bluuebunny/crossref_metadata_2025_split huggingface dataset:
Value of stable disease (SD) in drug development of targeted therapies (TGT)
Authors: Vidaurre T. , Wilkerson J. , Bates S. E. , Simon R. , Fojo A. T. 
Published: August 2020

2509 It has been widely asserted that the efficacy of TGT cannot be assessed by traditional response measures since they are not expected to cause tumor shrinkage. Despite the lack of substantiating data, this idea has become conventional wisdom, often guiding clinical trial design. Aware the acceptance of SD as a measure of activity led to its being increasingly reported with traditional cytotoxic agents (CTX), we set about to methodically compare the occurrence of SD in phase II trials of TGT and CTX. We systematically catalogued response assessments in 147 phase II studies reported between 10/06 and 3/08 in 5 journals (Cancer, BJC, CCR, JCO, and Lancet Oncology). Eighty used CTX, 59 used TGT and 8 used both “classes” of agents. Thirty-eight properties including CR, PR, SD, PFS, and OS were recorded for each study. CTX and TGT studies were comparable with similar distribution of histologies and similar PFS and OS in these patients with refractory tumors. For CTX vs. TGT, the median numbers of pts/study was 47.1 vs. 51.9; median PFS, 5.55 vs. 4.54 mos; and median OS, 12.55 vs. 12.88 mos. SD was defined by duration in only 31% of studies, a median duration of 9.5 weeks. SD rates were nearly identical for the two therapy groups - 34.6% for CTX and 33.1% for TGT- and their distribution by histology was similar, suggesting properties other than therapy are responsible for SD. Correlations or lack thereof between %SD and PFS or OS were similar for both CTX and TGT. The overall response rate (CR + PR) was higher with CTX than with TGT (29.4% vs. 13.3%) and demonstrated a strong correlation (p<0.0001) of uncertain importance with PFS and OS for all therapies. Examination of 33 NSCLC studies (16 CTX/17 TGT) found similar results. We conclude that SD as currently defined and measured in not a property of TGT but of the phase II patient population and is similarly found with CTX. Responses are observed with TGT as with CTX, and this analysis suggests that even for TGT it is a measure of activity that should be sought. Assertions that SD is a particular characteristic of TGT should be replaced by definitions that seek clinically meaningful SD. No significant financial relationships to disclose.
Dose-response relationships in phase I trials: Are patients treated at lower doses at a disadvantage?
Authors: Jain R. , Hong D. , Naing A. , Wheler J. , Lee J. J. , Kurzrock R. 
Published: August 2020

2519 Background: A major goal of phase I trials is to determine a drug's maximally tolerated dose (MTD). However, it has been argued that low-dose patient cohorts are at a disadvantage given the clear dose/response relationships seen with cytotoxics. Since an increasing number of targeted/biologic agents are entering the clinic, and the dose/response relationship of these drugs is less clear, we analyzed response versus benefit for patients on phase I trials. Methods: We evaluated 71 consecutive trials treating 1,420 patients with solid tumors or lymphoma from August 2004 to August 2008 in the Department of Investigational Cancer Therapeutics at M.D. Anderson for inclusion in our analysis. Twenty-four trials treating 687 patients met criteria (systemic therapy that has reached an MTD or a maximum test dose). 97.7% of these patients received a targeted/biologic drug. Patients were assigned to low (≤25%), medium (25–75%), or high dose (≥75%), where dose range = maxium - minimum dose for each study (for ≤ MTD analysis, max dose = MTD if it was achieved). Time on treatment (TOT), progression free survival (PFS), overall survival (OS), and response (complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) were assessed. Results: Of all comers (n = 683), the low-dose group stayed on treatment significantly longer than the high-dose group, primarily due to increased toxicity at higher doses. In ≤ MTD subgroup analysis (n = 588), there was also a trend for the low-dose group to stay on treatment longer (p = 0.06). PFS and OS were similar among groups. Favorable responses (CR/PR/SD) were as common for low dose as other dose groups. Conclusions: In a large cohort of pts treated on phase I studies that predominantly included one or more targeted/biologic agent, there was no downside to being on low versus medium or high doses. These data should alleviate concerns about relative lack of benefit for low-dose patient cohorts on phase I trials, and support the notion that dose/response relationships for targeted agents may be less clear than for cytotoxics. [Table: see text] No significant financial relationships to disclose.
