bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 study of CP-868,596 an oral, highly specific PDGFR inhibitor
Authors: Lewis N. , Eder J. P. , Guo F. , Pierce K. J. , Olszanski A. J. 
Published: March 2020

3524 Background: CP-868,596 is an orally available, highly specific inhibitor of platelet-derived growth factor receptors (PDGFR). PDGF and its receptor play an important role in angiogenesis, modulation of tumor interstitial fluid pressure (IFP), and influence cell growth, migration, and survival through signal-transduction pathways. Methods: The safety, tolerability and pharmacokinetics (PK) of daily oral CP-868,596 administered in 4-week cycles were assessed in patients with advanced solid malignancies. Original dose escalation cohorts were 100, 200, 280 and 340 mg QD administered on an empty stomach. Prevalence of persistent Grade 1 nausea and vomiting led to amendments that include “with food” cohorts. Safety assessments included adverse events (AEs), clinical laboratories, and ECG monitoring. PK blood samples were collected after a single dose and at steady state. PK parameters were estimated by non compartmental techniques. Results: Data is available for all 59 patients enrolled in the trial [(29 M/30F); mean age (range): 58.6 (18–80)]. The most common treatment related AEs were nausea (67.8%), vomiting (55.9%) and diarrhea (25.4%). The MTD with coadministration of anti-emetics on an empty stomach was 200 mg/day. Coadministration of CP-868,596 with food resulted in a decrease of nausea and vomiting. The recommended phase 2 dose is 100 mg BID given with food. CP-868,596 was rapidly absorbed after oral administration. Median Tmax ranged from 1 to 4 hours. Cmax and AUC of CP-868,596 increased with dose more-than proportionally. Moderate accumulation occurred with a mean AUC accumulation ratio of 1.4–4.0. The mean terminal t1/2 ranged from 11.6 to 16.8 hours and was similar across all dose levels. The effect of food on PK appeared to be dose-dependent in this parallel cohort design with a limited number of patients (n=3–8). Analysis of safety data showed increasing liver enzymes with increasing PK exposures. No objective responses were seen. Conclusion: Daily administration of CP-868,596 appears to be safe and well tolerated. DLTs were: N/V (2), elevated ALT/GGT (2/2), increased Mg (1), Hematuria (1), and Insomnia (1). Mean steady state serum concentrations in all dose cohorts exceeded the preclinically predicted minimal efficacious exposure (16 ng/mL). No significant financial relationships to disclose.
Phase I trial of intravenous 17-allylaminogeldanamycin (A) and oral sorafenib (B) in pretreated advanced malignancy: Plasma Hsp90α induction correlates with clinical benefit
Authors: Vaishampayan U. N. , Sausville E. A. , Horiba M. N. , Quinn M. , Heilbrun L. K. , Burger A. , Ivy P. , Li J. , Lorusso P. 
Published: March 2020

3531 Background: The combination of B with A was evaluated to recommend a phase II dose for using A in combination with B, since raf-kinase and VEGF inhibition by distinct pathways could result in synergy and prevent resistance to B. Patients and Methods: Eligibility included histologically confirmed advanced malignancy, at least 4 weeks since prior systemic cancer therapy and/or radiation, adequate organ function and performance status of 0–2. B was administered orally at fixed dose of 400 mg twice daily starting 2 weeks prior to A, which was added in escalating dose cohorts starting at 300mg/m2 intravenously over 3 hours on days 1, 8 and 15 in a 28 day cycle. Toxicity was assessed weekly and clinical response evaluated every 2 cycles. Results: 19 patients have been registered (6 clear cell renal, 1 papillary renal, 4 colorectal, 1 each with cervix, adrenal, oral, thyroid, pancreas cancer and 3 with melanoma). 16 have been treated for at least the first two cycles at 4 dose levels on this ongoing study. Dose limiting toxicity has not yet been reached at 400mg/m2 of A. Major toxicities were grade 3 fatigue in 1 patient and grade 2 nausea and diarrhea in 3 and 2 patients respectively. Grade 3 hand foot syndrome related to B was noted in 3 patients. Of 14 response evaluable patients, 1 demonstrated partial response (thyroid cancer) and 6 had stable disease;3 clear cell renal,1 each with papillary renal and cervix cancers, and 1 melanoma. Latter patient had stable disease for 10 cycles and was resected to render disease free. PK analysis reveals that steady-state was achieved after 1 week of B; addition of A did not alter PK of B. PK levels of A will be performed. Studies of Hsp90a in the plasma have been performed on 10 patients. Of the 10 patients evaluated for plasma Hsp90a (baseline values pre-A and at 4 and 18 days after A), 5 of the 6 clinically stable patients had 1.8 to 6.8- fold increase; 3 patients with clinical progression and 1 clinically inevaluable patient had induction of 0.8 to 1.7-fold. Conclusion: The combination of A and B is well tolerated and clinical benefit may correlate with induction of plasma Hsp90a. Supported by NIH# 5UO1CA062487- 14, 2MO1RR016500–006 and NCI CTEP. No significant financial relationships to disclose.
Phase 1 dose-escalation study of 17-allylamino-17-demethoxygeldanamycin (17AAG) in combination with irinotecan in patients with solid tumors
Authors: Tse A. N. , Carvajal R. , Shah M. , Dials H. , Fogel M. , O’Reilly E. , Chung K. , Maki R. , Wu N. , Egorin M. , Schwartz G. K. 
Published: March 2020

