bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of peptide vaccine with chemotherapy in patients with unresectable colorectal cancer
Authors: Yoshimatsu K. , Yokomizo H. , Otani T. , Osawa G. , Ogawa K. 
Published: August 2020

3067 Background: RNF43 is a cancer testis antigen expressed in colorectal cancer (CRC) but not in normal organs. RNF43–721 induces HLA A24 restricted cytotoxic T lymphocytes (CTL) against RNF43 expressed target. S-1/CPT-11 chemotherapy (CT) is reported to be obtained the similar result to FOLFOX or FOLFIRI as first-line for advanced CRC. We plan phase I study to evaluate the safety of different doses of RNF43–721 emulsified with Montanide ISA51 in combination with S-1/CPT-11 CT expecting synergistic effect. Methods: Inclusion criteria as follows: HLA A24 positive, pathological CRC, life expectancy > 3 months, WBC>3000/mm3, Hb>10mg/dl, Plt>75000/mm3, creatinine<1.2mg/dl, T. bil.<1.5mg/dl, AST, ALT<3x normal limits, written informed consent. Other malignancy, infection, treatment with steroids and immunosuppressive agents, and HBV, HCV, HIV infection are excluded. The study design is dose escalation of peptide (0.5, 1.0, 3.0 mg) with three patients’ cohort. The study regimen is that oral administration of S-1 at 40 mg b.i.d. for 21 consecutive days followed by a 7-day rest period and intravenous infusion of CPT-11 at a dose of 80 mg on days 1 and 15 are performed with weekly subcutaneous injection of peptide vaccine. Two courses are study periods and there is no restriction of therapy after study. Primary endpoint is safety and secondary are CTL, objective response rate and TTP. Results: Twelve patients (pts) were enrolled and 3 pts canceled treatment due to patient's proposal. In 9 evaluable pts, median age of pts with 7 males and 2 females was 61. Standard chemotherapy for CRC were failed in 8 pts. Systemic toxicities were observed in one pt with grade 2 and others were grade 1. Skin reactions were occurred in 7 pts. No pts were obtained CR and PR, 6 pts were SD and 3 were PD. CTL response was observed in 5 pts. TTP was calculated as 204 days. Conclusions: Treatment with peptide vaccine and S-1/CPT-11 CT was well tolerated. These results encourage further clinical trials of peptide vaccine with standard CT for advanced CRC. No significant financial relationships to disclose.
Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors
Authors: Shapiro G. , Kwak E. , Baselga J. , Rodon J. , Scheffold C. , Laird A. D. , Bedell C. , Edelman G. 
Published: August 2020

3500 Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed. [Table: see text]
Results of a phase I trial of KX2–391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies
Authors: Adjei A. A. , Cohen R. B. , Kurzrock R. , Gordon G. S. , Hangauer D. , Dyster L. , Fetterly G. , Barrientes S. , Hong D. S. , Naing A. 
Published: August 2020

3511 Background: Src kinase is central to the proliferation, apoptosis and metastasis of tumor cells. KX2–391 is a synthetic, orally bioavailable small molecule Src tyrosine kinase signaling inhibitor. KX2–391 is distinct from all other known Src kinase inhibitors in targeting the peptide substrate-binding site and not the ATP-binding site. KX2–391 is the first peptide site targeted tyrosine kinase inhibitor to enter clinical trials. KX2–391 has a much wider spectrum of solid tumor activity in vitro, and is more potent in mouse xenografts, as compared to other multikinase Src/Abl inhibitors. Methods: This multi-center Phase 1 trial utilized the standard 3+3 design to determine the Maximum Tolerated Dose (MTD), safety, and pharmacokinetics (PK) of KX2–391 in pts with refractory solid tumors. Results: To date, 32 pts (12 m 20 f, median age 59 (range 31–78)) have been enrolled in 7 dose cohorts. Dose limiting toxicities (DLTs), which were all reversible within 7 days, occurred in 4 pts and included elevated ALT and AST, neutropenia, and fatigue. 22 pts experienced no Grade 3 or 4 adverse events. Other Grade 1/2 adverse events include: hypokalemia, anemia, elevated AST, fatigue, dyspnea, fever, vomiting, constipation, hematuria, and lymphopenia. The MTD is 40 mg BID on a 3 out of 4 weeks dosing schedule. 7 pts had prolonged stable disease for 4 months or longer including 2 pts with papillary thyroid carcinoma, 2 with carcinoid, and 1 each with prostate, pancreas, and head and neck cancer. Both the prostate and pancreatic cancer pts had dramatic decreases in their biomarkers (PSA went from 205 ng/ml to 39 ng/ml, and CA19–9 went from 38,838 U/ml to 267 U/ml, respectively). The PK profile demonstrated dose-proportionality, a half-life of 4.5 hrs and a Tmax of 1 hr with no evidence of accumulation with multiple doses. Conclusions: KX2–391 has a favorable PK profile, is well-tolerated, demonstrates preliminary evidence of biologic activity and should be further evaluated in Phase II trials. [Table: see text] [Table: see text]
Early evidence of tolerability and clinical activity from a phase I study of TRC105 (anti-CD105 antibody) in patients with advanced refractory cancer
Authors: Rosen L. , Gordon M. S. , Hurwitz H. I. , Wong M. K. , Adams B. J. , Alvarez D. , Seon B. K. , Leigh B. R. , Theuer C. P. 
Published: August 2020