Population pharmacokinetic modeling for intravenous temsirolimus and sirolimus metabolite in subjects with various solid tumors
Authors: Sonnichsen D. , Liao S. , Berkenblit A. , Boni J. 
Published: August 2020

2522 Background: Temsirolimus (TEMSR) is an mTOR inhibitor approved for treatment of patients with advanced renal cell carcinoma, and under development for relapsed/refractory mantle cell lymphoma (MCL). In MCL, TEMSR showed a dose-related increase in median progression-free survival [4.8 vs. 3.4 mo] and objective response rate [22% vs 6%] for 175 mg x 3 wks then 75 or 25 mg weekly regimens (175/75-mg and 175/25-mg), respectively. We aim to characterize the population pharmacokinetic exposure, covariate influence, and differences afforded by these regimens. Methods: Nonlinear mixed-effects models of TEMSR and sirolimus (SIR; major active metabolite) blood concentrations were defined in healthy subjects and patients. Modeling for TEMSR employed a 4-compartment model with saturable distribution to red cells and peripheral tissue, and modeling for SIR utilized a linear 2- compartment model with factor for dose. Covariates included demographic factors, clinical labs, and disease condition. Following validation, simulations with variability were used to evaluate effects of covariates on exposure. Results: Final datasets comprised 1342 observations from 150 subjects (TEMSR) and 1648 observations from 279 subjects (SIR). In a typical patient (56-year-old male weighing 76.5 kg), disease affected TEMSR clearance (62.4 L/h in MCL, 92.1 L/h in breast cancer vs. 112 L/h for other subjects). Dose, single vs. multiple, and body weight affected SIR apparent clearance. Simulations for the 175/75-mg regimen indicate that significant covariates yield only modest differences on blood exposures. For MCL (175/75-mg regimen), TEMSR Cmax (week 3) was 2574 ng/mL and SIR Ctrough (week 6) was 10.7 ng/mL. AUC for the 75-mg maintenance arm was ∼2.3-fold (TEMSR) and ∼3.5-fold higher (SIR) than respective values of the 25-mg arm. Correlation of average AUC to clinical response was not apparent. Conclusions: No significant differential effects were observed for age, gender, race, or hepatic and renal laboratory measures. Covariates of disease, while significant, have only modest effects on the exposure profile. Higher clinical responses observed with the 175/75-mg regimen as compared with the 175/25-mg regimen may critically derive from differences in exposure. [Table: see text]
The utility of a specific hepatic CYP-3A4 probe (C14-Erythromycin breath test [EBT]) versus the general CYP-P450 probe (antipyrine clearance [ACL] test), for the prediction of docetaxel (D) pharmacokinetics (PK)
Authors: Michael M. , Booth R. J. , Milner A. , Hatzamihallis A. , Francis P. , Clarke S. J. , Schlict S. , Cullinane C. 
