bluuebunny/crossref_metadata_2025_split huggingface dataset:
AZD2171 in combination with various anticancer regimens: Follow-up results of a phase I multi-cohort study
Authors: Shields A. F. , Heath E. , DeLuca P. , Pilat M. , Wozniak A. , Gadgeel S. , Puchalski T. , Xu J. , Liu Q. , LoRusso P. 
Published: March 2020

3544 Background: AZD2171 is an oral, highly potent and selective inhibitor of VEGF signaling. Recent trials have shown that combining a VEGF signaling inhibitor with certain chemotherapies provides clinical benefit in patients with breast, colorectal and non-small-cell lung cancers. AZD2171 was evaluated with various anticancer regimens in heavily pretreated patients with advanced solid tumors. Methods: Once-daily oral AZD2171 20 mg, 30 mg and 45 mg was given in combination with: (1) mFOLFOX6 every 2 weeks; (2) docetaxel 75 mg/m2 every 3 weeks; (3A) irinotecan 300 mg/m2 every 3 weeks; (3B) irinotecan as in 3A + cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 every week); or (4) pemetrexed 500 mg/m2 every 3 weeks. The novel study design allowed simultaneous evaluation of the safety and tolerability of these regimens with AZD2171. Secondary objectives include preliminary evaluation of potential pharmacokinetic (PK) interactions and efficacy (RECIST). Results: As of Nov 2006, 54 patients were evaluable for safety ( Table ). No unexpected toxicities were observed, and the safety profile of AZD2171 was similar to that observed in single-agent AZD2171 studies. Across all five treatment arms, common adverse events irrespective of causality included fatigue (n=46), diarrhea (n=45) and hypertension (n=21). Efficacy data were available for 39 patients, 24 of which were evaluable according to RECIST. A best overall objective tumor response of partial response (n=3) or stable disease (n=19) was observed ( Table ). AZD2171 did not appear to have a major effect on the PK profile of oxaliplatin, 5-FU, pemetrexed, irinotecan [SN38] and docetaxel. Steady-state PK parameter values of AZD2171 in this study are comparable with single-agent AZD2171 studies. Conclusion: In this group of heavily pretreated patients, combination treatment with AZD2171 and various anticancer regimens has been generally well tolerated, with no apparent PK interaction and encouraging preliminary evidence of antitumor activity. [Table: see text] No significant financial relationships to disclose.
Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC)
Authors: Faivre S. J. , Raymond E. , Douillard J. , Boucher E. , Lim H. Y. , Kim J. S. , Lanzalone S. , Lechuga M. J. , Sherman L. , Cheng A. 
Published: March 2020

3546 Background: VEGFRs and PDGFRs play key roles in the proliferation of HCC and tumor angiogenesis. Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3. This study reports the results of the first European/Asian, open-label, single-agent SU phase II study in pts with unresectable HCC. Methods: Key eligibility criteria include histologically confirmed measurable HCC; ECOG PS =1; Child-Pugh (CP)-A/-B; adequate organ function; and no brain metastases, ascites, or prior liver transplant. Pts receive SU at 50 mg/d for 4 wks every 6 wks (4/2 schedule). The primary endpoint is ORR by RECIST. Other assessments include safety (NCI CTCAE v3.0), PK and antitumor activity (tumor density, volumetric measurement of percent tumor necrosis [VMTN] and intratumor blood perfusion on monthly CT scan). Results: 37 pts (median 61 yrs [range 34–82]; male 92%; PS 0:1, 50%:44%; CP-A/-B, 84%/14%; 40.5% with prior local treatments) received a median of 2 cycles (range 1–7+) of SU. Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and hemorrhage (14%). Grade 1–2 skin toxicity was frequently reported. Dose reductions were required in 27% of pts. Four pts developed grade 5 events including ascites, edema, bleeding, drowsiness and hepatic encephalopathy. Decreased tumor density was observed in 68% of pts and activity assessed by VMTN showed minor (<50%) and major (=50%) post-treatment tumor necrosis in 25% and 46% of pts, respectively. One confirmed PR and 39% SD (best confirmed response) have been achieved. Post-treatment tumor blood perfusion parameters (blood volume and blood flow), decreased by an average of 39% (range: 13–72%). Preliminary PK data do not suggest any differences in drug exposure between risk groups (CP-A or CP-B). Conclusions: Evidence of =50% tumor necrosis in 46% of pts receiving SU suggests outstanding antitumor activity. However, change in tumor size (RECIST) may be inappropriate as a primary endpoint to evaluate SU in patients with HCC. Initial safety findings indicate that further evaluation of SU in this pt population with improved pt selection and dose schedule modification is warranted. [Table: see text]
Results of a phase I study of bevacizumab (BV), everolimus (EV), and erlotinib (E) in patients with advanced solid tumors
Authors: Bendell J. C. , George D. , Nixon A. , Yu D. , Petros W. , Beci R. , Arrowood C. , Lockamy D. , O’Neill M. , Hurwitz H. 
Published: March 2020