3518 Background: CD105 (endoglin) is an angiogenic membrane protein that is over-expressed on proliferating vasculature in solid tumors and up-regulated following anti-VEGF therapy. TRC105 is a human/murine chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition, ADCC, and apoptosis. Methods: The safety and PK of TRC105 were evaluated in patients with refractory cancer. Subjects were to have adequate organ function and no CNS or central thoracic tumors. TRC105 was escalated in cohorts of 3–6 patients to a maximum feasible dose of 1.0 mg/kg i.v. every 2 weeks. Results: 19 ECOG PS 0–1 patients received TRC105 at doses between 0.01–1.0 mg/kg, including 11 men and 8 women aged 37 to 79 years (median 59). One patient experienced dose-limiting toxicity (DLT) at 0.1 mg/kg of grade 4 gastric ulcer bleeding on Day 4 which resolved spontaneously. No other grade 3 or 4 adverse events were reported. Possibly related grade 1–2 adverse events were rare including fatigue, anemia, proteinuria, dysgeusia, diarrhea, flushing, hyperuricemia and intermittent postcoital vaginal bleeding. One patient with castrate-refractory prostate cancer remains on study after 13 months of TRC105 at 0.01 mg/kg with a complete PSA response and bone scan normalization. In addition, 6-month stable disease was seen in a patient with ovarian cancer (CA125 decrease of 16%). Best response also included stable disease (n = 3) and progression (n = 14). Serum TRC105 concentrations expected to saturate CD105 binding sites (> 0.2 ug/mL) were achieved at a dose of 0.3 mg/kg, and concentrations > 10 ug/mL were achieved at 1.0 mg/kg. HAMA became detectable in 1 patient after 3 months of TRC105 therapy. Conclusions: TRC105 is tolerated at doses with evidence of clinical activity. Additional monotherapy and combination studies are planned. [Table: see text]
Final results of a pharmacokinetic (PK) and pharmacodynamic (PD) phase I trial of ARQ 197 incorporating dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies investigating the antiangiogenic activity of selective c-Met inhibition
Authors: Yap T. A. , Frentzas S. , Tunariu N. , Barriuso J. , Harris D. , Germuska M. , Waghorne C. , Li J. , deSouza N. , de Bono J. S. 
Published: August 2020