Published: August 2020

2523 Background: BSA-based cytotoxic dosing does not account for the individual variability in drug disposition. In the case of D, CYP 3A4 probes such as the EBT have been assessed to individualise dosing, but inconsistently. This report is the first study comparing the EBT directly with the widely available general P450 probe, the ACL test, for the prediction of D PK when given either q 21 days or weekly. Methods: Patients (pts) with pre-treated advanced malignancy suitable for D therapy, Se bilirubin≤1.0xUNL, AST≤1.5xUNL & ALP≤2.5xUNL, were entered. Prior to D therapy, pts underwent EBT and ACL test. Pts were given IV 14C N-methyl-erythromycin and exhaled breath samples were captured for 14CO2 from 5–120 mins post. The EBT parameters determined: 14CO2 flux at 10 min (CO2f10), & 20 min (CO2f20), (iii) terminal rate constant kCO2 (iv) AUCCO2,(0-∞) & AUCCO2,(0–60). For the ACL test, pts was given oral antipyrine 10mg/kg, blood samples were collected from 0, 4 & 24 hrs post, and serum levels measured: ACL was calculated as per Farrell et al.(Br J Clin Pharmacol 18:559). D was given 75mg/m2 q21 days or 35mg/m2 weekly. Samples taken for D PK in course 1 day 1, parameters included: half life (tD1/2), & clearance (CLD). Correlations were sought between EBT parameters, ACL values and D PK parameters. Results: 20 pts accrued, M:F= 12:8, Median age= 65. Mean BSA = 1.77m2 (1.44–2.07). D q21 days:D weekly= 13:7. EBT parameters (N= 19) (Mean, [CV%]): CO2f10 (%/min) 0.051 (106), CO2f20 0.052 (82), kCO2 (min- 1) 0.007 (22), AUCCO2,(0-∞) 7.9 (85), AUCCO2,(0–60) 2.64 (81). ACL (N=19) (ml/min); 35.8 (37). No significant differences observed for EBT parameters and ACL between the q21 days vs weekly dosing. D PK parameters (N=19): CLD (l/hr) 57.2 (36), tD1/2 (hrs) 12.7 (33). No correlations were observed between the D PK and EMBT parameters for all pts and regardless of the regimen given. For D weekly pts, a significant linear relationship was observed between CLD and ACL (P =0.007, R2= 79.47%). Conclusions: The utility of EBT for the prediction of D PK was not confirmed in this study. The Antipyrine Clearance test may be superior in this regard for D, but regimen dependent and hence warrants further evaluation. No significant financial relationships to disclose.
Pharmacokinetics (PK) of the highly lipophilic and blood stable camptothecin AR-67 (7-t-butyldimethylsilyl-10- hydroxycamptothecin) in adult patients with solid malignancies
Authors: Leggas M. , Horn J. , Tsakalozou E. , Moscow J. A. , Fields S. Z. , Houchins J. C. , Eckardt J. R. , DeSimone P. , Kee B. K. , Rinehart J. J. , Arnold S. M. 
Published: August 2020

2546 Background: Camptothecin analogs possess a labile lactone ring, which readily undergoes a pH dependent, albeit reversible, hydrolysis in plasma to yield a carboxylate moiety. The latter is considered inactive due to its electronegative charge that impedes transport into cells. Furthermore, the carboxylate is cleared rapidly and causes toxicity in eliminating organs due to lactonation. AR-67 is a highly lipophilic 3rd generation analog with superior stability of its lactone form in preclinical models. This report describes the PK of AR-67 in patients with refractory solid tumors enrolled in a phase I study. Methods: AR-67 was infused over 1 hr for 5 days every 21-days. PK was performed on the 1st and 4th day of cycle 1. Blood, plasma, and urine were collected (0–24 hrs) from 26 patients (see 09-AB-30336-ASCOAM) treated at 9 dose levels: 1.2–12.4 (mg/m2/day). AR-67 carboxylate and lactone were assayed with a validated chromatography method. Results: AR-67 was detectable at all dose levels. Blood concentrations mirrored those in plasma and were superimposable when adjusted by the hematocrit. AR-67 concentration peaked at the end of the 1-hr infusion and declined biexponentially with a terminal t1/2 of 1.4 hr (plasma lactone). A linear relationship was observed between dose and AUC. The lactone clearance on Day 1 was 16.6 (±5.5) vs. 19.6 (±6.3) L/hr/m2 on Day 5. The carboxylate clearance was ∼ 6-fold higher. Lactone was the major form in all samples and its area under the time vs. concentration curve (AUC) was 85.5% (range 74.0%-94.1%) of the total AUC. Urine (0–24 hr) contained 2.5% (0.3%-6.7%) of the dose on Day 1 vs. 2.7% (0.9–11.1%) on Day 4. Extensive metabolite peaks were not observed in plasma, blood, or urine samples. Plasma protein binding of the carboxylate was 90% (range 80%-96%) vs. 95% (range 90%-98%) for the lactone. Conclusions: AR-67 is a lipophilic camptothecin with a unique PK profile. Unlike other clinically approved analogs with lower lactone stability (35%-65%), over 85% of the AR-67 AUC is in the active lactone form. This high lactone-low carboxylate exposure coupled with the apparently limited metabolism of AR-67 may result in increased activity and decreased toxicity. [Table: see text]
Elucidation of the metabolic and elimination pathways of panobinostat (LBH589) using [14C]-panobinostat
Authors: Clive S. , Woo M. M. , Stewart M. , Nydam T. , Hirawat S. , Kagan M. 
