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BACKGROUND: In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study. METHODS AND FINDINGS: We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2

Background: CS1003 is a novel humanized IgG4 anti-PD-1 monoclonal antibody. In phase 1a dose-escalation, CS1003 showed a well-tolerated safety profile with no dose-limiting toxicity, and a wide therapeutic window at doses up to 10 mg/kg Q3W (maximum administrated dose, MAD) in patients (pts) with solid tumors. Two fixed-dose regimens were explored in the phase Ib portion of this ongoing clinical trial in pts with selected solid tumors. Method(s): Pts were enrolled in cohort A (200 mg Q3W) or cohort B (400 mg Q6W) to receive CS1003 intravenously. Safety, preliminary tumor activity (overall response per RECIST v1.1 by investigators) and PK were assessed. Result(s): As of 21 Mar 2020, 29 and 30 pts were enrolled in cohorts A and B, with a median treatment duration of 15.0 (range: 3.0-50.4) and 14.4 (range: 4.7-27.7) weeks, respectively. Following the first dose, the mean Cmax value of CS1003 in cohort B was around doubling of that in cohort A (112 vs 44 mug/ml) but lower than that (189 mug/ml) at the MAD, demonstrating sufficient safety margin. The mean Ctrough value of cohorts A and B were 9.2 and 18.8 mug/ml, respectively, expecting a complete PD-1 receptor occupancy throughout the dosing intervals with both regimens. The steady-state PK data of cohort B will be updated. In cohorts A and B, 97% (28/29) and 93% (28/30) pts had treatment-emergent adverse events; 41% (12/29) and 47% (14/30) pts had all-grade treatment-related adverse events (TRAEs), respectively. The TRAE profiles were comparable in both cohorts overall with two Grade (G) >= 3 events (G3 dermatitis and G4 Type 1 diabetes mellitus in cohort B), and the rest were G1/2. Among the 29 efficacy-evaluable pts in cohort A, there were 3 complete response (2 confirmed), 3 partial response (PR, 2 confirmed) and 5 stable disease (SD). Among the 27 efficacy-evaluable pts in cohort B, there were 4 PR (1 confirmed) and 13 SD. Conclusion(s): The preliminary safety and efficacy profiles of CS1003 at 200 mg Q3W and 400 m

Background: Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature. Objective(s): This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy. Patients and Methods: Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design. Demcizumab (2.5, 5.0, and 7.5 mg/kg) was given once every 3 weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance). Result(s): Initially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding. Conclusion(s): This study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5 mg/kg q3-weekly x4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.[Figure not available: see fulltext.].Copyright © 2017, Springer International Publishi

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade >= 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.Copyright © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Contains fulltext : 152869.pdf (publisher's version ) (Open Access), PURPOSE: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery patients with localized, high- or intermediate-risk GI stromal tumor (GIST). PATIENTS AND METHODS: Patients were randomly assigned to 2 years of imatinib 400 mg daily or no further therapy after surgery. The primary end point was overall survival; relapse-free survival (RFS), relapse-free interval, and toxicity were secondary end points. In 2009, given the concurrent improvement in prognosis of patients with advanced GIST, we changed the primary end point to imatinib failure-free survival (IFFS), with agreement of the independent data monitoring committee. We report on a planned interim analysis. RESULTS: A total of 908 patients were randomly assigned between December 2004 and October 2008: 454 to imatinib and 454 to observation. Of these, 835 patients were eligible. With a median follow-up of 4.7 years, 5-year IFFS was 87% in the imatinib arm versus 84% in the control arm (hazard ratio, 0.79; 98.5% CI, 0.50 to 1.25; P = .21); RFS was 84% versus 66% at 3 years and 69% versus 63% at 5 years (log-rank P < .001); and 5-year overall survival was 100% versus 99%, respectively. Among 528 patients with high-risk GIST by local pathologist, 5-year IFFS was 79% versus 73%; among 336 centrally reviewed high-risk patients, it was 77% versus 73%, respectively. CONCLUSION: This study confirms that adjuvant imatinib has an overt impact on RFS. No significant difference in IFFS was observed, although in the high-risk subgroup there was a trend in favor of the adjuvant arm. IFFS was conceived as a potential end point in the adjuvant setting because it is sensitive to secondary resistance, which is the main adverse prognostic factor in patients with advanced GIST.