3523 Background: ARQ 197 (ARQ) is a selective non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell proliferation, invasion and angiogenesis. Preclinical data and declines in circulating endothelial cell (CEC) levels in patients (pts) receiving ARQ suggest antiangiogenic potential of c-Met inhibition. Methods: ARQ was administered orally twice daily (bid) to pts with advanced solid tumors. Pre and post-therapy tumor biopsies were mandated for c-Met and FAK immunohistochemical studies during dose escalation (n = 16). CEC enumeration was evaluated. 12 pts are being investigated in the maximum tolerated dose (MTD) expansion cohort with DCE and Diffusion Weighted (DW) MRI. Results: 29 pts (14 F/15 M; mean 54.4 yrs) received ARQ at doses of 100 (n = 3), 200 (n = 6), 300 (n = 16), and 400 (n = 4) mg bid. 3 pts experienced dose limiting toxicities of CTCAEv3 grade (G)3 fatigue (200 mg bid); G3 hand-foot syndrome, G3 mucositis and G3 febrile neutropenia (400 mg bid). This established the ARQ MTD/recommended phase II dose (RP2D) at 300 mg bid. Other toxicities were G1–2, such as fatigue (n = 5); diarrhea, nausea and vomiting (n = 3). Mean AUC0–12h and Cmax increased linearly through the MTD. Statistically significant post-ARQ inhibition of high baseline phosphorylated c-Met and FAK expression in tumor tissue was seen in all dose cohorts confirming target inhibition. Disease stabilization (SD) was seen in 11 pts for up to 23 weeks with tumor regressions up to 12.4%. 13 of 20 pts had post-ARQ CEC declines of up to 100%. In the DCE-MRI cohort to date, preliminary analyses of ktrans histograms from pelvic lesions were consistent with antiangiogenic effects, with a ktrans median reduction of 20.1% on day 7 of ARQ (intrapatient baseline variability: 2.8%). This effect was still present (ktrans median decline: 8.3%) on day 56 of ARQ. Conclusions: ARQ is well tolerated with MTD/RP2D of 300mg bid, linear PK and evidence of phosphorylated c-Met and FAK inhibition. CEC and preliminary DCE-MRI data support the antiangiogenic effects of c-Met inhibition with ARQ. Correlation with other DCE parameters and DW changes will be presented. [Table: see text]
Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor
Authors: Jimeno A. , Hong D. S. , Hecker S. , Clement R. , Kurzrock R. , Pestano L. A. , Hiscox A. , Leos R. A. , Kirkpatrick D. L. , Eckhardt S. G. , Herbst R. S. 
Published: August 2020

3542 Background: PX-866 is an orally available nanomolar pan-inhibitor of PI-3K whose administration results in antitumor activity and pathway (AKT, S6 and mTOR) inhibition in animal models. Loss of PTEN and/or PI 3K mutations have been associated with enhanced susceptibility to PX-866. PX-866 is being evaluated in a phase 1 clinical trial to determine the MTD, and measure safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in PBMCs and tumor tissue in patients with solid tumors. Methods: Patients with advanced metastatic cancers receive PX-866 orally once daily for 5 of 7 days for 2 weeks in a 28-day cycle. Dose levels of 0.5, 1, 2, 3, 4.5, 6, 8, and 10 mg are planned. PK and PD samples are collected days 1, 2, 5, 8, 12, and 15 of cycle one and days 1 and 12 of cycle two. A PD assay has been developed that utilizes flow cytometry to test the inhibition of S6RP and mTOR in PBMC. Once the MTD of this PX-866 schedule of administration has been identified, an expansion cohort is planned to investigate tumor PD events and correlate tumor and PBMC endpoints with efficacy. Results: Four cohorts (0.5, 1, 2, 3 mg) comprising 12 patients (age 42–74, median PS 1) have completed accrual, with the 4.5 mg cohort actively enrolling. The total number of cycles to date is 30 (median 2, range 1–5+). Abdominal discomfort and mild diarrhea have been possibly associated with PX-866. No drug-related severe adverse events or dose-limiting toxicities have occurred. Of the 6 patients treated in the first 2 cohorts, 3 previously progressing patients had stable disease (SD) as best response and were on study for 105, 147 and 162+ (still active) days. Two patients (squamous cell skin cancer and melanoma) had decrease in pain allowing discontinuation of analgesics. Proof-of-concept PD studies in PBMCs evidenced a dose dependent inhibition of both p-S6RP and p-mTOR levels. Conclusions: PX-866 is a novel oral PI-3K inhibitor that is undergoing development in a clinical trial with built-in PD endpoints. PX-866 has shown to have a mild side effect profile while inducing stabilization of disease in previously progressing cancer patients. Oral PX-866 provides target inhibition even at low drug doses and inhibition is maintained for an extended time following the last dose. Updated clinical, PK and PD results will be presented. [Table: see text]
Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors
Authors: Sangha R. , Ho C. , Beckett L. , Lau D. H. , Lara P. N. , Davies A. M. , Mack P. C. , Koslan G. M. , Holland W. S. , Gandara D. R. 
Published: August 2020

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]
Axitinib (AG-013736; AG) combined with chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) and other solid tumors
Authors: Martin L. P. , Kozloff M. F. , Krzakowski M. , Samuel T. A. , Rado T. A. , Tarazi J. , Rosbrook B. , Tortorici M. , Olszanski A. J. , Cohen R. B. 
Published: August 2020

