bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive biomarker discovery and validation for the targeted chemotherapeutic ixabepilone
Authors: Lee H. , Xu L. , Wu S. , Paul B. , Baselga J. , Llombart A. , Steger G. G. , Galbraith S. , Clark E.
Published: March 2020

3011

Background: Ixabepilone is a microtubule stabilizing agent with significant therapeutic value in breast cancer (BC) patients. To identify predictive biomarkers capable of identifying patients likely to receive optimal benefit from ixabepilone treatment, preclinical and clinical studies were carried out. Several biomarkers discovered using preclinical models were validated in a neoadjuvant BC clinical study ( CA163080 ) and one, estrogen receptor 1 (ER), was shown to double the pathological complete response (pCR) rate in patients treated with ixabepilone. To identify candidate sets of biomarkers that could further increase the pCR rate we have performed post-hoc analyses of the preclinical and clinical data. Methods: Eighteen BC cell lines were classified as sensitive or resistant (S/R) based on the IC50 values for ixabepilone treatment. Gene expression profiling of the BC cell lines was conducted and genes correlated with the S/R classification were identified using a k-Nearest Neighbors algorithm. Patients in clinical study CA163080 underwent a pretreatment core needle biopsy from which RNA was isolated and gene expression profiles generated (data available on 134 patients). Analyses using the preclinical and clinical markers were conducted using various statistical tools. Results: Several markers used in combination with ER were found to be capable of tripling the pCR to ixabepilone in CA163080. In addition to ER other predictive markers were identified that were as predictive as ER, including several genes whose expression is anti-correlated with ER and are part of the ER pathway. Finally, various sub-group analyses were performed and manifested the importance of clinical sample variation that needs to be considered for the analysis. Conclusions: Several single biomarkers identified from preclinical studies were validated in the clinical study CA163080 , demonstrating the utility of this approach. Such markers can be used in combination to better identify patients likely to respond to ixabepilone in future clinical trials. Furthermore, molecular response markers that can be tied to the mechanism of drug resistance can be used for further developing chemotherapy in drug development.

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Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors
Authors: Jimeno A. , Kulesza P. , Cusatis G. , Howard A. , Khan Y. , Messersmith W. , Laheru D. , Garrett-Mayer E. , Baker S. D. , Hidalgo M.
Published: March 2020

3020

Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner.

No significant financial relationships to disclose.
A phase I study of IMC-11F8, a fully human anti-epidermal growth factor receptor (EGFR) IgG1 monoclonal antibody in patients with solid tumors. Interim results
Authors: Kuenen B. , Witteveen E. , Ruijter R. , Ervin-Haynes A. , Tjin-A-ton M. , Fox F. , Ding C. , Giaccone G. , Voest E. E.
Published: March 2020

3024

Background: This ongoing phase I study is being conducted to determine the safety profile and recommended dose of IMC-11F8, a fully-human IgG1 monoclonal antibody that targets the EGFR. Methods: Patients (pts) with advanced solid tumors who are refractory to or have no available standard therapy are eligible to receive IMC-11F8 intravenously either weekly or every other week for 6 weeks (1 cycle). The initial cohort of patients will receive 100 mg of IMC-11F8. In the absence of a dose-limiting toxicity (DLT), dose escalation will be 200, 400, 600, 800, and 1000 mg in successive cohorts. Prior to the initial cycle, pts receive one IMC-11F8 infusion at their assigned cohort followed by a 2-week pharmacokinetic (PK) period. Pts with stable disease or better after cycle 1 are eligible to receive additional cycles of IMC-11F8. Results: 31 of 40 pts have been enrolled in the 100-, 200-, 400-, 600-, and 800-mg cohorts. Pt characteristics are M/F 20/11, median age 58 years (37 - 76), median ECOG score 1 (0–2). No DLTs have been observed. Only grade 1/2 skin rashes were reported. The most frequent adverse events were nausea, vomiting, fatigue, and headache. No infusion reactions were observed. 2 pts (1 confirmed) have achieved a PR, 1 pt with melanoma in the 200-mg cohort with 39+ weeks of weekly IMC-11F8 treatment and 1 pt with rectal cancer in the 400-mg cohort with 20+ weeks of IMC-11F8 administered every other week. 5 pts in the 200- to 600-mg cohorts have stable disease and have received from 11+ to 35+ weeks of IMC-11F8 treatment. A noncompartmental analysis of 20 pts demonstrated that IMC-11F8 exhibits nonlinear PK. As IMC-11F8 escalated from 100 to 600 mg, T1/2 increased from 67 to 84 hrs, Cmax increased from 30 to 368 μg/mL, AUCinf increased from 1753 to 67295, and CL decreased from 57.0 to 8.9 mL/hr. Conclusions: These interim results indicate that IMC-11F8 is well tolerated in this patient population. Although a maximum tolerated dose has not been established, IMC-11F8 has shown activity at two different dose levels.