3533 Background: 17AAG is an inhibitor of the molecular chaperone Hsp90. Pre-clinical studies from our laboratory showed that treatment of cancer cells with 17AAG caused depletion of two critical checkpoint kinases, Chk1 and Wee1, resulting in abrogation of the G2/M checkpoint triggered by topoisomerase I poison, and selective induction of apoptosis in p53-defective cells. Methods: We initiated a phase 1 study of irinotecan (CPT) and 17AAG to determine the maximally tolerated doses (MTD) and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. During the dose-escalating phase, patients (Pts) received CPT over 30 min followed by 17AAG over 2 hrs once weekly for two weeks in a 21-day cycle. At the MTD, Pts underwent post-treatment tumor biopsy for PD biomarker analysis after CPT only during week 1 and after the combination during week 2. Results: 22 Pts (median age 53; range 32–73; median KPS 80) with a wide spectrum of solid tumor types were enrolled. Four Pts developed dose-limiting toxicity in cohort 4 (100 mg/m2 CPT and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The PKs of 17AAG and its metabolite 17AG were not affected by the co-administration of CPT. Although no CR/PR’s by RECIST criteria have been seen, minor responses were observed in CPT-naive Pts with pancreas (2), breast (1), and high grade neuroendocrine tumor (1). Pts are currently enrolled to the MTD expanded cohort for further assessment of tolerability and PD analysis. So far, paired tumor biopsies have been successfully obtained in 8/8 Pts and samples will be analyzed for p53 status, Hsp90 client protein depletion, G2/M checkpoint abrogation, and apoptosis. Conclusions: The combination of 17AAG and CPT can be given to Pts with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 CPT and 300 mg/m2 17AAG. (Supported by ASCO CDA and NCI K08 awards) No significant financial relationships to disclose.
First-in-human study of AMG 655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors
Authors: LoRusso P. , Hong D. , Heath E. , Kurzrock R. , Wang D. , Hsu M. , Goyal L. , Wiezorek J. , Storgard C. , Herbst R. 
Published: March 2020

3534 Introduction: AMG 655 is a fully human monoclonal agonist antibody that binds human TRAIL receptor 2 (TR-2/DR5), activates caspases, and induces apoptosis in sensitive tumor cells. The primary objectives of this ongoing first-in-human study were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 655 in patients (pts) with advanced solid tumors. Methods: Three to 9 pts were enrolled into 1 of 5 sequential dose cohorts (0.3, 1, 3, 10, or 20 mg/kg) of AMG 655 administered intravenously Q2W. No AMG 655 was administered on day 43 to allow assessment of terminal PK parameters. RECIST and FDG-PET were analyzed by central radiology. Pts remained on study until tumor progression or unacceptable toxicities occurred. Results: As of October 19, 2006, 16 pts (4 in the 10 mg/kg cohort; 3 in each of the other cohorts) had received = 1 dose of AMG 655; 12 pts were men, mean (SD) age was 53 (±8.9) years. No DLTs or AMG 655-related serious AEs were reported. The MTD was not reached. Nine pts reported AMG 655-related AEs. Treatment-related AEs in 3 or more pts were: pyrexia (4 pts), fatigue (3 pts), and hypomagnesaemia (3 pts). Fatigue and elevated serum lipase were the only grade 3 or higher AMG 655-related AEs and both occurred in the same pt (0.3-mg/kg cohort). No anti-AMG 655 antibodies were detected. PK data were available from dose cohorts 1 to 3 (0.3, 1, and 3 mg/kg); AMG 655 demonstrated dose-linear kinetics with a half-life of ∼10 days. Tumor- response data were available for 13 pts. Partial response was observed in 1 pt with non-small cell lung cancer (NSCLC) who experienced a 46% reduction in tumor volume by RECIST and remains on study after 48 weeks. Stable disease was reported in 4 pts (range 6 to 35 weeks), and progressive disease in 8 pts. One pt with colorectal cancer and stable disease demonstrated a metabolic partial response with a 34% reduction in maximum standardized uptake value (SUVmax). Conclusions: AMG 655 administered up to 20 mg/kg Q2W appeared to be well tolerated in these pts. The anti-tumor activity of AMG 655 was confirmed with observation of a partial response in NSCLC and a metabolic partial response in colorectal cancer. Further studies evaluating AMG 655 in combination with chemotherapy and targeted agents are warranted. No significant financial relationships to disclose.
Pharmacokinetic (PK) and phase I study of sorafenib (S) for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction (HD or RD): CALGB 60301
Authors: Miller A. A. , Murry D. J. , Owzar K. , Hollis D. R. , Abou-Alfa G. K. , Desai A. , Hwang J. , Villalona-Calero M. , Dees E. C. , Lewis L. D. , Ratain M. J. 
Published: March 2020

