bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies.
Authors: Appleman Leonard Joseph , Beumer Jan Hendrik , Jiang Yixing , Puhalla Shannon , Lin Yan , Owonikoko Taofeek Kunle , Harvey R Donald , Stoller Ronald , Petro Daniel P. , Tawbi Hussein Abdul-Hassan , Argiris Athanassios , Strychor Sandra , Kiesel Brian , Chu Edward , Shepherd Stacie Peacock , Giranda Vincent L. , Chen Alice P. , Belani Chandra Prakash , Ramalingam Suresh S. 
Published: March 2020

3049 Background: Veliparib (ABT-888, NSC 737664) is an orally available inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and -2: enzymes that recruit base excision repair machinery to single-stranded DNA breaks. Expression of PARP-1 may be increased in cancer cells and confer resistance to DNA-damaging agents. The objectives of this phase I study included determination of the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of veliparib in combination with paclitaxel (P) and carboplatin (C). Methods: Eligibility criteria included advanced solid tumors, ≤ 3 prior chemotherapy regimens for advanced disease, ECOG performance status 0-2. Veliparib was given PO BID on days 1-7 of each 21 day cycle, and P and C were administered on day 3. In dose levels 1-7, veliparib was not given during cycle 1 to serve as intra-patient control for toxicity and PK assessment, and DLT was evaluated during cycle 2. A standard “3+3” dose escalation was utilized starting at veliparib 20 mg BID, P 150 mg/m2, C AUC 5. Plasma concentrations of veliparib, P and C were determined by LC-MS/MS and AAS during cycle 1 and 2. Results: To date, 68 patients have been enrolled. Tumor types included lung (15), breast (14), melanoma (10), squamous cell of head/neck (7), and urothelial (5). Toxicities observed were expected with C plus P chemotherapy, including neutropenia, thrombocytopenia, peripheral neuropathy. DLTs were seen in 2 out of 7 evaluable patients at the maximum administered dose: veliparib 120 mg BID, P 200 mg/m2, C AUC 6, (febrile neutropenia, hyponatremia). Veliparib 80 mg, P 200 mg/m2, C AUC 6 was well tolerated with 1 out of 9 DLT (febrile neutropenia). Median number of cycles was 5 (1-17). Partial response was seen in 11 (Lung-2, breast-2, melanoma-2, urothelial-2, head and neck, gastric, unknown primary) and complete response in 1 patient with breast cancer and 1 patient with urothelial cancer. Stable disease was observed in 35 patients. Veliparib did not affect the PK disposition of P or C. Conclusions: Veliparib in combination with P and C was well-tolerated with a safety profile similar to P and C alone. Promising anti-tumor activity was observed in several tumor types.
Phase I dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as single‑agent and in combination with temozolomide in patients with advanced solid tumors (NCT00920595).
Authors: Campone Mario , Plummer Ruth , Stephens Peter , Brakchi Zahir , Aissat-Daudigny Louiza , Kasiborski Fabrice , Cambois Anne , Moachon Gilbert , Brown Peter D. , Kayitalire Louis 
Published: March 2020

3052 Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in cellular processing of DNA damage via the base excision repair pathway. CEP-9722, an orally available PARP1-2 inhibitor, demonstrated single-agent antitumor activity and synergy with temozolomide (TMZ) in xenograft models. This phase I study evaluated the pharmacokinetics, pharmacodynamics, and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy and combination with TMZ. Methods: Adult patients with advanced solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722 (days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was 150 mg/day in the first cohort and was escalated depending on the occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall, 26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of 3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of CEP-9722 in combination with TMZ (150 mg/m2) was reached at 1000 mg/day. The recommended dose was 750 mg/day. A total of 9 patients were treated at the recommended dose. DLTs were observed in 2 patients during cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000 mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this study, 4 grade 3 treatment-related adverse events were observed. The pharmacokinetics showed high intra- and inter-patient variability at all doses. The pharmacodynamic analysis demonstrated PARP inhibition at all doses, but the high inter- and intra-patient variability prevented any conclusion regarding a dose / PARP inhibition relationship. Conclusions: TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5 and the combination CEP-9722/TMZ was well tolerated. In addition, a clear signal of PARP inhibition was demonstrated.
High concordance for MammaPrint 70 genes by RNA next generation sequencing.
Authors: Mittempergher Lorenza , de Rink Iris , Nieuwland Marja , Kerkhoven Ron M , Glas Annuska , Bernards Rene' , van't Veer Laura 
Published: March 2020