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Phase 1 study with BIBW 2992, an irreversible dual tyrosine kinase inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) in a 2 week on 2 week off schedule
Authors: Mom C. H. , Eskens F. A. , Gietema J. A. , Nooter K. , De Jonge M. J. , Amelsberg A. , Huisman H. , Stopfer P. , De Vries E. G. , Verweij J.
Published: March 2020

3025

Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR and HER2. A phase 1 study of orally administered BIBW 2992 was performed to determine its safety, PK and PD. Methods: Patients (pts) with advanced solid malignancies received BIBW 2992 once daily (OD) for 2 weeks, in 4 week cycles. Adverse events were evaluated according to CTCv3.0 and tumor response according to RECIST. In cycle 1 and 2, BIBW 2992 plasma PK analysis was performed. Before and after cycle 1, biomarkers involved in EGFR activation were assessed in skin biopsies. Results: 38 pts received 10 mg (n=3), 20 mg (n=3), 30 mg (n=3), 45 mg (n=3), 70 mg (n=18), 100 mg (n=2) and 85 mg (n=6) OD. At 100 mg dose-limiting toxicities (DLTs) consisted of grade 3 skin rash (n=1) and grade 3 diarrhea despite loperamide (n=1). At the dose level of 85 mg, DLTs were seen in 2 pts (diarrhea in both). An additional 12 pts were subsequently enrolled at 70 mg. A total of 3 DLTs was seen in the 18 pts treated at 70 mg (all 3 diarrhea, in one case with additional grade 3 nausea and ALT increase). In other pts, diarrhea was controllable with loperamide, whereas skin events could be ameliorated with minocycline. The dose of 70 mg BIBW 2992 OD was therefore set as the recommended phase 2 dose. Exposure (AUC0-∞ and AUCτ,ss range 82–2080 ng·h/mL) and peak plasma concentrations (Cmax and Cmax,ss range 7–150 ng/mL) increased with increasing doses. High interpatient variability in all PK parameters was found, but was within the range expected for an orally administered drug. The volume of distribution (Vz/F) ranged from 800–2900 L, indicating high tissue distribution. Median tmax values ranged between 1–4 h. The gMean terminal t1/2 ranged between 13–32 h. Accumulation ratio based on AUC was between 2–2.9. Steady state was reached around day 8. After cycle 1, a >20% reduction in Ki-67 (range 20–83%), reflecting inhibition of keratinocyte proliferation, was seen in paired skin biopsies of 31 pts. Ki-67 positive cells (mean ± SD) decreased from 14 ± 4.5% pre-treatment to 7.9 ± 4.5% on day 13 (p<0.0001). SD lasting ≥4 cycles occurred in 8 pts. Conclusions: 70 mg BIBW 2992 OD can be safely administered in a 2 week on, 2 week off schedule. Further evaluation in phase 2 trials in warranted.

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Phase I study of erlotinib (E) for solid tumors in patients with hepatic or renal dysfunction (HD or RD): CALGB 60101
Authors: Miller A. A. , Murry D. J. , Hollis D. R. , Owzar K. , Lewis L. D. , Kindler H. L. , Marshall J. L. , Villalona-Calero M. , Edelman M. J. , Ratain M. J.
Published: March 2020

3026

Background: We sought to determine a tolerable dose and characterize the pharmacokinetics (PK) of E in patients with HD or RD. Methods: Patients with biopsy-proven solid tumors that commonly express EGFR, refractory to or without available standard therapy, performance status 0–2, and without biliary or renal obstruction were assigned to one of 3 cohorts (C): C1, AST ≥ 3 × ULN but no RD; C2, direct bilirubin 1–7 mg/dl but no RD; C3, creatinine 1.6–5.0 mg/dl but no HD. After slow accrual of 3 patients, an amended C1 for albumin < 2.5 g/dl accrued 3 additional patients. E was administered po daily in groups of at least 3 evaluable patients in escalating doses of 50, 75, 100, 150 mg starting with 50 mg in HD and 75 mg in RD. Patients had to take E for at least 4 weeks to be considered evaluable for toxicity unless dose-limiting toxicity (DLT) occurred sooner. DLT was defined as: grade 4 neutrophils or platelets; bilirubin ≥ 1.5 × baseline in C1/2 and ≥ 2.5 × ULN in C3; creatinine ≥ 2 × ULN in C1/2 and ≥ 2.5 × baseline in C3; grade ≥ 3 nausea,vomiting,diarrhea despite optimal supportive care; or any other grade ≥ 3 non-hematologic toxicity. Blood samples were obtained before and 1, 2, 3, 4, 6, 24 hrs after the first dose. Plasma E concentrations were measured by HPLC. A 2-compartment PK model was used to estimate total clearance of E. Results: Between 12/01 and 5/05, 55 patients were accrued but 1 never started therapy: male/female, 34/20; white/black, 46/8; median age 56 (range, 39–78); PS 0/1/2, 12/25/17. The distribution of treated/evaluable patients was: 6/5 in C1, 30/16 (attrition due to progressive disease) in C2, and 18/18 in C3. DLT consisted of both total and direct bilirubin ≥ 1.5 × baseline in 3 patients: C1, 1 of 5 at 50 mg; C2, 2 of 6 at 100 mg. In C2, 1 of 7 patients had grade 4 diarrhea/dehydration and grade 3 hypotension at 75 mg. No DLT was encountered in C3 with 12 patients at 150 mg. Clearance (mean ± SD) was cohort-dependent: 1.51 ± 0.64 (C1), 2.36 ± 1.17 (C2), 4.34 ± 2.53 (C3) l/hr; 2-sided exact Kruskal-Wallis p < 0.0006. Conclusions: Patients with RD tolerate 150 mg and appear to have normal clearance of E. Patients with HD should be treated at a reduced dose (i.e. 75 mg) consistent with their reduced clearance.

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Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors
Authors: Lorusso P. M. , Heath E. , Valdivieso M. , Pilat M. , Wozniak A. , Gadgeel S. , Shields A. , Puchalski T. , Ewesuedo R.
Published: March 2020

3034

Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses.