3548 Background: BV inhibits vascular endothelial growth factor (VEGF). EV is an mTOR (mammalian target of rapamycin) inhibitor. E inhibits epidermal growth factor receptor (EGFR) tyrosine kinase. VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination targeted therapy, we evaluated BV + EV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: Cycle length was 28 days. Doses: BV 10mg/kg IV q14d. EV 5mg PO QD, escalating to 10mg QD. Once the recommended phase II dose (RPTD) of BV + EV was reached, E was added, starting at 75 mg PO QD. DLT was defined as any treatment-related grade 4 heme or grade 3/4 non-heme event in Cycle 1. Results: 34 pts have been enrolled (18 F, 16 M), 28 evaluable for DLT, 24 for efficacy. Median age is 58y (range 29–73). Dose level 1 (BV 10mg/EV 5mg) had no DLT’s. Dose level 2 (BV 10mg/EV 10mg) had no DLT’s and the cohort was expanded to 13 evaluable pts. E (75mg) was added to BV 10mg/ EV 10mg. 2/6 patients had DLT (grade 3 mucositis and grade 3 rash). The doses were adjusted to BV 5mg/EV 5mg/E 75mg. 3 patients had no DLT and this dose is the MTD and RPTD for the 3-drug combination. 20 more patients are being enrolled at the RPTD for biomarker studies. Other grade ¾ toxicity included: nephrotic syndrome, cardiac ischemia, ventricular thrombus, portacath thrombosis, and bowel perforation. 2 patients had PR: 1 renal and 1 osteosarcoma. 16/24 pts had SD (10–112+ weeks). 5/6 patients with colorectal cancer (CRC) previously progressing on BV had SD (16+ - 112 weeks). One CRC patient had 19% radiologic decrease. Conclusions: BV + EV + E preliminary clinical activity (notably in refractory CRC) and class-related side effects were seen. The MTD is BV 5mg/kg IV q14d + EV 5mg PO QD + E 75mg PO QD. Updated data will be presented. No significant financial relationships to disclose.
A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991
Authors: O’Dwyer P. J. , LoRusso P. , DeMichele A. , Gupta V. , Barbi A. , Dials H. , Chen I. , Courtney R. , Wilner K. , Schwartz G. K. 
Published: March 2020

3550 Background: PD-0332991 is a novel oral inhibitor of CDK 4/6, which is active against Rb positive tumors and has never before been tested in humans. A phase I dose escalation trial of PD-0332991 administered as a daily oral single agent was conducted to investigate safety, pharmacokinetics and pharmacodynamics in patients with advanced cancer. Methods: PD-0332991 was administered daily for 21 days in 28-day cycles (Schedule 3/1) to patients in successive dose escalating cohorts at doses from 25 mg to 150 mg QD. An alternative schedule of 14 days dosing in 21-day cycles (Schedule 2/1) was tested at 100 mg to 225 mg QD. Patients with advanced Rb positive solid tumors were enrolled in the study. Results: Fifty-seven patients have been enrolled into the study. The most common tumor types were: breast, colorectal, liposarcoma, and melanoma. The median age across the study was 57 years. For Schedule 3/1, the MTD/RP2D was determined to be 125 mg QD. For Schedule 2/1, the MTD/RP2D is still to be identified but the maximum administered dose (MAD) was determined to be 225 mg QD. Six DLTs have been observed, all relating to myelosuppression. The most common AEs were neutropenia, anemia, fatigue, nausea, constipation, vomiting and diarrhea. Concentrations were moderately variable (% CV range in AUC on Day 8 of Cycle 1 was 14–64%) with dose-dependent increases in exposure observed following PD-0332991 administration (mean AUC(0–10 hr) values were 724 and 1,500 ng.hr/mL at the 125 mg and 225 mg dose levels, respectively). The effect of food on PD-0332991 pharmacokinetics is currently being evaluated. In Schedule 3/1, there have been 6 patients with stable disease (= 10 cycles) with 3 patients (one each with breast cancer, colon cancer and ovarian cancer) with stable disease for at least 20 cycles. In Schedule 2/1, one patient has had stable disease for at least 10 cycles. Updated data will be presented. Conclusions: The principal and dose limiting toxicity of PD- 0332991 is myelosuppression. The RP2D for Schedule 3/1 is 125 mg QD. The MAD has been determined for Schedule 2/1 as 225 mg QD and the dose in this schedule has been de-escalated to 200 mg QD to evaluate the MTD. Tumor specimens, when available, from patients in both schedules are also being tested for pharmacodynamic modulation of phospho-RB protein. No significant financial relationships to disclose.
Mechanism of bevacizumab-induced arterial hypertension: Relation with skin capillary rarefaction in patients treated for metastatic colorectal cancer
Authors: Morere J. F. , Des Guetz G. , Mourad J. , Lévy B. I. , Breau J. 
Published: March 2020