Published: August 2020

2549 Background: Panobinostat (PAN), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor, demonstrating anti-tumor activities in a wide variety of preclinical models and showing promising clinical activity. This study elucidates the metabolic and elimination pathways of PAN using [14C]-PAN. Methods: Four patients with advanced cancer received a single oral 20 mg dose of [14C]-PAN (50 μCi). Whole blood, plasma, urine, and feces were collected over 7 days. Total radioactivity was measured in blood, plasma, and excreta by liquid scintillation counting. PAN and its metabolite concentrations in plasma and excreta were measured by LC-MS/MS and HPLC with radiometric detection. Patients were monitored for safety. Results: The single PAN dose was well tolerated with no clinically significant laboratory or ECG abnormalities observed. PAN had a rapid oral absorption [median Tmax 0.8 h (range, 0.5–1 h)] and moderate elimination (median t1/2 31 h). The median t1/2 for blood and plasma radioactivity was 54 and 75 hours, respectively. Mass balance was achieved with ≥87% of the administered radioactivity being recovered in the excreta of all patients after 7 days. 44–77% and 29–51% of the dose was recovered in the feces and urine, respectively. Unchanged PAN accounted for ≤3% of the administered dose in the feces, suggesting good oral absorption. The most prominent metabolic pathways involved modifications of the hydroxamic acid (HA) side chain, to form an amide via reduction, carboxylic acid via either hydrolysis or one- and two-carbon (M1) shortening of the HA side chain. Oxygenation and glucuronidation were also observed. PAN accounted for ≤9% of the total radioactivity AUC. The most abundant circulating metabolites in plasma were the glucuronide of M1 (19%) and carbamoyl glucuronide of PAN (13%). At least 40 metabolites, many at trace levels, were observed circulating in plasma. Conclusions: PAN and its metabolites are equally excreted in the urine and feces. Elimination of PAN is primarily by metabolism via reduction, hydrolysis, oxidation and glucuronidation. The balanced elimination and absence of a single major route of PAN metabolism suggest that clinical drug-drug interactions are unlikely with PAN. [Table: see text]
A UGT1A1 genotype-directed phase I study of irinotecan (CPT-11) combined with fixed dose of capecitabine in patients with metastatic colorectal cancer (mCRC)
Authors: Kim T. , Sym S. , Lee S. , Ryu M. , Lee J. , Chang H. , Kim H. , Shin J. , Kang Y. , Lee J. 
Published: August 2020

2554 Background: The risk of severe toxicity of CPT-11 can be in part explained by polymorphism of UGT1A1. The most common polymorphism in Whites is UGT1A1*28. UGT1A1*6 is another common polymorphism in Asians. We designed a phase I study to investigate UGT1A1 genotype-directed maximum tolerated dose (MTD) of CPT-11 plus fixed dose of capecitabine in patients (pts) with Korean mCRC. Methods: Pts with mCRC screened UGT1A1 genotyping (*28 and *6) and were stratified into one of 3 groups according to the number of defective allele (DA): 0 (none of *28 or *6 allele), 1(only one of *28 or *6 allele), and 2 (*28/*28, *6/*6, or double heterozygous for *28 and *6). The dose of CPT-11 was escalated as following: Level -I:200, I:240, II:280, III:320, IV: 350, V: 380 mg/m2 (IV, once every 3 weeks). Capecitabine (1,000 mg/m2 PO BID) was administered on days 2–15 every 3 weeks. Dose limiting toxicity (DLT) and pharmacokinetic analyses was determined at cycle 1. Results: Forty-two pts, median age 50 years, EOOG performance ≤1 were recruited: 0 DA group (18 pts), 1 DA (18), and 2 DA (6). In 0 DA group, two of six pts experienced DLT at 380 mg/m2 with grade III asthenia (1 pts) and febrile neutropenia (1). In 1 DA group, all of two pts experienced DLT at 380 mg/m2 with grade III asthenia. In 2 DA group, two of three pts experienced DLT at 240 mg/m2 with febrile neutropenia (1) and grade IV neutropenia (1). The MTD was defined as CPT-11 350 mg/m2 for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine. Median SN-38G/SN-38 AUC was 10.45, 8.78, and 1.66 in pts with 0, 1, and 2 DA group, respectively. Conclusions: CPT-11 dosing by UGT1A1*28 and *6 genotypes is feasible in Korean pts with mCRC. A dose of CPT-11 350 mg/m2 IV for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine every 3 weeks, is recommended for further study. [Table: see text] No significant financial relationships to disclose.