[Table: see text]
A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs)
Authors: Eder J. P. , Appleman L. , Heath E. , Malburg L. , Zhu A. , Pilat M. J. , Shapiro G. , Lorusso P.
Published: March 2020

3041

Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and vascular endothelial growth factor (VEGF) family receptor tyrosine kinase (RTK). PDGFRβ, KIT, FLT3, and Tie-2 are also inhibited at low nM concentrations in vitro. XL880 is the 1st orally bioavailable small molecule Met inhibitor to enter the clinic. Methods: Pts with advanced STs were enrolled in successive cohorts to receive XL880 orally as a single dose on Day (D) 1 with pharmacokinetic (PK) sampling, followed by 5 consecutive daily doses (DD) starting on D 4 with additional PK sampling. Pts then continued to receive XL880 for 5 consecutive days, repeated every 14 days. Results: Nineteen pts have been treated across 5 dose levels: 0.1, 0.2, 0.4, 0.8, and 1.6 mg/kg. No dose-limiting toxicities have been observed. Two pts have demonstrated grade 2 hypertension, at 0.8 and 1.6 mg/kg respectively. PK analysis indicated that systemic drug exposure (AUC) and peak plasma levels (Cmax) increased approximately dose-proportionally (r2 values = .89 and .87 respectively) with increasing XL880 dose (0.1–1.6 mg/kg). Following 5 consecutive DD, AUC values were 175–304% higher and Cmax values were 30–203% higher than following a single XL880 dose, suggesting possible drug accumulation with repeat dosing. Terminal half-life values were ∼60 hours (hrs) following 5 consecutive DD (D 8 range: 40–66 hrs), were more variable following a single dose (D 1 range: 26–87 hrs), and appeared to be unaffected by dose. A pt with papillary renal cell carcinoma has a partial response (DD = 0.2 mg/kg) and pts with carcinoid and melanoma have had minor responses. Conclusions: XL880 is a RTK inhibitor with a novel spectrum of activity that targets both tumor cells and tumor-associated vasculature. XL880 is well tolerated up to the 1.6 mg/kg dose, with continued dose escalation ongoing. XL880 demonstrates biologic activity through hypertension and antitumor activity.

[Table: see text]
A phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of CHIR-258, a novel oral multiple receptor tyrosine kinase (RTK) inhibitor
Authors: Sarker D. , Evans J. , Hardie M. , Molife R. , Marriott C. , Morrison R. , Garzon F. , Heise C. , Michelson G. , De-Bono J.
Published: March 2020

3043

Background: CHIR-258 is a potent small molecule inhibitor of VEGF, FGF, PDGF and c-KIT RTKs with IC50≤10nM that demonstrates activity in a variety of angiogenesis, tumour and metastasis models. Methods: Patients (pts) with histologically confirmed advanced solid tumors, ECOG PS 0–2 were treated in cohorts of 3–6 with CHIR-258. Treatment was as single daily doses on a repeated 7 days (d) on/7d off schedule (25–100mg), with a subsequent protocol amendment to continuous (cont) daily dosing. The objectives were to determine maximum tolerated dose (MTD) and dose limiting toxicity (DLT), evaluate PK and PD endpoints - ERK phosphorylation in PBL - and describe anti-tumour activity. Results: 35pts (median age 56.5 yrs; 15F/20M) were treated in 4 intermittent dosing cohorts (25, 50, 75, 100 mg/d) and 3 continuous dosing cohorts (100,125, 175 mg/d). The most common drug related adverse events were (grade [gr], number of pts): nausea (gr 1–3, 12); fatigue (gr 1–2, 9); headache (gr 1–3, 8); vomiting (gr 1–2, 7); anorexia (gr 1–2, 7); diarrhoea (gr 1–2, 6); dysgeusia (gr1–2, 6); anaemia (gr 2–3, 4); hypertension (gr 1–3, 3) and reversible asymptomatic drop in left ventricular ejection fraction (gr 2, 2). DLTs were gr 3 hypertension (HTN) in 1 pt with pre-existing HTN (100mg, cont); asymptomatic uncomplicated grade 2 elevation in cardiac troponin I (125mg); gr 3 anorexia/fatigue and gr 3 rise in alkaline phosphatase (both at 175mg). 3 pts have had prolonged stable disease (all 4m+; parotid, renal and imatinib-refractory GIST). The plasma PKs of CHIR-258 were linear over the dose range of 25–175 mg with respect to Cmax and AUC. On d1, the mean Cmax was 13.5(5.3) ng/mL to 109 (26) ng/mL, the mean AUC (0–24) was 224(97.4)ng*h/mL to 1740(466)ng*h/mL, and the t½ was 17h. Trough CHIR-258 concentrations at doses >50 mg/d were above the concentrations known to inhibit target receptor activation in vitro. Data on evaluable samples demonstrate up to 90% inhibition of basal ERK phosphorylation. Conclusions: CHIR-258 was safely administered at continuous daily doses up to 175mg/d. Modulation of p-ERK was demonstrated. Treatment is associated with disease stabilization.