3065 Background: The development of new biomarkers often requires fresh frozen (FF) samples. Recently we showed that microarray gene expression data generated from FFPE material are comparable to data extracted from the FF counterpart, including known signatures such as the 70-gene prognosis signature (Mittempergher L et al., 2011). As described by Luo et al (2010) RNA profiling using next generation sequencing (RNA-Seq) is now applicable to archival FFPE specimens. Methods: Technical performance and the comparison between the RNA-Seq 70-gene read-out and the MammaPrint test (Glas et al., 2006) is evaluated in a series of 15 patients (11/15 with matched FFPE/FF material). RNA-Seq was carried out using minor adjustments of the Illumina TruSeq RNA preparation method. RNA sequencing libraries were prepared starting from 100ng of total RNA. Next, the DSN (Duplex-Specific Nuclease) normalization process was used to remove ribosomal RNA and other abundant transcripts (Luo et al, 2010). The libraries were paired-end sequenced on the Illumina HiSeq 2000 instrument with multiplexing of 4 libraries per lane. The resulting sequences were mapped to the human reference genome (build 37) using TopHat 1.3.1(Trapnell et al., 2009). The HTSeq-count tool was used to generate the total number of uniquely mapped reads for each gene. Results: Between 14% and 45% of the total number of reads were assigned to protein-coding genes. The minimum coverage per 1000bp of CDS was 38 reads. The 70 MammaPrint genes were successfully mapped to the RNA-Seq transcripts. We calculated the Pearson correlation coefficient between the centroids of the original good prognosis template (van’t Veer et al., 2002) and the 70-gene read count determined by RNA-Seq of each sample. Predictions based on the 70-gene RNA-Seq data showed a high agreement with the actual MammaPrint test predictions (>90%), irrespective of whether the RNA-seq was performed on FF or FFPE tissue. Conclusions: New generation RNA-sequencing is a feasible technology to assess diagnostic signatures.
Tumor drug distribution and target engagement of MLN9708, an investigational proteasome inhibitor, in patients with advanced solid tumors.
Authors: Di Bacco Alessandra , Berger Allison , Gupta Neeraj , Gao Feng , Blakemore Stephen , Qian Mark , Chen Susan , Stringer Bradley , Yang Yu , Liu Ray , Tirrell Stephen , Bowman Doug , Smith David C. , Sullivan Daniel , Infante Jeffrey R. , Kauh John S. , Siu Lillian L. , Vlahovic Gordana , Thompson John A. , Kalebic Thea 
Published: March 2020

3077 Background: MLN9708 is a potent investigational proteasome inhibitor, which upon intravenous (IV) administration immediately hydrolyzes to the active form MLN2238. MLN9708 is currently being evaluated in a phase 1 trial in solid tumors (NCT00830869). This trial has a dose-escalation arm and five expansion cohorts: non-small cell lung cancer (NSCLC), soft tissue sarcoma, head and neck cancer, prostate cancer, and a tumor biopsy cohort of mixed histology. The purpose of the tumor biopsy cohort was to obtain pre- and post-dose biopsies to determine drug distribution and target engagement in post-dose tumor samples. The latter was measured by the increase in levels of ATF-3, a marker of unfolded protein response/endoplasmic reticulum stress, which is upregulated in response to proteasome inhibition. Methods: The tumor biopsy cohort included 20 patients dosed at the maximum tolerated dose who consented to core needle biopsies during screening and after either the first or second dose of MLN9708 (IV 1.76 mg/m2; 4–20 hours post-dose). Tumor biopsies were individually weighed, homogenized, and analyzed for the presence of MLN2238 using a quantified LC/MS/MS methodology. ATF-3 levels in tumors were determined by an immunohistochemical assay (IHC) on six sections for each tumor biopsy. Tumor area was identified using Aperio Genie, a machine learning program for pattern recognition, and the percentage of ATF-3 positive area in the tumor was measured. Results: Biopsies from 20 patients were collected for assessment of drug distribution and target engagement. Ten patients with paired pre- and post-dose biopsies of sufficient size were considered evaluable for PK analysis; MLN2238 was present in all 10 (100%) post-dose biopsies analyzed. Tumor pairs from 7 patients passed quality control by H&E staining for tumor content and were evaluable for ATF-3 IHC. Six of 7 paired samples (86%) showed a statistically significant (p<0.05) increase in post-dose ATF-3 levels. Conclusions: Overall, emerging data from MLN9708 phase 1 solid tumor analysis show that MLN2238 is present in tumors and demonstrates target engagement upon inhibition of the proteasome in tumor tissue biopsies.
A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors (NCT01193595).
Authors: Del Conte Gianluca , Bahleda Rastilav , Moreno Victor , Damian Silvia , Perotti Antonella , Lassau Nathalie , Farace Françoise , Ong Michael , Stimpson Sarah Jane , Tunariu Nina , Micallef Sandrine , Demers Brigitte , Oprea Corina , Capri Giuseppe , Soria Jean-Charles , Sessa Cristiana , Molife L Rhoda 
Published: March 2020