3557 Background: Bevacizumab in combination with chemotherapy is the standard treatment of metastatic colorectal cancer (mCRC). Hypertension (HT) has been reported in all studies, in particular grade 3 HT (3 - 16%) (Saif and Mehra, 2006 Expert Opinion on Drug Safety). The mechanism underlying bevacizumab-related HT is not yet clearly understood and recent studies have demonstrated that humoral factors involving the renin-angiotensin system and the sympathetic nervous system had little role in the observed increase in BP. As far as microvascular rarefaction has been reported in all forms of human and experimental HT, we tested the hypothesis that anti VEGF therapy could induce microvascular rarefaction in non tumoral tissues and, thus, result in an increase in BP Methods: For 16 patients treated for mCRC, Bevacizumab was administered at 5 or 7.5 mg/kg every 2 or 3 weeks depending on the frequency of concomitant chemotherapies which were FOLFIRI (4 patients) or XELOX (12 patients) We used intravital video-microscopy to measure basal and maximal (during venous congestion) skin capillary densities in the dorsum of the fingers. Aortic stiffness was evaluated using pulse wave velocity, and microvascular endothelial function was assessed by laser-Doppler flowmetry combined with iontophoresis of three different doses of acetylcholine (ACh). All measurements were performed in 16 patients (mean age: 59±10 y) before and after a 6 month treatment with bevacizumab (mean cumulative dose: 3.16±0.90 g) Results: are summarized in the following table : Conclusions: Pharmacological blockage of VEGF receptors result in endothelial dysfunction and capillary rarefaction in humans. Both changes are closely associated with and seem responsible for the rise in blood pressure observed in patients receiving this treatment. This could be considered for future study about anti- angiogenic treatment and HT. [Table: see text] No significant financial relationships to disclose.
Evaluation of AZD2171, an oral, highly potent and selective VEGFR signaling inhibitor, in renal cell carcinoma (RCC): Combined results from two phase I studies
Authors: van Herpen C. , Drevs J. , van Cruijsen H. , Voest E. E. , Punt C. J. , Robertson J. , Saunders O. , Zirrgiebel U. , Unger C. , Giaccone G. 
Published: March 2020

3560 Background: Antiangiogenic agents have recently demonstrated promising activity in patients with advanced RCC. AZD2171 is an oral, highly potent and selective inhibitor of VEGFR-1, -2 and -3 tyrosine kinases, and is currently in Phase II/III development in NSCLC and CRC. Safety and efficacy results are presented for patients with RCC who participated in two Phase I dose-escalation studies of AZD2171 in advanced solid tumors. Methods: Patients with advanced recurrent metastatic RCC received once-daily oral AZD2171, either as monotherapy (Drevs et al. Proc Am Soc Clin Oncol 2005: abst 3002; completed) or in combination with gefitinib (van Cruijsen et al. Proc Am Soc Clin Oncol 2006: abst 3017; ongoing). All patients had received prior interferon-a ± interleukin-2/ 5-FU or radiotherapy. Results: Twenty-one patients received AZD2171, 4 as monotherapy (20 mg, n=1; 60 mg, n=3) and 17 as combination therapy (AZD2171 20–45 mg with gefitinib 250 or 500 mg). The adverse event (AE) profile in RCC patients was similar to that reported previously for all patients in these studies; hypertension, dysphonia, nausea, vomiting, diarrhea and fatigue were the most common AEs. The most common CTC grade 3 AEs were hypertension (n=5) and diarrhea (n=4). Reductions in plasma levels of sVEGFR-2 were observed in RCC patients when AZD2171 was administered as a monotherapy or in combination with gefitinib; the reductions in the combination study were dose- and time-dependent (sustained). Nineteen patients were evaluable for efficacy (RECIST): 2/3 monotherapy patients experienced tumor regression, one of which was confirmed as a partial response (duration of response [DR] 87 days); in the combination study, 6/16 (38%) patients achieved a partial response (median DR 6 months; 3/6 ongoing at data cut off) and 7/16 (44%) patients had stable disease (4/7 had a confirmed 10–30% reduction in maximum tumor diameter). Conclusion: AZD2171, both as monotherapy and in combination with gefitinib, showed encouraging antitumor activity and a manageable toxicity profile in patients with advanced RCC who had failed prior therapy. A randomized Phase II investigation of AZD2171 monotherapy (45 mg/day) vs placebo in patients with advanced RCC is ongoing. [Table: see text]
A phase I trial of RX-0201 (AKT anti-sense) in patients with an advanced cancer
Authors: Marshall J. , Posey J. , Hwang J. , Malik S. , Shen R. , Kazempour K. , White L. R. , Fraser K. M. , Chang C. G. , Ahn C. H. 
Published: March 2020