[Table: see text]
Imaging with FLT-PET demonstrates that PF-477736, an inhibitor of CHK1 kinase, overcomes a cell cycle checkpoint induced by gemcitabine in PC-3 xenografts
Authors: McArthur G. A. , Raleigh J. , Blasina A. , Cullinane C. , Dorow D. , Conus N. , Hicks R. J. , Kornmann J. , Chen E. , McCarthy T. J. , Anderes K.
Published: March 2020

3045

Background: The development of strategies to monitor the molecular and cellular response to novel agents that target the cell cycle is vital to provide proof of mechanism and biological activity of these compounds. The protein kinase CHK1 is activated following DNA damage in the S and G2-phases of the cell cycle and mediates cell cycle arrest. In vitro studies demonstrate that inhibition of CHK1 can overcome cell cycle arrest induced by DNA damage and enhance cytotoxic activity of DNA damaging agents. In vivo studies show that combining DNA damaging agents with a CHK1 inhibitor potentiates antitumor activity. We hypothesize that functional imaging with 18F-fluorine-L-thymidine (FLT), a PET-tracer where tumor uptake is maximal in the S and G2 phases of the cell cycle can be used to non-invasively monitor the induction and therapeutic inhibition of a cell cycle checkpoint in vivo. Methods: Nude mice harbouring PC-3 xenografts were treated with vehicle controls, gemcitabine, the CHK1-inhibitor PF-477736 or gemcitabine + PF-477736. FLT-PET scans were performed and tumors harvested for ex-vivo biomarkers to assess S-phase, M-phase and DNA-repair. Results: Gemcitabine induced a 8.3 ±0.8 fold increase in tumoral uptake of FLT at 21 hours that correlated with a 3.3 ±0.2-fold increase in thymidine kinase activity and S-phase arrest as demonstrated by BrdU incorporation and elevated expression of cyclin-A. Treatment with PF-477736 at 17 hours after gemcitabine abrogated the early FLT-flare at 21 hours by 82% (p<0.001). This was associated with both an increased fraction of cells in mitosis and G1-phase of the cell cycle as determined by phos-histone H3 and flow cytometry. Furthermore, the combination of gemcitabine and PF-477736 enhanced DNA damage as measured by phos-gamma-H2AX and significantly delayed tumor growth when compared to tumors treated with gemcitabine alone. Conclusion: These data clearly indicate that the CHK1-inhibitor PF-477736 can overcome the cell cycle checkpoint induced by gemcitabine and increase associated DNA damage in tumors in-vivo. The PET studies indicate that functional imaging with FLT-PET is a promising strategy to monitor responses to therapeutic agents that target cell cycle checkpoints.

[Table: see text]
Dasatinib (BMS-354825) pharmacokinetics correlate with pSRC pharmacodynamics in phase I studies of patients with cancer (CA180002, CA180003)
Authors: Luo F. R. , Luo F. R. , Barrett Y. , Ji P. , Holly P. , McCann E. , Rhyne P. , Clarke E. , He K. , Bleichardt E. , Blackwood-Chirchir M.
Published: March 2020

3046

Background: Dasatinib - an inhibitor of several oncologenic kinases including BCR-ABL and SRC - has demonstrated efficacy in CML and Ph+ ALL, and is being evaluated in patients with solid tumors. Studies CA180–002, and CA180–003 were multiple ascending dose studies of dasatinib in patients with refractory Ph+ leukemia, and solid tumors, respectively. We have analyzed the preliminary results of pharmacokinetics (PK) and pharmacodynamic (PD) biomarker phospho-SRC (pSRC) combined across the CA180002 and CA180003 studies. Methods: Dasatinib was administered orally at doses of 15 - 180 mg QD or 25 - 160 mg BID. Dasatinib PK was determined by LC MS/MS. The level of phospho-SRC in peripheral blood mononuclear cells (PBMCs) was determined by an ELISA and was used as a surrogate biomarker of the level of kinase activity of the SRC family members. PK-PD modeling was performed using a two-compartment PK model with first-order absorption kinetics and an indirect inhibitory Emax model as the PD model. Results: On the BID regimen, pSRC inhibition was approximately dose-dependent across the dosing range. Inhibition also appeared to be directly correlated with dasatinib plasma concentration, with maximal inhibition achieved at ∼2.5 hr. Based on PK-PD modeling, the estimated EC50 (the plasma concentration required to achieve 50% inhibition of pSRC) is 14.4 ng/mL. Conclusions: SRC family kinase activity is substantially inhibited at the exposures of dasatinib achieved to date. The optimal regimens of dasatinib to achieve both target inhibition and solid tumors efficacy will be determined based on biomarkers, clinical responses, and toxicity profiles.

[Table: see text]
Apo2L/TRAIL pharmacokinetics in a phase 1a trial in advanced cancer and lymphoma
Authors: Ling J. , Herbst R. S. , Mendelson D. S. , Eckhardt S. G. , O’Dwyer P. , Ebbinghaus S. , Osborne R. , Cheu M. , Lieberman G. , Lum B. L.
Published: March 2020