3538 Background: We sought to characterize the PK and determine a tolerable dose of S in patients with HD or RD. Methods: Patients with performance status 0–2 and pathologically proven solid tumors, multiple myeloma, or non-Hodgkin’s lymphoma, for whom standard therapy was exhausted, were assigned to one of 9 cohorts: [1] Bilirubin (B) =ULN and SGOT =ULN and creatinine clearance (CC) =60 ml/min; [2] B > ULN but = 1.5 x ULN and/or SGOT > ULN; [3] CC between 40 and 59 mL/min; [4] B > 1.5 x ULN to = 3 x ULN (any SGOT); [5] CC between 20 and 39 mL/min; [6] B > 3 x ULN to 10 x ULN (any SGOT); [7] CC < 20 mL/min; [8] albumin < 2.5 mg/dL (any B/ SGOT); and [9] hemodialysis. S was administered po as a 400 mg test dose on day 1 with blood sampled before and 1, 2, 3, 4, 6, 24, and 168 hrs afterwards for PK. Total S concentrations were fit to a 2-compartment model and population parameters from previous studies were utilized. On day 8, continuous daily po S started with dose escalation in groups of at least 3 evaluable patients. Dose-limiting toxicity (DLT) by day 29 was defined as: grade 4 neutrophils or platelets; B = 1.5 x baseline in HD and = 2.5 x ULN in RD; CC reduction by > 20 mL/min in RD and >10 mL/min in HD; grade = 3 nausea/vomiting/diarrhea despite optimal supportive care; or any other grade = 3 non-hematologic toxicity. Results: Between 1/05 and 12/06, 146 patients (target 150) were registered but 12 never started therapy. With the exception of cohorts 6 and 7, at least 12 patients per cohort were evaluable. The dose level in each cohort with DLT in less than one third of patients was: [1] 400 mg bid; [2] 400 mg bid; [3] 400 mg bid; [4] 200 mg bid; [5] 200 mg bid; [6] not even 200 mg every third day tolerable; [7] n/a; [8] 200 mg qd; and [9] 200 mg qd. All DLT was non-hematologic: 9 of 12 events in patients with HD were increase in B; other DLT included abdominal pain, rash, fatigue, nausea/vomiting, hand-foot syndrome, congestive heart failure, diarrhea, hemorrhage, and hypertension. PK data are available for 51 patients. Apparent S clearance was: highly variable, median 5.69 (range 1.27 - 19.98) L/hr; not related to age, body weight, or sex; and not different among cohorts. Conclusions: Apparent S clearance does not depend on cohort. We propose the above empiric starting doses by cohort. No significant financial relationships to disclose.
A phase I study of bevacizumab (BV) plus ABT-510 in patients with advanced solid tumors
Authors: Uronis H. E. , Bendell J. , Blobe G. , Morse M. , Geier D. , Nixon A. , Howard L. , Evans D. , Li H. , Hurwitz H. 
Published: March 2020