Background: Aurora kinases A and B are oncogenic serine/threonine kinases with distinct, crucial functions in regulation of mitosis and control of the G2 checkpoint. Aurora kinases are amplified and/or over-expressed in many solid tumors and associated with poor prognosis and therapeutic resistance. AMG 900 is an investigational, orally administered, highly potent, selective small molecule pan-aurora inhibitor that has shown activity in taxane-resistant human tumor xenograft models. An open-label, first-inhuman study evaluated the safety, tolerability, pharmacokinetics (PK), and clinical activity of AMG 900 in patients with advanced, treatment-refractory solid tumors. In the dose-escalation phase, AMG 900 showed activity in ovarian and endometrial carcinoma. Here, we present interim results of the dose-expansion phase in ovarian carcinoma (OC), triple-negative breast cancer (TNBC), and castration-resistant prostate cancer (PC). Method(s): Eligibility criteria included age >=18 years, measurable disease, ECOG <=2, adequate organ function, and diagnosis of platinum- and taxane-resistant epithelial OC, taxane-resistant TNBC, or taxane- or cisplatin-etoposide-resistant stage IV PC with neuroendocrine features. AMG 900 was administered at 40 mg daily for 4 consecutive days every 2 weeks with prophylactic G-CSF support (maximum tolerated dose defined in the dose-escalation phase). PK parameters were estimated using data from the dose-escalation and dose-expansion phases of this study. Tumor response was measured per RECIST guidelines for all patients and by Rustin criteria (RECIST + CA-125) for OC patients. Aurora A and B amplification/over-expression and p53 mutational status/amplification were investigated in archival tissue when available. This Amgen-sponsored study (NCT00858377) has completed enrollment. Result(s): As of April 21, 2014, the dose-expansion phase of this study included 46 patients (OC = 24, TNBC = 10, PC = 12). Table 1 shows demographics, treatment-emer

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material(s) and Method(s): Patients received DEM (2.5, 5, or 7.5 mg/kg), pemetrexed 500 mg/m2, and carboplatin (AUC = 6) every 3 weeks followed by maintenance DEM (first 4 cohorts) or pemetrexed (7.5 mg/kg cohort) every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were administered as pemetrexed pre-medication. The primary study objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic and biomarkers of Notch signaling. Result(s): Thirty patients have been enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg and 4 received 7.5 mg/kg of DEM once every 3 weeks. The median age was 63 years and 90% had stage IV disease. Related adverse events (all grades) in >=10% of pts included: nausea (53%), fatigue (50%), hypertension (37%), vomiting (33%), neutropenia (27%), increased B-type natriuretic peptide (BNP) (23%), anemia (20%), peripheral edema (20%), increased ALT (20%), increased AST (17%), dyspnea, (17%), diarrhea (17%), decreased appetite (17%), pulmonary hypertension (13%), dysgeusia (13%), thrombocytopenia (13%), constipation (10%), and rash (10%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two patients receiving 5 mg/kg developed reversible pulmonary hypertension and heart failure on days 16

Background: Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth, decrease CSC frequency & cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect in human tumor xenograft models. Method(s): Pts received DEM (2.5, 5 or 7.5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 weeks followed by maintenance DEM or PEM (7.5 mg/kg cohort) every 3 weeks until progression. The objectives were to determine the MTD, safety, efficacy, immunogenicity, pharmacokinetics & biomarkers of Notch signaling. Result(s): Thirty-two pts were enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg & 6 received 7.5 mg/kg of DEM. Related AEs in > 20% of pts were: nausea (53%), fatigue (47%), hypertension (41%), vomiting (34%), edema (28%), neutropenia (25%), & increased B-type natriuretic peptide (BNP) (22%). Increased BNP values are an early indicator of the cardiac effects of DEM & mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two pts receiving 5 mg/kg developed reversible pulmonary hypertension & heart failure on days 167 and 183, respectively. As a result, DEM treatment was limited to 63 days in subsequent cohorts. One of 28 (4%) evaluable pts had a RECIST CR, 12 (43%) had a PR and 11 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5 and 7.5 mg/kg pts were 4.8, 5.3 and 4.4 months, respectively. Five pts who discontinued the study for a reason other than progression (3 continued to receive CARBO & PEM off-study) were progression-free through Day 223+, 243+, 457+, 497+, 680+ and a sixth pt (who continued to receive CARBO & PEM off-study) progressed at Day 850. Conclusion(s): DEM, CARBO & PEM was generally well tolerated with nausea, fatigue & hypertension being the most common drug related toxicities. The duration of DEM therapy is