3080 Background: O is a vascular-disrupting agent derived from combretastatin A4-phosphate that induces rapid but transient tumor vascular shutdown. In experimental models, the combination of O with VEGF-blockade induced more regressions than O alone. This phase I study was performed to determine the maximum tolerated dose (MTD), and assess the overall safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O plus B. Trial is funded by sanofi. Methods: Patients (pt) with advanced solid tumors, ECOG PS ≤1, and adequate organ function were eligible. Increasing doses of O (mg/m²) was administered intravenously (IV) on day (d) 1; B (5 or 10mg/kg) was administered IV on d2, in 21d cycles (C). A Bayesian design was applied to determine dose escalation steps and MTD. PK sampling was performed in C1 and C2. PD sampling for circulating endothelial cells (CEC) and progenitors (CEP) were performed throughout. Dynamic contrast-enhanced ultrasound (DCE-US) to assess tumor perfusion was performed before and after C1 and C2 dosing. Results: 25 pts (M:F 6:19; median age 49 years [range 27-75]) have been treated at 8 dose levels of O/B: 8/5 (3), 11.5/5 (4), 11.5/10 (3), 15.5/10 (3), 20/10 (3), 25/10 (3); 35/10 (3) and 42/10 (3). Ovarian cancer was the most frequent tumor type (n=11). Median Cs received was 3 (1 to 14). No DLTs were observed during C1. Drug-related grade (g) 3-4 adverse events (AE) included hypertension in 2 pts (8/5; 11.5/5) and ileal perforation in 1 pt with peritoneal carcinomatosis at laparotomy (11.5/10). A case of duodenal perforation was unlikely related (25/10). Two pts with ovarian cancer (11.5/5; 20/10) had confirmed partial responses (4.4 months (mo) and 7+ mo). 13/23 (57%) pts with ≥ 1 tumor assessment had stable disease (n=8; median 4.3 mo [1.8-9.5]; 5 ongoing). Data from cohorts 1 and 2 demonstrated no evidence of a PK interaction.17/25 patients demonstrated a peak in CEC, and 7/9 patients a peak in CEP. 4/7 DCE-US evaluable pts had >50% drop in tumor perfusion (AUC) at Day 8 of C1. Conclusions: O combined with B is well tolerated with early evidence of clinical activity. The MTD has not been reached (current dose level 50/10); cohorts of O combined with B at 15 mg/kg will be tested.
A phase I dose-escalation study of the HSP90 inhibitor AUY922 and erlotinib for patients with EGFR-mutant lung cancer with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).
Authors: Johnson Melissa Lynne , Yu Helena Alexandra , Hart Eric M , Worden Rebekah , Rademaker Alfred , Gupta Rajesh , Miller Claire , Patel Jyoti D. , Kris Mark G. , Miller Vincent A. , Riely Gregory J. 
Published: March 2020