3541 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity both alone and in combination. ABT-510 is a 9 amino acid synthetic analog of the N-terminal region of thrombospondin (TSP-1), an endogenous inhibitor of angiogenesis. ABT-510 exhibits anti-angiogenic effects in preclinical models and has been well-tolerated as a single agent in previous Phase I & 2 studies. As a combination anti-angiogenesis therapy, we evaluated BV + ABT-510 in a phase I biomarker study. Methods: In cohorts of 3–6 patients, BV and ABT-510 were evaluated. BV was dosed in mg/kg IV q2weeks and ABT-510 was given daily in mg SC BID; cycle length was 28 days. Dose levels were as follows: (1) BV 5/ ABT-510 50; (2) BV 10/ ABT-510 50; (3) BV 10/ ABT-510 100. At the recommended phase II dose, 20 patients are being enrolled for detailed biomarker studies. DLT was defined as any hematological toxicity = grade 4 or grade = 3 non- hematological event in Cycle 1 related to treatment, with the exception of grade 3 hypertension adequately controlled by medication. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities suggesting increased risk for class-related toxicities. Dermal wound angiogenesis assays were analyzed for visualization as well as phospho-VEGFR2, TGFβ, phospho-AKT, and thrombospondin-1 and -2, both pre- and on-treatment. Plasma was assayed for multiple angiogenic factors. Results: 22 patients have been enrolled; 17 are currently evaluable for toxicity and 14 for efficacy. No DLT were seen in any cohort. Possible treatment related adverse events occurring in later cycles included: gr3 GI bleed (n=1) and gr3 headache (n=1). 7 patients had stable disease as best response (range 8- 64+ weeks); 2 remain on therapy, one at 64+ weeks and one at 24+ weeks. Conclusions: BV + ABT-510 is well-tolerated and has hints of activity in refractory tumors. The recommended phase II dose is BV 10mg/kg IV q14d and ABT-510 100mg SC BID. Updated clinical and biomarker data will be presented. No significant financial relationships to disclose.
Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancers (NCI protocol 7156 supported by NCI grant UO1 CA062461)
Authors: Hong D. S. , Camacho L. , Ng C. , Wright J. , Newman R. A. , Moulder S. , Tannir N. , Wheler J. , Khan R. , Kurzrock R. 
Published: March 2020

3549 Background: The Ras and Raf kinases are sequential signaling proteins in the MAPK pathway and inhibition of both targets may confer synergistic effects, particularly in tumors with activation of either kinase through mutation or other mechanisms. Therefore, we sought to combine sorafenib, a multikinase inhibitor (Raf, VEGFR, PDGFR) and tipifarnib an inhibitor of farnesyltransferase that is critical for Ras activity in a phase I study to determine the safety, pharmacokinetics (PK), and tumor response. Methods: The trial was a phase I trial of advanced cancer patients(pts) with a conventional dose escalation design. Each cycle consisted of 28 days of sorafenib and 21 days of tipifarnib. Dose levels are listed in the table . Results: To date, a total of 27 pts have been enrolled (median age 54.5 yrs, M:F 1:1. 3 RCC, 3 breast, 4 sarcoma, 4 melanoma, 3 CRC, 4 thyroid, 2 H&N, one thymic, one adrenal cortical, one SCC of the lung, and one unknown primary SCC). Two pts developed grade 3 DLT-skin rash on the first dosing level (tipifarnib at 100 mg po BID and sorafenib at 400 mg po BID). Dose escalation was modified as per table below. At dose level 4, 2/5 pts entered experienced a DLT of grade 3 rash and grade 3 drug fever, therefore MTD has been determined to be tipifarnib 100 mg BID, sorafenib 400 mg qam, 200 mg qpm. The most common treatment related toxicities included lymphopenia (18), hyperglycemia (17), and skin rash (14). Currently, 19 of the 27 pts are evaluable; 13 pts had SD (8–44 weeks); 2 RCC pts for 32 weeks, an adrenal cortical ca pt for 32 weeks, one melanoma pt for 44 weeks. PK analysis suggested findings similar to single agent PK profiles, no PK interactions were apparent. Conclusions: Significant toxicity with the combination of these two agents, even doses well below single agent maximum levels were observed. The MTD was determined to be tipifarnib at 100 mg BID, sorafenib at 400 mg qam, 200 mg qpm. PK analysis, to date show,no pharmacokinetic interaction between tipifarnib and sorafenib. [Table: see text] [Table: see text]
Sorafenib (S) and dacarbazine (D) combination in patients (pts) with advanced malignant solid tumors: Phase I study with tumor biopsy genomic analysis and dynamic contrast enhanced ultrasonography (DCE-US)
Authors: Soria J. , Lazar V. , Lassau N. , Pena C. , Massard C. , Robert C. , Koscielny S. , Deutsch E. , Zafarana E. , Armand J. P. 
Published: March 2020

