bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of bevacizumab in patients with metastases to the central nervous system
Authors: Rohr U. P. , Augustus S. , Lasserre S. F. , Compton P. , Huang J.
Published: August 2020

2007

Background:. The background rate of CNS hemorrhage (CH) in cancer patients with brain metastases not receiving bevacizumab (BV) treatment is 5%-29%, depending on tumor type. Patients with CNS metastases were routinely excluded from most BV late-stage clinical trials, following the occurrence of CH in one hepatocellular carcinoma patient with occult CNS metastasis in a BV phase I trial. In this particular tumour type, up to 87.5% has been reported as a background rate of CH without BV use. Available safety information in BV-treated patients with CNS metastases has been reviewed to determine whether the exclusion of these patients from trials is still justified. Methods: A retrospective exploratory analysis was conducted using safety data from three datasets: A.) 13 randomized controlled phase II or III trials (RCTs); B.) Two ongoing open-label trials MO19391 (ATHENA) and MO19390 (SAIL). While patients with known CNS metastases, based on imaging or clinical signs and symptoms, were excluded from trial in A and B datasets, patients who were found to have CNS lesions had either unrecognized CNS metastases at study entry or had developed these during the trial.; C.) 2 ongoing open-label studies AVF3752g and AVF3671g in patients with NSCLC, where inclusion of patients with treated CNS metastases was allowed. Incidence of CH in patients with brain metastases was quantified in each dataset. Results: A.) In 13 RCTs, with a total of 8443 patients with locally advanced, unresectable, or metastatic breast, renal, pancreatic, colorectal cancer, or NSCLC, brain metastases were identified in 187 patients (91 in BV-arms and 96 in control arm). Three of 91 (3.29%) BV-treated patients developed grade 4 CH, and one in 96 patients in the control arm (1.04%) developed grade 5 CH; B.) In open-label studies no CH was reported in 68 patients with CNS metastases, out of 3,252 patients enrolled. C.) In two studies in patients with treated CNS metastases, one subject in 83 (1.2%) BV treated patients developed a grade 2 CH. Conclusions: In this retrospective review, the rates of CH in BV-treated patients with CNS metastases is low, and appears consistent with historical rates of CH in these patient populations. Ongoing trials are expected to provide additional data regarding the risk of CH in patients with primary and metastatic CNS tumors.

[Table: see text]
A phase I study of ABT 510 and concurrent temozolamide and radiotherapy for patients with newly diagnosed glioblastoma multiforme
Authors: Kekan M. , Fiveash J. , Markert J. M. , Gillespie G. Y. , Kuo H. , Meleth S. , Gladson C. L. , Nabors L. B.
Published: August 2020

2023

Background: ABT-510 (Abbott Laboratories, Abbott Park, IL, USA) is a Thrombospondin-1 (TSP-1) mimetic drug with anti-angiogenic properties. This phase I dose escalation trial was designed to study the maximum tolerated dose (MTD) of ABT 510 when used concurrently with temozolomide (TMZ) and radiotherapy (RT) in patients with newly diagnosed glioblastoma multiforme (GBM). Methods: A total of 23 patients with newly diagnosed, histologically verified GBM were enrolled between April 2005 and January 2007, after obtaining written consent. The study was approved by the University of Alabama at Birmingham (UAB) Institutional Review Board. Four cohorts with three patients in each, receiving subcutaneous ABT 510 injection at doses of 20, 50, 100, and 200 mg/day were studied. The starting dose was primarily based on preclinical findings from animal studies and phase I studies on healthy subjects and cancer patients. Treatment plan included 10 weeks of induction phase (TMZ and RT with ABT 510) followed by a maintenance phase (ABT 510 and TMZ) of 14 cycles each consisting of 28 days. Patients were monitored with brain MRI along with laboratory values for dose limiting toxicities (DLT) defined as grades 3–4 non-hematological toxicities and grade 4 hematological toxicities (neutropenia or thrombocytopenia). In the absence of a DLT in at least two of the three patients, the dose was increased by 50% in the next cohort of patients. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression and survival statistics were analyzed. Results: During this trial, grade 3/4 DLT were not observed even after the dose was increased to 200 mg/day, hence, the last cohort was expanded to include 14 patients. A MTD was not defined. The median time to tumor progression (TTP) was 220 days and the median overall survival was 422 days. Gene expression analysis of the tumor pathology will be performed to evaluate the relationship between the expression of TSP-1, TSP-2, and patient response to the drug. Conclusions: ABT 510, at subcutaneous doses up to 200 mg/day, is tolerated well with concurrent TMZ and RT in patients with newly diagnosed GBM.