Aim: To evaluate the efficacy and tolerability of lapatinib (L) and intravenous vinorelbine (V) in patients with metastatic HER2-positive breast cancer who have previously received two lines of anti-HER2 therapy (i.e. trastuzumab [T] with chemotherapy and lapatinib with capecitabine [LC]). Method: Consenting patients with measurable or evaluable disease and normal cardiac function who had progressed were recruited. Patients received LV (lapatinib 1250 mg orally daily, vinorelbine 20 mg/m2 intravenously on days 1 and 8 every 3 weeks) until progressive disease, intolerable toxicity or patient request. Results: The trial was closed early following inclusion of 19 patients due to slow accrual. Ten, five and four patients had received two, three and more than four lines of chemotherapy with T and LC, respectively, prior to study entry. Patients received a median of 5 cycles (range 1–18) of LV. Confirmed partial response was seen in 2 of 16 patients with measurable disease (12.5%); stable disease >24 weeks was seen in two patients (10.5%) with a clinical benefit rate of 20%. Fatigue and any grade neutropenia occurred commonly, but grade 4 severity occurred in only 5 and 11%, respectively. There were no episodes of cardiac dysfunction and no treatment-related deaths. The median progression-free survival was 3.9 months and overall survival (OS) was 9.1 months. Conclusion: The combination of LV demonstrated modest efficacy but was well tolerated. This combination may be of benefit to those patients who are unable to access the newer anti-HER2 agents and the low rate of treatment-emergent adverse effects will enable patients' symptoms, such as pain, to be minimized.

Summary: Purpose CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997. Experimental design We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results A total of 56 doses were administered to 21 patients over 8 dose levels (15-164 mg/m2). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11-fold dose range. At doses of 84 mg/m 2 and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour Ktrans in some patients. Conclusions CYT997 is orally bioavailable. The 118 mg/m2 dose level should be used to guide dosing in future studies. © 2012 Springer Science+Business Media, LLC.

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. Demcizumab is a humanized, anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models, using an in vivo tumorigenicity limiting dilution assay. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material(s) and Method(s): Patients received demcizumab (2.5 or 5 mg/kg) plus pemetrexed 500 mg/m2 and carboplatin (area under the concentrationtime curve, 6 mg/mL x min) once every 3 weeks for 6 cycles followed by maintenance demcizumab once every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were also administered as pemetrexed pre-medication. The primary study objective was to determine the safety profile and optimal dose of demcizumab when combined with pemetrexed and carboplatin. Other objectives included: preliminary efficacy, immunogenicity, pharmacokinetics, and biomarkers of Notch signaling and CSCs in blood, hair follicles and tumor cells. Result(s): Twelve patients have been enrolled; 6 patients received 2.5 mg/kg and 6 patients received 5 mg/kg of demcizumab. The median age was 64 years and all 12 patients had stage IV disease. Adverse events reported as related to study drug in at least 10% of patients included: fatigue (50%), hypertension (42%), dyspnea on exertion (25%), ALT increased (25%), AST increased (25%), nausea (25%), vomiting (25%), neutropenia (17%), diarrhea (17%), palpitations (17%), decreased appetite (17%) and rash (17%). The hypertension was successfully managed with anti-hypertensives and no patients developed cardiac toxicity. The pharmacokinetic, immunogenicity and blood and hair biomarker specimens are being analyzed and these data will be presented. Six of the 10 (60%) evaluable patients h

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤ 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥ 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.

BACKGROUND: This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. METHODS: Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6). RESULTS: Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. CONCLUSIONS: Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01235416.

The aim of this phase II study was to assess the feasibility and efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-fluorouracil (CI 5FU) sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. Patients with inoperable cancer in the pancreatic head or body without metastases were given gemcitabine at 1000 mg m(-2) weekly for 3 weeks followed by a 1-week rest and a 6-week period of radiotherapy and concurrent CI 5FU (200 mg m(-2) day(-1)). The defined target volume was treated to 54 Gy in 30 daily fractions of 1.8 Gy. After 4 weeks' rest, gemcitabine treatment was re-initiated for three cycles (days 1, 8, 15, q28). Forty-one patients were enrolled. At the end of radiotherapy, one patient (2.4%) had a complete response and four patients (9.6%) had a partial response; at the end of treatment, three patients (7.3%) had a complete response and two patients (4.9%) had a partial response. Median survival time was 11.7 months, median time to progression was 7.1 months, and median time to failure of local control was 11.9 months. The 1- and 2-year survival rates were 46.3 and 9.8%, respectively. Treatment-related grade 3 and 4 toxicities were reported by 16 (39.0%) and four (9.8%) patients, respectively. Sixteen out of 41 patients did not complete the planned treatment and nine due to disease progression. This approach to treatment of locally advanced pancreatic cancer is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomised trial.