2AX in tumor and CTCs, and preliminary evidence of activity, has been demonstrated in this first-in-human trial of indenoisoquinoline-class of TOP1 inhibitors. Accrual is ongoing.