3047

Background: Apo2L/TRAIL (Apo2L ligand/tumor necrosis factor-related apoptosis-inducing ligand) is the first recombinant human protein that selectively induces apoptosis or programmed cell death in cancer cells while sparing normal cells. The molecule used in this joint clinical development between Genentech, Inc. and Amgen, Inc., is an optimized recombinant human Apo2L/TRAIL protein produced in E. coli. It displays broad activity in preclinical models of a variety of solid and hematologic cancers. This is the first report of the pharmacokinetics of Apo2L/TRAIL in humans. Methods: Thirty-nine patients enrolled in a phase 1a study had PK assessments at dose levels ranging from 0.5–15 mg/kg in two cohorts, those with and those without liver metastases. Recombinant human Apo2L/TRAIL was administered as a 1-hr IV infusion for 5 consecutive days over a 21-day cycle. Serum concentrations were determined using a sensitive ELISA assay. PK calculations were performed using Non-compartmental analyses. Results: Currently Apo2L/TRAIL PK data are available for 27 patients, 15 in cohort 1 (no liver metastases) and 12 in cohort 2 (liver metastases). Mean (± SD) PK data for patients in cohort 1 and cohort 2 did not differ. PK data for cohort 1 are outlined in the table below. Apo2L/TRAIL clearance appeared proportional to dose and consistent with that predicted from nonclinical models. Cmax achieved at doses ≥ 4 mg/kg are equivalent to or greater than those displaying activity in preclinical models. There was no evidence of drug accumulation between day 1 and day 5 of treatment. Conclusions: Apo2L/TRAIL at doses which can be safely administered in humans produces serum concentrations consistent with those demonstrating efficacy in tumor xenograft models. Hepatic metastases with or without mild liver dysfunction do not appear to influence the PK of Apo2L/TRAIL.

[Table: see text]

[Table: see text]
A phase 1 dose finding study of CHR-2797, an inhibitor of M1 aminopeptidases, in patients with advanced solid tumours
Authors: Reid A. , Protheroe A. , Attard G. , Cowsill C. , Spicer J. , Vidal L. , Bone E. , Hooftman L. , Harris A. , De-Bono J. S.
Published: March 2020

3053

Background: CHR-2797 is a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases, in particular PuSA, and LTA4 hydrolase. Exposure of cancer cells to CHR-2797 results in the generation of the active metabolite CHR-79888 which is poorly membrane-permeable, resulting in intracellular accumulation. CHR-2797 has shown anti-proliferative activity in syngeneic (rat) and xenograft (mouse) cancer models, and is anti-angiogenic in vitro. Methods: Patients (pts) (ECOG PS ≤ 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. The accelerated titration design of the trial involved two phases for evaluation of schedule and dose: 1) fixed dose with increasing duration, and 2) dose escalation over a fixed duration (28 days). Results: 16 pts (median age: 64.5 years [range 48.8–80.1], 13M/3F)were treated with once daily doses ranging from 10mg to 130mg. The first four patients received a 10mg dose for 7, 14, 21 or 28 days respectively. Five subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity ≥ Grade 2. Thereafter dose was escalated in ≤ 40% increments in 3-patient cohorts. The most frequent adverse events were: gr 1–2 thrombocytopenia (44%), gr 1 diarrhea (25%), gr 1–2 transaminitis (19%), gr 1–2 fatigue (13%), gr 1 hot flushes (13%), and gr 1 lightheadedness (13%). There were no DLTs. Five patients continued therapy after 28 days; stable disease has been achieved in 1 pt for 6 months with granulosa cell carcinoma of ovary, who was progressing prior to study entry. CHR-2797 and CHR-79888 demonstrate dose proportional increases in AUC and Cmax. The terminal half-life for CHR-2797 is around 1–2 hours, whereas it is between 9 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to both CHR-2797 and CHR-79888 is good, with CHR-79888 accumulating over 28 days, such that by day 28 the intracellular levels are comparable to plasma. Conclusions: CHR-2797 is well tolerated and can be safely administered at doses that reach plasma concentrations associated with activity in pre-clinical models. Accrual into the study continues.

No significant financial relationships to disclose.
A prospective pharmacogenomic (PG), pharmacodynamic (PD), and pharmacokinetic (PK) study of determinants of erlotinib toxicity
Authors: Rudin C. M. , Desai A. A. , Janisch L. , Carducci M. , Karrison T. , Liu W. , Fleming G. F. , Ramirez J. , Innocenti F. , Ratain M. J.
Published: March 2020

3080

Background: A strong but unexplained association between skin toxicity (rash) and survival from erlotinib therapy has been noted for patients with several epithelial malignancies. The correlation between rash and clinical benefit appears to extend across classes of epidermal growth factor receptor (EGFR)-targeted agents. Several hypothetical explanations for this association have been suggested including polymorphisms of the EGFR locus as well as PD and PK variability. Methods: We conducted this 80-subject prospective study in patients with lung (N=43), head and neck (N=9), and ovarian cancer (N=28) given erlotinib 150 mg daily to evaluate several of these hypotheses. Patients underwent toxicity monitoring, response assessment, skin biopsies pretreatment and after 28 days for immunohistochemical (IHC) analysis, as well as blood collection for PK analysis and evaluation of EGFR genetic polymorphisms reported to influence EGFR expression level. Results: 72/80 subjects are evaluable for toxicity. Response correlates with both worst grade diarrhea (p=0.003) and rash (p=0.044). Initial PK analysis suggests a positive association between d15 erlotinib trough level and both diarrhea (p=0.091) and rash (p=0.076). Controlling for d15 erlotinib level, EGFR intron 1 CA repeat length is also associated with rash (p=0.030). Polymorphisms in the EGFR promoter (216 G/T and 191 C/A) correlated with diarrhea (p=0.053 and 0.005 respectively) but not rash. IHC analyses including EGFR, p-EGFR, Akt, p-Akt, ERK, and p-ERK have been completed on 35 paired, pre-post treatment skin biopsies and demonstrate no strong correlations with toxicity. Conclusions: These data suggest that both interindividual PK variability and EGFR polymorphisms may contribute to erlotinib toxicity. Erlotinib effects on EGFR signaling in skin do not appear to correlate with toxicity. Samples obtained in this study are available for analysis of other candidate PG determinants of both toxicity and PK variability.