No significant financial relationships to disclose.
Intra-CSF trastuzumab in patients with neoplastic meningitis from breast cancer or primary brain tumors
Authors: Allison D. L. , Glantz M. , Werner T. L. , Kirkegaard S. L. , Murdock K. , Jensen R.
Published: August 2020

2066

Background: Neoplastic meningitis is a devastating complication of extra-CNS malignancies and primary brain tumors with few available treatments and none of outstanding efficacy. Trastuzumab, a large molecule monoclonal antibody directed against the HER-2/neu receptor (overexpressed on some breast cancers, glioblastomas, and medulloblastomas), has negligible access to the CSF after intravenous administration. Intra-CSF administration could circumvent this barrier. Methods: Sixteen patients with neoplastic meningitis (11 GBM, 4 breast cancer, 1 medulloblastoma) and progressive neurologic deterioration were treated with intra-CSF trastuzumab (20–60 mg per dose, either weekly or every other week) for four treatments. Age ranged from 35 to 74 (median 51) years; KPS ranged from 60 to 90 (median 70). Patients who were neurologically and radiographically stable or improved after four treatments were continued on every other week therapy until neurologic progression. CSF cytology, neurologic status, and KPS were assessed at each treatment. MRI scanning of sites of previously demonstrated leptomeningeal tumor was performed after four treatments and then at 8 week intervals. HER-2/neu status of the primary tumors was also evaluated. Results: Two of the four patients with breast cancer (both HER-2/neu+) are responding clinically and cytologically 4 and 14 weeks after initiating treatment. The patient with medulloblastoma (also HER-2/neu+) continues to respond clinically and cytologically after 6 weeks. Seven of 11 patients with GBM have responded (two cytologically, two radiographically, all seven clinically), with response durations ranging from 4 to 12+ weeks. HER-2/neu status is being assessed. There were no adverse events related to the trastuzumab. Conclusions: Trastuzumab can be safely administered into the CSF in patients with solid tumor neoplastic meningitis. Sustained clinical and cytologic responses may occur in patients with breast cancer and primary brain tumors. HER-2/neu status may predict response. Further study to establish the biologically optimum dose and efficacy of this agent may be warranted.

No significant financial relationships to disclose.
A long-term open-label extension study examining the steroid-sparing effects of corticorelin acetate in patients with cerebral tumors
Authors: Mechtler L. , Wong E. T. , Hormigo A. , Pannullo S. , Hines V. , Milsted R. , O'Connor P. C. , Ryan R. P. , Recht L.
Published: August 2020

2079

Background: Corticorelin acetate (CrA) is a synthetic peptide formulation of corticotropin-releasing factor, which is undergoing clinical trials as a treatment for peritumoral edema. The objective of this study was to evaluate long-term safety, tolerability and steroid-sparing potential of CrA in patients with primary or secondary brain tumors and peritumoral edema. Methods: Patients from two randomized double-blind controlled studies who received either CrA (CrA-CrA group) or placebo (PLA) (PLA-CrA group) were permitted to receive open-label CrA 1 mg SC bid after participation in the initial studies. Treating physicians were requested to attempt and maintain the maximum possible reduction of the dexamethasone (dex) dose without knowledge of their patients’ prior treatment regimen in the controlled feeder studies. During this extension study, patients’ dex doses and adverse events were monitored monthly; neurologic function and clinical status were recorded 3 monthly. For this analysis, data up to October 17, 2008, are reported from this ongoing study. Results: Of the 110 patients enrolled, 47 (43%) reduced their dex dose to zero and 67 (61%) were able to reduce their dose to ≤1 mg/day. At entry to this extension study, the daily baseline dex dose was lower for patients who had previously received CrA (3.9 mg; n = 59) than for those who had previously received PLA (6.2 mg; n = 51). The PLA-CrA group showed a greater percent decrease in dex dose than the CrA-CrA group at Week 4 (24.0% vs. 12.6%). At week 8 the mean prescribed dex dose was similar in the two groups (PLA-CrA 3.7 mg vs. CrA-CrA 3.4 mg). Long-term treatment with CrA has been well tolerated with no reported safety concerns. To date, 48 patients remained on study for ≥6 months, 27 patients for ≥12 months, 5 patients for >2 years; 31 patients remain on study. Conclusions: These findings indicate that CrA is safe and well-tolerated, and may enable substantial reduction or cessation of dex therapy for many patients with cerebral tumors.

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Pharmacology and safety factors affecting use of flat (rather than weight-based) dosing of tesetaxel, an orally administered taxane
Authors: Warrell R. P. , Beeram M. , Spindler E. , Papadopoulos K. , Patnaik A. , Tolcher A. W.
Published: August 2020