3564 Background: Akt-1, a proto-oncogene, plays a vital role in cancer progression by stimulating proliferation and inhibiting apoptosis of cancer cells. RX-0201, a 20-mer oligonucleotide with sequence complementary to Akt-1 mRNA, is designed to inhibit the expression of Akt-1 within cancer cells in cancer patients (pts). Non-clinical studies conducted on RX-0201 demonstrated that RX-0201 bears significant in vitro and in vivo anti-cancer activities with favorable safety. Purposes: The aims of the current phase I trial were to determine the maximum tolerated dose (MTD) and to establish pharmacokinetic (PK) and safety profiles of RX-0201 in pts with an advanced cancer. Methods: RX-0201 was administered to pts with an advanced cancer by up to 2 cycles of continuous infusion; each cycle of infusion lasted for 14 days which was followed by a 7-day rest. Rapid dose escalation had been used until at least a grade (G) 2 toxicity was observed, and then a traditional dose escalation followed. Entry criteria included Karnofsky Performance Status score =70, advanced cancer, tumor accessible for paired biopsy, and signed informed consent. 17 pts were enrolled and treated at a dose level ranging from 6 to 315 mg/m2/d on D1–14, repeated q 21 d. Results: G 3 fatigue was observed in two pts at the 315 mg/m2/d dose; three pts dosed at 250 mg/m2/d were not noted with any G 3 toxicity, which make this dose (250 mg/m2/d) the recommended phase II trial dose. No other significant, compound-related, adverse events were observed in those 17 pts participated. Pts PK profiles of RX-0201 and AKT-1 immunohistochemistry results on pts’ tumor biopsy samples will also be presented. Conclusion: MTD of RX-0201 is 315 mg/m2/d in pts with an advanced cancer when the compound is administered in the current continuous infusion regimen. No significant financial relationships to disclose.
A phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17- DMAG, alvespimycin) administered weekly
Authors: Pacey S. C. , Wilson R. , Walton M. , Eatock M. , Moreno-Farre J. , Gallerani E. , Davergne V. , Raynaud F. , Workman P. , Judson I. 
Published: March 2020

3568 Background: The geldanamycin analogue 17-DMAG inhibits the ATPase activity of HSP90, thus altering client protein & chaperone interactions and targeting client proteins for degradation. The plethora of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer causing signalling pathways in cancer. Methods: 17-DMAG was administered weekly to patients with advanced, solid tumours using a dose-doubling 3 + 3 Phase I design. The pharmacokinetic (PK) and pharmacodynamic (PD) analyses undertaken were validated to comply with U.K clinical trial legislation. Results: 10 patients, 7 male and 3 female with a mean age of 60 years (range 38 - 78) have received 107 infusions (mean 10.7 weeks, range 2 - 30) at dose levels of 2.5mg/m2, 5mg/m2 & 20mg/m2. No dose-limiting or drug related grade 3 or 4 toxicity has occurred in 9 patients eligible for toxicity assessment. A linear relationship exists between dose and AUC and Cmax (see table ). Hsp72 induction and CDK4 depletion (consistent with HSP90 inhibition) have been detected at doses of 20mg/m2 in peripheral blood mononuclear cells. A confirmed partial response (by PSA and RECIST) has occurred in a patient with hormone refractory prostate cancer (HRPC). Conclusions: We have shown linear PK for 17-DMAG up to 20mg/m2. No dose-limiting toxicity has been encountered. A robust biologically active dose has not been reached but evidence of the pharmacological signature of HSP90 inhibition has been detected in surrogate tissue and a confirmed PR seen in a patient with HRPC. These data support dose escalation to 40mg/m2 and paired tumor biopsies will be taken to further define the PK-PD-clinical relationships. [Table: see text] [Table: see text]
A phase I safety and pharmacokinetic study of apomab, a human DR5 agonist antibody, in patients with advanced cancer
Authors: Camidge D. , Herbst R. S. , Gordon M. , Eckhardt S. , Kurzroc R. , Durbin B. , Ing J. , Ling J. , Sager J. , Mendelson D. 
Published: March 2020