[Table: see text]
A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently
Authors: Dejonge M. , Savage S. , Verweij J. , Collins T. S. , Eskens F. , Whitehead B. , Suttle A. B. , Pandite L. B. , Ho P. T. , Hurwitz H.
Published: March 2020

3088

Background: P is a potent tyrosine kinase inhibitor of VEGF-R1, -R2, and R3, PDGF-α/β, and c-Kit. L is a potent inhibitor of ErbB1 and ErbB2 tyrosine kinases. Several lines of evidence support combined inhibition of VEGFR and Erb in the treatment of malignancies. Methods: Patients (pts) with solid tumors received P and L daily. Safety, limited PK, biomarkers, and clinical activity were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on DLT. Results: Thirty-three pts received L/P doses of 750/250 (n=4), 750/500 (n=6), 1000/250 (n=3), 1000/400 (n=2), 1000/500 (n=4), 1250/250 (n=6), 1250/400 (n=5) and 1500/200 (n=3) mg once daily (qd). Preliminary mean plasma P concentrations 24 h after administration (C24) on Day 22 were ∼19 μg/mL and 23 μg/mL after administration of 250 mg and 500 mg, respectively. These values are similar to mean C24 values observed after administration of 800 mg P alone (23.1 μg/mL). Plasma L concentrations at 750 - 1500 mg qd were similar to those observed after monotherapy. The most frequent AE’s were diarrhea (Grade (G)1 n=10, G2 n=2, G3 n=3), fatigue (G1: n=7, G2 n=5, G4 n=1), nausea (G1 n=9, G2 n=2), anorexia (G1 n=8, G2 n=3), vomiting (G1 n=9), hair depigmentation (n=7), rash (G1 n=6, G2 n=1) and abdominal cramps (G1 n=3, G2 n=2, G3 n=1). Prolonged disease stabilization of > 16 wks (median 21.5 wks) occurred in 10 pts (RCC n=3, CRC n=3, GIST n=1, mesothelioma n=1, adenocarcinoma GE junction n=1, aggressive fibromatosis n=1). 3 pts (renal cancer n=2, and giant cell tumor of the bone n=1) demonstrated tumor shrinkage of < 30% (i.e. SD by RECIST). Conclusions: Concurrent administration of pazopanib and lapatinib was generally well tolerated. Coadministration of lapatinib may alter the PK of pazopanib.

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Relationship between tumor gene expression and recurrence in stage II/III colon cancer: Quantitative RT-PCR assay of 757 genes in fixed paraffin-embedded (FPE) tissue
Authors: O’Connell M. J. , Paik S. , Yothers G. , Costantino J. P. , Cowens J. W. , Clark K. M. , Baker J. , Hackett J. , Watson D. , Wolmark N.
Published: March 2020

3518

Background: As an initial step in developing abetter method of assessing prognosis following potentially curative surgery for colon cancer, we performed an exploratory gene identification study. Methods: RNA was extracted from three 10-micron sections of the FPE tumor tissue obtained at the initial diagnosis from 353 patients entered between 1977 and 1984 into the surgery-only or surgery-plus BCG arms of NSABP C-01/C-02. Expression was quantified for 757 cancer-related and reference genes with RT-PCR. Results: Blocks from 270 patients were evaluable after pre-specified exclusions: 128 were stage II and 142 were stage III. All patients had ≥ 5-year follow up. In univariate Cox proportional hazard analyses, 148 genes exhibited a nominally significant (unadjusted p-value <0.05) linear association with recurrence-free interval (RFI) (7 genes p≤0.001, 66 genes 0.001<p<0.01; 75 genes 0.01≤p<0.05). False discovery rate calculations suggest that about 25% of the 148 genes are expected to be false positives. Higher expression was associated with shorter RFI for 118 genes including SERPINB5, DUSP1, AKT3, TIMP1, ANXA2, RHOB (p≤ 0.001) and with longer RFI for 30 genes including BRCA1 (p≤0.001). The relationship between gene expression and RFI was similar for stage II and stage III patients for 143 of the 148 genes found to be significant. The largest cluster of genes is functionally related to extracellular matrix remodeling. The magnitude of the hazard ratios is similar to that observed in the early Oncotype DX studies in breast cancer and should allow clinically useful separation into low/intermediate/high risk groups. Conclusions: Quantitative RT-PCR assay of FPE colon cancer tissue can be used to identify large numbers of genes associated with RFI in patients with stage II and III colon cancer. If these results are confirmed by additional studies in progress, this technique has promise to improve selection of colon cancer patients for adjuvant chemotherapy. Funded in part as a collaborative arrangement under contract between the NSABP Foundation, Inc., and Genomic Health, Inc.

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Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer. A meta-analysis of two randomized trials
Authors: Mitry E. , Fields A. , Bleiberg H. , Labianca R. , Portier G. , Tu D. , Torri V. , Lazorthes F. , Van Cutsem E. , O’Callaghan C. J. , Rougier P.
Published: March 2020