Isolated chemotherapeutic perfusion as neoadjuvant therapy for advanced/unresectable pelvic malignancy
Authors: Wanebo H. J. , Begossi G. , Belliveau J. , Gustafson E. 
Published: August 2020

2555 Background: Isolated pelvic perfusion (IPP) provides higher tissue drug levels than high-dose systemic therapy and may enhance resectability and survival in patients failing chemo radiation ± surgery. We performed 113 IPP in 68 patients (34 palliative, and 44 pre op) using a simplified balloon occlusion technique. Methods: 42 patients had advanced (irradiated) rectal cancer, 8 pts had advanced anorectal cancer, 5 patients had sarcoma. Other cancers included melanoma (M 4pts), endometrial cancer (EC) 2, ovarian cancer (OC) 2, and bladder cancer (BC) 1. Chemotherapy agents included 5FU, (1,500–2,000mg/M2), cisplatinum (100mg/M2), Oxaliplatin and mitomycin (10–20mg/M2) for epithelial cancer and selected agents (Adriamycin, Ifosamide, DTIC, Phenyl Alanine Mustard (PAM) for the remaining tumors: 6 pts received high dose PAM (110/M2), Paclitaxel 60mg/m2 and Cisplatin 150mg/m2, 3 required stem cell support (advanced M (1 pt), SCC (1 pt), Endometrial ca (1pt). Results: Palliative IPP for advanced rectal cancer pts provided significant pain control (1–4 months) in 11 of 14 pts with narcotic resistant pain and induced tumor regression in 6 pts. Preoperative perfusion in 26 advanced rectal cancer pts induced a complete path response (in pelvis) in 2 pts and significant regression in 11 pts rendering them resectable. 7 had RO resection with clear margins: of the other pts 1 had a path CR negating resection, 3 refused pelvic resection, 2 became inoperable. Median survival post IPP was 24 mos in 12 patients considered resectable vs. 8 mos in 12 patients considered non resectable p<0.05. It was 30 months in 8 pts with advanced anorectal squamous cancer (1pt survived >90 mos), 20 months in 4 patients with endometrial/ovarian recurrence, (1 died NED >48 mos), 13 mos in 4 melanoma pts and only 5 months in 5 pts pelvic sarcoma (4–34 mos-NED). Overall 17 of 44 pts (39%) were resected and 24 had significant palliative benefit. Conclusions: IPP with high dose chemo therapy has promise in palliating or augmenting resectability of advanced pelvic malignancy persisting after conventional surgical and chemoradiation therapy. Stem cell support and biologic therapy merit further exploration. No significant financial relationships to disclose.
Phase I study of SB939 three times weekly for 3 weeks every 4 weeks in patients with advanced solid malignancies
Authors: Yong W. , Goh B. , Toh H. , Soo R. , Diermayr V. , Goh A. , Ethirajulu K. , Lee S. , Seah E. , Zhu J. 