3582 Background: Apomab, a fully human affinity-matured IgG1 monoclonal antibody, is a DR5 pro-apoptotic receptor agonist that triggers the extrinsic pathway of apoptosis. DR5 is expressed both on malignant and normal cells; however, pre-clinical data indicate that DR5 activation stimulates apoptosis predominantly in malignant cells. This first-in-human study assessed the safety, pharmacokinetics (PK) and any early evidence of anti-cancer efficacy of Apomab. Methods: Patients with advanced treatment-refractory solid tumors received Apomab IV on Day1 (cycle 1 = 28 days, cycles 2–8 = 14 days) at 1, 4, 10, 15, or 20 mg/kg (stage 1); with cohort expansion at 10 mg/kg or the MTD (if lower) every 14 days (stage 2). Tumor assessments were made after 2, 4 and 8 cycles. Therapy continued past 2 cycles as permitted by on-going evidence of benefit, until disease progression or unacceptable toxicity occurred. Results: 26 patients ECOG PS â‰¤1 have been enrolled and treated through 20 mg/kg. The 20 (8M, 12F) with confirmed data (up to 15mg/kg) received a median of 2 cycles (range 1–8). All dose levels have been tolerable (<33% dose limiting (Grade 3 drug-related) toxicities in the first 2 doses + 24 hours). 2 disparate DLTs occurred among 11 patients treated at 10 mg/kg. 1 patient (ovarian cancer) had asymptomatic transaminitis (ALT and AST) at C1D5, reaching Grade 3 by D29, received no further Apomab with resolution by D53. 1 patient (colorectal cancer) had a pulmonary embolism C1D4. Six patients completed at least 4 cycles of Apomab, 4 completed 8 cycles. No objective responses have been seen but at 10 mg/kg 1 patient (appendiceal cancer) remains on study (stable disease) past 8 cycles and 1 patient (colorectal cancer) had 28% shrinkage of target lesions and symptomatic improvement after 4 cycles. PK of Apomab is dose-proportional at 1 and 4 mg/kg with a typical IgG1 half-life of ∼15–20 days. AUC/Css,min concentrations at >4 mg/kg are greater than those displaying activity in preclinical models. No HAHA responses have been seen to date. Conclusions: Apomab is well tolerated with a minor response seen in a colorectal cancer patient. Enrollment is continuing at 10mg/kg. Further safety and efficacy data will be presented. No significant financial relationships to disclose.
Phase I clinical trial of CX-3543, a protein-rDNA quadruplex inhibitor
Authors: Papadopoulos K. P. , Northfelt D. W. , Hufnagel D. M. , Ricart A. D. , Griffin P. P. , Oslund M. D. , Von Hoff D. D. , Rice W. G. , Lim J. K. , Marschke R. F. 
Published: March 2020

3585 Background: CX-3543 inhibits over-expressed ribosomal RNA synthesis in cancer cells by disrupting an essential protein-rDNA quadruplex complex, thereby inducing selective apoptosis. A phase I clinical trial for CX-3543 was undertaken to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of this agent. Methods: Eligible patients with advanced solid tumors received CX-3543 in successive dose cohorts at: 10, 20, 40, 80, 160, 240, 360 and 480 mg/m2. Drug is administered by daily intravenous infusion on the first five consecutive days of a three week cycle, and the infusion duration has varied from one hour to six hours. Response by RECIST is determined after every 2 cycles. Results: Thirty-three patients (M/F:19/14; median age 69, range 44–83) with advanced solid tumors were treated with intravenous CX-3543. No drug related serious adverse events (SAEs) were encountered. DLTs of infusion-related cough and headache were identified at 480 mg/m2 (The MTD was 360 mg/m2). These adverse events were fully and rapidly reversible upon slowing or interrupting the infusion. Other drug-related adverse events were of mild to moderate intensity. Four patients had stable disease for longer than 4 months and one patient, with stable disease for over one year, currently continues on study. CX-3543 demonstrated an increasing plasma terminal half life at the higher dose levels due to a ‘reservoir‘ effect from CX-3543 reversibly binding to blood cells. Conclusions: CX-3543 administered as a 6 hour infusion for five consecutive days of a three week cycle is well tolerated and has stabilized disease in a number of patients enrolled in this phase I study. This trial is now in an expanded enrollment phase at 360 mg/m2 and pharmacodynamic measures, specifically FDG-PET scans and circulating tumor cells, have been included to detect biological activity at this dose level. No significant financial relationships to disclose.