3556 Background: S is a multikinase inhibitor targeting VEGFR-1, -2, -3, PDGFR-a and -β and Raf kinase. The combination of S (400 mg bid) and D (1,000 mg/m2, 21-day [d] cycle [C]) was previously defined as maximum tolerated dose. Objectives were to define the pharmacokinetic (PK) profile of D ± S, assess safety of the combination and collect antitumor activity data by genomic analysis and by DCE-US. Methods: All pts received D (1,000 mg/m2 by 1-hr infusion) with continuous oral S 400 mg bid (except Day1C1). PK was performed during 1st and 2nd infusions. RNA expression profiling was performed on sequential tumor biopsies at baseline (BL) and Day 21. DCE-US was assessed at BL and Day 8, 21 of C1. Results: 23 pts treated (median age 59 y) had melanoma (4), leiomyosarcoma (4), adenocarcinoma (5), mesothelioma (3), neuro-endocrine tumor (3) and other (4). 22 had = 1 prior chemotherapy (range, 1–7). Median (range) number of D cycles was 4 (1–9), median (range) duration of S treatment was 15 wks (3–48). Toxicities were manageable and included diarrhea (48% any grade [G], no G3/4), hand-foot skin reaction (48% any G, 4% G3), fatigue (26% G3), thrombopenia (22% G4), and neutropenia (13% G4). Of 22 evaluable pts, 1 (melanoma) had confirmed PR, 13 pts had SD as best response, with a median (range) duration of 161 d (75–258). 7 pts continue with SD. PK (n=15) showed increased mean AUC by 41% and mean Cmax of AIC (an inactive D metabolite that is formed in an equal proportion to the active moiety, diazomethane, that cannot be analytically measured) by 45%. Genomic analysis in 10 pts with PFS =3 mos and in 7 with PFS <3 mos identified a subset of 4 genes whose modulation differentiates these groups with 100% accuracy. 99 DCE-US performed in 17 pts showed 3/7 with short PFS had increased volume on Day 21 and in 3 an increase in maximal intensity >50% on Day 8. Of 10 pts with long PFS, maximal intensity decreased by >50% on Day 21 in 8 pts. Conclusion: Combination of D and S is manageable with clear evidence of antitumor activity. Preliminary data strongly suggest a new paradigm based on sequential tumor genomic analysis allowing early identification of responders. Early stage DCE-US may predict PFS duration. No significant financial relationships to disclose.
A phase I study of vorinostat in combination with bortezomib in refractory solid tumors
Authors: Schelman W. R. , Kolesar J. , Schell K. , Marnocha R. , Eickhoff J. , Alberti D. , Wilding G. , Bailey H. 
Published: March 2020

3573 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) inhibitor that has anti- tumor activity in hematologic malignancies and advanced solid tumors. Based on studies showing that HDAC inhibitors increase the activity of the 26S proteasome, vorinostat has been postulated to act synergistically with bortezomib. This study was conducted to determine the toxicities and efficacy of vorinostat with bortezomib. Correlative studies included pharmacokinetics and the effects of vorinostat/bortezomib on cell cycle, proteasome inhibition, histone acetylation, gene expression and apoptosis. Methods: This study used standard eligibility criteria except pts must have had no prior bortezomib. The treatment plan consisted of vorinostat given orally on days 1–14 with bortezomib IV on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (Step A, level 1) was once-daily vorinostat (400 mg) and bortezomib (0.7 mg/m2). Step B consisted of twice-daily dosing of vorinostat (200mg) with bortezomib at MTD established in Step A. RECIST was used to measure response. Effects on G2/M-phase arrest in buccal mucosa cells (BMC) were measured using flow cytometry. Samples were collected on days 1 and 9, at 0, 2 and 4 hr following treatment. Results: 22 pts have been enrolled; 14 men, 8 women. Tumor types: 5 sarcoma, 5 colorectal, 3 pancreatic, 2 lung, 1 breast, 1 ovarian, 1 bladder, 1 gastric, 1 germ cell, 1 mesothelioma, 1 GIST. Grade 3–4 toxicities at least possibly related to vorinostat at any dose level were as follows: fatigue (3), n/v (1), thrombocytopenia (1), and hyponatremia (1). One pt was unevaluable. DLTs included fatigue (3), hyponatremia (1) and elevated ALT (1). The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. One pt with refractory soft tissue sarcoma had a PR > 9 mo. There was no effect on cell cycle arrest observed with vorinostat in BMCs. Conclusions: The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. Accrual continues at Step B, dose level 1. Subjective and objective evidence of clinical activity has been observed in pts with refractory solid tumors. (Supported by NCI grant UO1 CA062491, NCI SAIC contract 25XS097 and GCRC M01 RR03186.) No significant financial relationships to disclose.