3559 Background: AG is an oral, potent and selective inhibitor of VEGFRs 1, 2, 3. Anti-VEGF therapies combined with chemotherapy improve survival vs chemotherapy alone in pts with advanced solid tumors, including NSCLC. This phase I trial assessed AG combined with chemotherapy. Methods: Pts with advanced solid tumors without prior treatment with platins or taxanes received paclitaxel/carboplatin (P: 200 mg/m2 / C: AUC 6 mg*min/mL) every 3 weeks + AG at lead-in doses of 1, 3 or 5 mg BID. AG was increased to 5 mg BID post lead-in. Another cohort of pts with any prior chemotherapy for metastatic disease received AG 5 mg BID + gemcitabine/cisplatin (G: 1250 mg/m2 on days 1 and 8 / Cis: 80 mg/m2 on day 1) in 3-week cycles. For all cohorts, cycle 1 consisted of a 3–5-day lead-in period followed by AG for 18 days. On day 19, AG was held and then continued without interruption on day 3, cycle 2. Following determination of the maximum tolerated doses (MTDs) of AG + P/C or G/Cis, pts with squamous NSCLC were enrolled into an expansion cohort (prior anti-VEGF therapy not permitted) and received AG 5 mg BID + P/C. Dose-limiting toxicities (DLTs), adverse events (AEs), objective response rate (ORR), and pharmacokinetics (PK) were evaluated. Results: A total of 47 pts were enrolled; 26 pts were evaluable in the P/C cohort (including 12 pts with squamous NSCLC) and 21 pts in the G/Cis cohort. The MTD for AG in combination with standard doses of P/C and G/Cis was 5 mg BID. DLTs included fatigue, proteinuria and rash (1 each). Treatment-related AEs included hypertension (42%), diarrhea (35%) and fatigue (35%) in the P/C cohort, and headache (29%), hypertension (29%) and fatigue (24%) in the G/Cis cohort. There was no grade ≥3 hemoptysis among 12 pts with squamous NSCLC. The ORR was 29% and 26% for P/C (n = 24) and G/Cis (n = 19) cohorts, respectively. AG, P, C, G and Cis PK parameters and profiles were similar when administered alone and in combination (eg P: mean (%CV) AUCinf 20,822 (21) and 20,596 (21) ng.h/mL, respectively). Conclusions: AG 5 mg BID can be combined with standard P/C and G/Cis regimens with no apparent overlapping toxicities and unaltered PK. Both combinations have antitumor activity. In pts with squamous NSCLC, AG + P/C was well tolerated with no evidence of grade ≥3 hemoptysis. [Table: see text]
Mass balance, pharmacokinetics, and metabolism of [14C] brivanib (BMS-582664), prodrug of BMS-540215, in subjects with advanced or metastatic solid tumors
Authors: Ganapathi R. , Mekhail T. , Wu C. , Fischer B. , Gong J. , Iyer R. A. , Gan J. , Pursley J. , Patricia D. , Masson E. 
Published: August 2020

3566 Background: Brivanib alaninate (BMS-582664, B) is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling pathways which are important for angiogenesis and tumor growth. The recommended phase II/III dose of B is 800 mg daily. Methods: A two-part, open-label, single-dose study was conducted in subjects with advanced or metastatic solid tumors. Part A represented the period for assessment of the pharmacokinetics (PK), metabolism, and elimination of B, In part A, subjects received a single oral dose of 800 mg [14C]-labeled B containing 100 μCi of total radioactivity (0.125 μCi/mg). Blood was collected at selected time points for analyses of PK, biotransformation, and total radioactivity over a 10-day period. Complete urinary and fecal output was collected over the 10-day period or until discharge, and analyzed for total radioactivity and biotransformation. Part B began when subjects completed Part A. Part B subjects received B administered orally at a dose of 800 mg once daily starting on approximately Day 15 to 17 of study. Subjects continued in this study until disease progression or unacceptable toxicity. Results: 4 subjects (2 NSCLC, 1 ovarian, 1 renal cell carcinoma) were treated with B in both parts A & B. B was tolerable with few G3/4 AEs (increased fatigue, 1 event, cognitive disturbance, 1 event). The results revealed that B is completely converted to active moiety, BMS-540215, after oral administration. BMS-540215 is extensively metabolized in humans. Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled B, approximately 12% and 82% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. BMS-540215 accounted for 0.00% and 7.4% of the administered dose in urine and feces, respectively, with the remainder of the dose being minor metabolites. The mean terminal t1/2 of BMS-540215 was 14 hours. Conclusions: After oral administration of single 800 mg oral doses of [14C] B, BMS-540215 was found to be the major active circulating moiety in plasma (22.5%). BMS-540215 is primarily eliminated via metabolism. [14C]-labeled B formulation was well tolerated with no AEs leading to the discontinuation of any subject. [Table: see text]