3524

Background: Adjuvant systemic chemotherapy (CT) administered after resection of colorectal cancer (CRC) metastases (M) may reduce the risk of recurrence and improved survival but its benefit has never been demonstrated. Two phase III trials (FFCD 9002 and EORTC/NCIC CTG/GIVIO (ENG) trials) with a very similar design showed a trend for improvement in survival after adjuvant CT but had to close prematurely because of slow accrual, lacking the statistical power to demonstrate any significant difference in survival. We report here a pooled analysis based on individual data from these trials. Methods: Patients were required to have a WHO performance status ≤2 and a histologically proven CRC with a complete (R0) surgical resection of the primary tumour and of ≤4 liver or lung metastases. They were randomized between chemotherapy (CT arm) [5FU 400 mg/m2 (FFCD) or 370 mg/m2 (ENG) IV q.d. x 5 days plus dl-leucovorin 200 mg/m2 (FFCD) or l-leucovorin 100 mg/m2 (ENG) IV q.d. x 5 days, 6 cycles at 28 days intervals] or surgery alone (S arm). Results: 129 pts were included in the ENG trial between 1994 and 1998, 173 in the FFCD trial between 1991 and 2001. 24 pts (ENG: 22, FFCD: 2) were excluded from analysis for missing post-baseline data: 278 pts were included in the present analysis (CT: 138, S: 140). Patients’ characteristics by treatment arm (% CT/S): males 58.0/63.6, age <70 years: 79.7/79.3, stage IV primary tumor: 29.0/47.1 (p=0.02), liver M 94.2/93.6, ≥2 M resected: 33.3/31.4. Conclusion: Adjuvant CT with a 5FU bolus based regimen tends to improve survival after complete resection of CRC metastases. The observed improvement in median PFS was almost statistically significant whereas the improvement in median OS (more than 1 year) was not (lack of statistical power?). This pooled analysis supports the use of adjuvant CT, with a more effective regimen, after potentially curative resection of CRC metastases. Updated results will be presented. (Supported by AROLD)

[Table: see text]

No significant financial relationships to disclose.
A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK/ZK to determine clinical benefit on progression-free survival (PFS) in high LDH pts
Authors: Major P. , Trarbach T. , Lenz H. , Kerr D. , Pendergrass K. , Douillard J. , Chen B. , Laurent D. , Jacques C. , Van Cutsem E.
Published: March 2020

3529

Background: PTK/ZK is an oral, antiangiogenic inhibitor of tyrosine kinase signaling of all known vascular endothelial growth factor receptors (VEGFR). PTK/ZK in combination with FOLFOX4 has been investigated in first line (CONFIRM 1[C1]) and second line (CONFIRM 2 [C2]) mCRC pts. Methods: In both trials, pts were randomized to receive PTK/ZK or placebo. Since high LDH and poor performance status (PS) have been shown to indicate poor prognosis in mCRC, pts were stratified by baseline serum LDH (≤ or > 1.5 X ULN) and PS (0, 1–2), yielding 4 strata per trial. Exploratory analysis of the high LDH strata in C1 indicated that these pts may derive the most benefit from PTK/ZK treatment. The purpose of this pre-planned meta-analysis of C1 and C2 is to determine whether the treatment effect of C1 and C2 are consistent. Results: Both trials showed strikingly similar results. High LDH pts comprise approximately 30% of the total pt population. PTK/ZK seems to have the same strong effect on PFS in high LDH pts in both 1st and 2nd line mCRC with a HR for PFS of 0.67 (p =0.010) for C1 and 0.63 (p < 0.001) for C2 (N=250 and N=316, respectively). The safety profile of PTK/ZK was highly consistent. The most frequent grade 3/4 AEs attributable to PTK/ZK were hypertension, diarrhea, fatigue, nausea, vomiting and dizziness. Increases in AEs associated with antiangiogenic therapy such as bowel perforations and bleeding complications were not observed in the PTK/ZK arms of both trials. In the meta-analysis, PTK/ZK effect on PFS is moderate in the overall population (HR 0.85, p-value 0.005). In contrast, the effect on PFS is strong and clinically meaningful in the high LDH population (HR 0.65, p-value < 0.001, N=566). Conclusion: This meta-analysis is the largest study of poor prognosis pts with high serum LDH in metastatic colorectal cancer. These data suggest that PTK/ZK significantly improves PFS in high LDH pts. Further evaluation of PTK/ZK in this pt population is planned.

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Alterations in molecular networks of metastatic colorectal carcinoma reveal organ-specific signatures: Implications for targeted therapy of metastatic disease
Authors: Pierobon M. , Calvert V. , Lipsky M. , Sheehan K. , Speer R. , Mammano E. , Belluco C. , Wulfkuhle J. , Nitti D. , Liotta L. , Petricoin E.
Published: March 2020

3532

Background: Proteomic analysis of aberrant protein kinase activity is poised to provide crucial knowledge that could drive molecular-targeted therapeutics and personalized medicine. Many cancers are detected at late stages when metastasis has already occurred. Knowledge about the molecular derangements in the metastatic lesion is crucial for the rational selection of therapeutics. Very little is known about the signaling networks in the metastatic microenvironment. We employed reverse phase protein microarrays coupled to laser capture microdissection for a multiplexed phosphoproteomic fingerprint of colorectal metastatic disease to begin to understand the molecular functional changes that occur upon metastasis. Methods: 68 frozen cases of patient-matched colorectal cancer and hepatic metastasis, 15 cases of pulmonary metastasis, and 27 cases of hepatic metastasis of other primary cancers including breast, melanoma, pancreatic, ovarian, and stomach cancers (all taken at the same time at surgery), were subjected to laser capture microdissection. Procured tumor epithelia (20,000 cells per sample), were lysed and subjected to reverse phase protein microarray analysis. Using this technique, we measured the phosphorylation state of 75 kinase substrates. Molecular network analysis was performed using commercially available software. Results: Our results indicate that, unlike analysis of gene microarray data, we observe a significant difference between the molecular networks of activated kinase substrates within the metastatic lesion compared to the patient-matched primary tumor. In fact, despite overall patient-specific heterogeneity of the portraits, organ specific signatures that were independent of the primary origin of the tumor were identified. Conculsions: Effective treatment in the new era of personalized targeted therapeutics will require the ability to understand the functional activation of cellular signaling pathways since these are the drug targets themselves. Our results indicate that treatment of metastatic disease, and patient stratification for matching with the appropriate therapy may be organ-specific and not predicated upon the primary site of the disease.