Published: August 2020

2560 Background: SB939 is a novel orally bioavailable inhibitor of class 1 and 2 histone deacetylases. We conducted a phase I study to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary efficacy of SB939 in patients with advanced solid malignancies. Methods: SB939 was administered orally every other day 3 times a week for 3 consecutive weeks, in a 4-week cycle. Cohorts of patient were treated with escalating doses of SB939 starting from 10 mg. PK and PD (Acetylated Histone 3 in PBMCs) samples were collected in the first cycle. Results: 31 patients were enrolled at 10 mg (n=3), 20 mg (4), 40 mg (8), 60 mg (10) and 80 mg (6). The median number of treatment cycles received was 3.6. Fatigue, elevation of troponin T and QTc prolongation were the observed dose-limiting toxicities (DLT). At 80mg, one patient each (3/6) experienced a DLT of grade 3 fatigue, grade 3 asymptomatic elevation of troponin T and grade 3 QTc prolongation respectively. All DLTs were reversible and no treatment mortality was observed. Grade 1–2 fatigue occurred in 56% of patients occurring mainly at the 4th week, and 37% of pts had G1–2 anorexia. Grade 3–4 thrombocytopenia was observed in 2 patients at 60 mg at cycles 1 and 6 of treatment. SB939 was rapidly absorbed reaching Tmax between 1–3 h after ingestion, and mean elimination half-life and oral clearance of SB939 were 7.2 + 0.6 hrs and 53 + 8.5 L/h respectively. Cmax and AUC (0-∞) were dose-proportionally increased at this dose range. There was no substantial accumulation of SB939 on day 15 following repeated dosing. Concentrations above IC50 of SB939 for HDAC I was reached at all doses. Acetylation of H3 was dose dependent and consistent at 60mg. Of the 13 patients evaluable for response, stable disease was seen in 1 patient with follicular thyroid carcinoma and 1 with hepatocellular carcinoma for 51 and 164 days respectively. Conclusions: SB939 has similar toxicity profiles as that of other HDAC inhibitors and a favorable PK/PD profile. The MTD of SB939 in this regimen was 80 mg and 60mg is the recommended dose, at which acetylation of H3 is consistently observed. Further phase 2 studies with SB939 in specific indications are being planned. No significant financial relationships to disclose.
Clinical development of namitecan (ST1968), a novel camptothecin derivative with high antitumor activity: Phase I clinical data
Authors: Hess D. , Boehm S. , Delmonte A. , Gallerani E. , Barbieri P. , Pace S. , Carminati P. , Marsoni S. , Coceani N. , Sessa C. 
Published: August 2020

2570 Background: Namitecan is a new water-soluble camptothecin analogue which showed high antitumor activity in preclinical models. Aim of this trial was to determine safety, PK profile and activity in adult patients with advanced solid tumors. Methods: The dose escalation started at 2.5 mg i.v. on days 1 and 8 of a 21 day cycle (D1, D8 Q21D) and increased according to 3+3 cohort design depending on the observed toxicity. Dose limiting toxicity (DLT) definitions were: ANC <0.5x109/L for >5 days; PLT ≥ Grade 3 (CTC V3); grade ≥2 liver/renal toxicity not recovered by D22; any non-hematologic toxicity ≥ Grade 3; D8 dose skipping due to toxicity. Maximum tolerated dose (MTD) and recommended dose (RD) were the primary end-points. Blood and urine samples were collected at cycle 1 for PK evaluation. Results: 31 pts (11 endometrial ca., 5 CRC, 5 ovarian ca., 2 NSCLC, 8 other) have been included, with 6 dose levels evaluated (2.5; 5; 10; 15; 17.5 and 20 mg). 17.5 mg was introduced later when 2/7 DLTs at 20 mg were observed (ANC G4>5days, one with D8 skipping). At 17.5mg 2/4 pts experienced DLTs (ANC G4; D8 skipped). Uncomplicated neutropenia and thrombocytopenia were the most relevant G3/4 hematological toxicities. Other toxicities were mild or moderate asthenia, fatigue and alopecia. The MTD was defined at 17.5 mg and the RD was 15 mg. Stable disease ≥ 6 cycles was recorded in 6 pts (2 stable diseases ≥ 10 cycles). PK was linear and data suggest an entero-hepatic recirculation. No metabolites were found in plasma and the product resulted poorly excreted into urine. Conclusions: The MTD and RD of D1, D8 Q21D schedule have been identified. The study will continue with the evaluation of MTD and RD of a single administration per cycle (D1 Q21D), to optimize the schedule of treatment. [Table: see text]