3083 Background: AUY922 is a highly potent, non-geldanamycin analog, HSP90 inhibitor that degrades mutated EGFR and MET. Preclinical studies demonstrate that HSP90 inhibitors have anti-tumor activity in EGFR mutant, EGFR TKI-sensitive and TKI-resistant lung cancer xenograft models. To prevent disease flare after stopping EGFR TKIs in patients (pts) with EGFR mutated lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase I study will determine the maximally tolerated dose (MTD) of AUY922 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs. Methods: All pts have EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumor biopsies after development of AR and prior to study entry. Pts receive AUY922 IV weekly and E oral daily in 28-day cycles, with dose escalation using standard 3+3 design. Pharmacokinetics, serial ophthalmology evaluations and weekly assessment for toxicity are required. Tumor tissue from re-biopsy at study entry is analyzed for EGFR T790M and MET. Results: Since April 2011, 11 pts have been enrolled, in 4 of 5 planned cohorts (AUY922 25 mg/m2 + E 75 mg; AUY922 25 mg/m2+ E 150 mg; AUY922 37.5 mg/m2+ E 150 mg; AUY922 55 mg/m2+E 150 mg). Prior to developing AR, pts were treated with EGFR TKIs for a median of 9 months (range 8-32). Of 9 pts with tissue analyzed thus far, 6 had EGFR T790M. Pts have received a median of two cycles (range 1-7), and 5 remain on study. There have been no dose-limiting toxicities. Adverse events reported in ≥ 20% of pts were diarrhea, nausea, vomiting, fatigue, and rash, all graded 1 or 2. No cardiovascular, renal or hepatic toxicities have been observed. Three pts have reported “flashing lights” and 2 pts transient night blindness, all grade 1. Dose escalation continues. No partial responses have been seen in 6 evaluable pts, 4 patients have confirmed stable disease at 8 wks. Conclusions: AUY922 and E is a well-tolerated combination at dose levels up to AUY922 55 mg/m2+ E 150 mg. Further dose-escalation, MTD, and correlation with markers of AR will be reported. Supported by Novartis, Inc.
A phase I study of dovitinib (TKI258) in Japanese patients with advanced solid tumors.
Authors: Takiuchi Hiroya , Gotoh Masahiro , Yoshida Motoki , Kii Takayuki , Yamashita Keishi , Sunakawa Yu , Kaneta Toshikado , Robson Matthew , Kakizume Tomoyuki , Sasaki Yasutsuna 
Published: March 2020

3088^ Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on responses observed in renal cell carcinoma, breast cancer, AML, melanoma, and multiple myeloma in clinical studies in the West, we investigated dovitinib in Japanese patients (pts). Methods: This multicenter phase I study determined the maximum tolerated dose (MTD) of dovitinib based on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in period, dovitinib was administered orally once daily on a 5-days-on/2-days-off schedule in 28-day cycles until disease progression or withdrawal. The planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic regression model based on the principle of escalation with overdose control was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 7), 400 mg (n = 9), and 500 mg (n = 6). The median age was 58.5 years (range, 30-76); 16 of 28 pts (57%) were male. All pts had stage IV disease, with an ECOG performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, cycle 19), 23 discontinued due to disease progression, and 4 discontinued due to adverse events (AEs). All DLTs were grade 3: anorexia (n = 1; 300 mg), nausea/vomiting (n = 1; 400 mg), liver function disorder (n = 1; 400 mg), and increased alanine transaminase (n = 1; 500 mg). The most common grade 3/4 AEs (occurring in >10% of pts) suspected to be related to study drug were lymphopenia (18%), neutropenia (14%), abnormal hepatic function (14%), decreased white blood cell count (14%), decreased appetite (14%), and hypertension (14%). Best responses were confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 10 pts (36%). No treatment-related deaths have been reported. Safety and PK parameters were comparable to those of non-Japanese pts in the global study. Conclusions: The study has completed enrollment. Dovitinib was found to be tolerable at doses up to 500 mg, which was declared as the MTD in Japanese pts.
A phase I and pharmacokinetic study of multiple schedules of ganetespib (STA-9090), a heat shock protein 90 inhibitor, in combination with docetaxel for subjects with advanced solid tumor malignancies.
Authors: Kauh John S. , Harvey R Donald , Owonikoko Taofeek Kunle , El-Rayes Bassel F. , Shin Dong Moon , Murali Sujatha , Lewis Colleen Margaret , Karol Michael D. , Teofilovici Florentina , Du Yuhong , Fu Haian , Khuri Fadlo Raja , Ramalingam Suresh S. 
Published: March 2020