No significant financial relationships to disclose.
Preliminary results of a phase I study of external beam radiation therapy (EBRT), oxaliplatin (OX), bevacizumab (BV), and capecitabine (CAP) for locally advanced or metastatic adenocarcinoma of the rectum
Authors: Czito B. , Bendell J. , Willett C. , Vaccaro G. , Morse M. , Yu D. , Honeycutt W. , Franklin A. , Hurwitz H.
Published: March 2020

3543

Background: BV, a monoclonal antibody against vascular endothelial growth factor, increases survival when added to first and second line chemotherapy for metastatic colorectal cancer. Preclinical studies suggest BV may enhance tumoral radiation sensitivity. Preliminary studies of OX and 5-FU based chemoradiation therapy for rectal cancer have suggested improved pathologic CR rates compared to 5-FU/ radiation alone. CAP allows fluoropyrimidine treatment without the inconvenience of an infusion pump. We investigated CAP + BV + OX + EBRT for pts with rectal cancer to evaluate for the MTD and preliminary efficacy results. Methods: Pts with adenocarcinoma of the rectum and no prior pelvic irradiation received 5040 cGy EBRT (180 cGy/fx), CAP (625–825 mg/m2 PO BID on EBRT days), BEV (15 mg/kg d1 and 10 mg/kg d8 and d22), and OX (50–75 mg/m2/week during radiation, weeks 1–5) in dose-escalating fashion. DLT was defined as any grade 3 heme tox ≥ 7d, grade 4 heme tox, grade 4 non-heme tox during chemoradiation, or inability to deliver >85% of planned treatment. Pts eligible for surgical resection could have surgery 6–8 wks after treatment completion. After recovery from surgery, patients could be treated with CAP, BV, and OX. Results: 11 patients (5 men/6 women) have been enrolled. All have completed chemoradiation and resection. At dose level 1 (CAP 625 mg/m2 BID, OX 50mg/m2) there were no DLT’s in 3 pts. 1/3 pts had G3 subarachnoid hemorrhage during adjuvant chemotherapy. At dose level 2 (CAP 825 mg/m2, OX 50 mg/m2) 2/2 pts had DLT (1 G4 diarrhea; 1 G2 rectal pain, causing treatment hold for study-defined DLT). 6 more pts were treated at dose level 1. 1pt had DLT of G3 diarrhea. G2 toxicities included diarrhea (3/11), fatigue (2/11), skin changes (2/11), and pain (2/11). 9/11 patients were downstaged. 2/11 patients had pCR at surgery and 2/11 microscopic disease only. Conclusions: CAP + BEV + OX + EBRT is a well-tolerated, active regimen for the treatment of rectal cancer. MTD was determined to be CAP 625 mg/m2 BID + BEV 15 mg/kg d1 + 10 mg/kg d 8 and 22 + OX 50 mg/m2/week. Further study of efficacy at the MTD is warranted.

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Prognosis prediction of stage II colon cancer by gene expression profiling
Authors: Barrier A. , Brault D. , Houry S. , Dudoit S. , Lemoine A. , Flahault A. , Boelle P.
Published: March 2020

3565

Background: The aims of the present study were: 1) to identify a prognosis signature (PS), based on microarray gene expression measures, in stage II colon cancer patients and to assess its accuracy with resampling techniques ; 2) to assess the accuracy, also with resampling techniques, of a previously proposed 23-gene PS. Methods: Colon tumor mRNA samples from 50 patients were profiled using the Affymetrix HGU133A GeneChip (22283 sequences). In a first part, the 50 patients were randomly divided into 2 groups (G1 and G2) of equal size that were considered alternately as training and validation sets. In a second part, the 50 patients were randomly divided into 1600 training (size=n) and validation (size=50-n) sets. Informative genes were selected on the training set by taking the 30 most differentially expressed genes between patients who recurred and those who remained disease-free; the accuracy of this PS was assessed by comparing the predicted prognosis (using a diagonal linear discriminant analysis (DLDA)) and the actual evolution for all the validation set patients. Using the same random splits, the accuracy of the 23-gene PS was assessed with a DLDA that used learning set patients as reference samples. Results: The 30-gene PS that was identified from G1 (G2) patients yielded a 80% (84%) prognosis prediction accuracy when applied on G2 (G1) patients. With resampling techniques, the prediction accuracy regularly increased with the learning set (LS) size: 65.5% (range=52.5–75%) with LS of size 10, and 82.7% (range=60–100%) with LS of size 40. Comparisons of compositions of the 100 PS for a given value of n suggested a high instability of informative genes; with LS of size 10, 7 genes were part of at least 10% of signatures; with LS of size 40, 7 genes were part of all the 100 signatures. The accuracy of the previously proposed 23-gene PS also increased with the learning set size. Conclusion: Microarray gene expression profiling represents a promising technique to predict the prognosis of stage II colon cancer patients. The present study also outlines the high instability of informative gene selection and suggests the usefulness of resampling techniques to obtain an honest assessment of prognosis prediction accuracy.

No significant financial relationships to disclose.