3094 Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has superior activity to these agents in preclinical studies. Ganetespib is well tolerated with promising antitumor activity. Based on synergy between ganetespib (G) and docetaxel (D), a phase I study evaluating preclinical dosing models was performed. Methods: Patients (pts) with advanced solid tumor malignancies and ECOG performance status (PS) 0-2 were eligible. Sequential cohorts of pts were treated (3+3 design) with increasing doses of D (day 1) and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C) were completed. PK sampling was performed during schedule A. The primary endpoint was determination of optimal doses and schedule of the two agents for combination therapy. Results: Twenty-seven patients were enrolled in schedules A (n=12), B (n=8), and C (n=7). Median age-64 (44-75); 11-M, 16-F; ECOG PS: 0 (n=5), 1 (n=21), 2 (n=1). Most pts had NSCLC (n=9), others were head/neck (n=4), and SCLC (n=3). The defined MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3 (D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of level 2. The median number of cycles received is 2 (1-11), with 3 pts in schedule C still on study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12 had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18 weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue, nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was not used at any time. PK data indicates similar G exposure alone compared to G administered prior to D. No accumulation was observed following once-weekly dosing, consistent with studies of G alone. Conclusions: The combination is well tolerated at the recommended doses of D 75 mg/m2 and G 150 mg/m2. Promising anti-cancer activity was noted, and a randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is ongoing in advanced NSCLC (NCT01348126).
A phase Ib trial of FOLFIRINOX plus saridegib, an oral hedgehog (Hh) inhibitor, in pts with advanced pancreatic cancer (PDAC).
Authors: Ko Andrew H. , LoConte Noelle K. , Kantoff Emily , Ross Robert W. , Trehu Elizabeth G. , Tempero Margaret A. , Kelley Robin Katie , Venook Alan Paul , Wu Timothy , Kindler Hedy Lee 
Published: March 2020

3105 Background: FOLFIRINOX has emerged as the optimal 1st-line treatment option for pts with advanced PDAC and good performance status; whether it can serve as the backbone upon which to add targeted agents in clinical trial design remains uncertain. The goal of this multicenter phase Ib study is to evaluate FOLFIRINOX in combination with saridegib, a novel oral agent that inhibits the Hh signaling pathway. In preclinical models of PDAC, saridegib increases chemotherapy delivery by depleting peritumoral stroma and increasing vascularity. Methods: Pts with previously untreated metastatic or locally advanced PDAC and ECOG PS 0-1 were eligible. Treatment consists of once-daily saridegib with concurrent administration of biweekly FOLFIRINOX (omitting the 5-FU bolus). A 3+3 dose escalation design was used (see dose levels below). Prophylactic WBC growth factor support is mandated. DLT definitions include ALT/AST ≥10x ULN, grade 4 plts or ANC ≥5 d, or grade 3-4 nonheme toxicity. CT scans are obtained every 4 cycles. Limited PK analyses are performed. Results: Seven pts have been enrolled at the first 2 dose levels. Grade 1-2 AEs include GI (N/V/D), dehydration, fatigue, and LFT abnormalities. There was one DLT (grade 3 ALT elevation) at DL2. Other serious toxicities seen include grade 3 nausea (DL1) and grade 3 diarrhea (DL2). Tumor shrinkage has been observed in all 4 pts at DL1, ranging from 17-54%, with 2 unconfirmed PRs. Final MTD determination and updated safety and efficacy data will be presented at the meeting. Conclusions: A modified FOLFIRINOX regimen can be safely administered in combination with novel agents in clinical trials of PDAC. While saridegib was not beneficial when added to gemcitabine in a separate randomized phase II study, early evidence of significant responses on the current trial suggests that a more intensive chemotherapy platform may represent a preferable strategy in PDAC trial design. [Table: see text]