2510

Background: As a class, taxanes have wide interpatient (pt) pharmacokinetic (PK) variability at their effective dose, which has been associated with adverse reactions, especially neutropenia. Tesetaxel is an oral taxane with Phase 2 activity in pretreated pts with colorectal, non-small cell lung, gastric, and breast cancers. Tesetaxel is not a substrate for P-glycoprotein; it is associated with lower neurotoxicity at equi-myelotoxic does, and it displays a long terminal half-life in plasma (∼180 hrs). We explored PK and clinical safety to determine the feasibility of using flat dosing in future studies. Methods: PK parameters were evaluated in 21 pts treated at the maximum tolerated dose (27 mg/m2) either alone or in combination with capecitabine. We then compared actual dose (total mg) with the weight-based dose and correlated the incidence and severity of Grade 3–4 neutropenia with weight-based vs. flat dosing. Results: A total of 174 pts were treated with tesetaxel in Phase 2 trials at doses of 27 or 35 mg/m2 once every 3 weeks. For pts prescribed with weight-based dosing (27 mg/m2), mean Cmax in 3 separate cohorts was 24.6, 42.5, and 47.9 μg/L, with AUC0-inf of 1363, 1592, and 1663 h*μg/L, respectively. In 103 pts prescribed a dose of 27 mg/m2, 17% and 16% of pts received doses of 40 mg or 60 mg, respectively, whereas 67% received 50 mg. Correlations between drug exposure AUC0-inf and actual dose (mg and mg/m2) across the entire range of administered doses showed r2 values of 0.455 and 0.492, respectively. Similar correlations after a second repeat dose showed r2 values of 0.731 and 0.653, respectively. The incidence of Grade 3–4 neutropenia at 27 mg/m2 was 33%. Conclusions: PK and clinical safety suggest that weight-based dosing offers no substantial advantage compared with flat dosing. Future studies could incorporate a starting dose of 50 mg administered once every 3 weeks. Flat dosing should also be tested using different schedules, including weekly x 3 weeks and “metronomic dosing” (1–2 mg/d).

[Table: see text]
Proportion of subjects with an ethically acceptable reason for enrolling in a phase I trial
Authors: Pentz R. D. , Khuri F. , Kauh J. , Owonikoko T. , White M. M. , Harvey R. D.
Published: August 2020

2512

Background: Concern persists that phase I subjects, who frequently enter trials for personal benefit, are deluded. They may suffer from therapeutic misconception (TM) - conflating research and clinical care, or from therapeutic misestimation (TMis) - misestimating benefits or risks. Methods: To estimate the proportion of phase I subjects who have an ethically acceptable reason for participation, we both interviewed and surveyed subjects to obtain qualitative and quantitative data. Ethically acceptable reasons included 1) Altruism (sole motive for entering trial was to help others or advance science); 2) Self-regarding motives but no TM (correctly identifying that the trial mostly intends to help research and gain knowledge, the study decides the treatments and the subjects get different doses of drug); 3) Self-regarding motives, TM but no TMis (chance of benefit < 20% and chance of risk > 0%); or 4) Self-regarding motives, TM, overestimation of benefits but broad view of benefit (with collateral benefits like getting careful disease monitoring or access to an academic center listed) and chance of risk > 0%. This generous interpretation of ethically acceptable reasons hinges on the view that subjects at least must recognize there is some risk, that chance of disease benefit is not high and that collateral benefits count. Results: The 86 subjects were mostly white, male, with incomes more than $60,000. 49% were college educated with a mean age of 60. 53.5% had an ethical reason for participation, with 10.5% altruistic, 16.3% no TM, 8.1% TM but no TMis, and 18.5% overestimating benefit but including collateral benefits. In both univariate and multivariate analyses age younger than 60 yo and having at least a college education were the only characteristics significantly correlated with having an ethically acceptable reason for participation. Those who reported strong religious beliefs (p = 0.01) were significantly more likely not to have an ethically acceptable reason. Conclusions: With almost half of participants lacking an ethically acceptable reason for participation, interventions are necessary to bolster understanding. Older participants lacking a college education are particularly at risk and could be the target for an intervention trial.

No significant financial relationships to disclose.
Novel phase I design for oncology research
Authors: Lupinacci L. , Anderson K. , Sun L. , Tymofyeyev Y.
Published: August 2020

2517

Background: Phase I studies in oncology patients seek to identify a dose of a new investigational agent that is tolerable and has the potential to be effective. Toxicity data are the key to defining dose levels of the new agent that are acceptable for further study. Several Phase I designs are available to researchers. Some are practical and easy to implement. Others are complex but yield better information on the toxicity of studied doses. We sought a Phase I design that had a high probability of selecting a dose with acceptable toxicity, allowed adaptation based on observed dose-limiting toxicity (DLT) data and did not create considerable enrollment delays. Methods: We compared the 3+3 design, an algorithmically-determined adaptive method proposed by Ji, et al. (2007), and variations on Ji's design including a 2-stage design combining a 3+3 with a modified Ji design. We simulated Phase I trials with 6 dose levels and 12 dose response relationships and studied the properties of the designs including how often the dose with the target toxicity level was selected, the expected percentage of patients with a DLT and the expected sample size. We also implemented operational conventions on top of the preferred design to enhance the practicality and clinical usefulness of the design. Results: In general, the adaptive, Ji-based designs outperformed the 3+3, selecting the target dose up to 18% more often. The 2- stage and other Ji-based designs were comparable in most scenarios and performed the best when the target dose was among the middle doses in the dose range tested. When the target dose was the highest dose or higher than all of the doses tested, the 3+3 and 2-stage designs outperformed some of the other Ji-based designs. Conclusions: For single agent studies, we prefer a 2-stage design in which a 3+3 is implemented until a preliminary maximum tolerated dose (MTD) is identified. Then, a modified Ji design (target toxicity rate = 20%) is used to confirm the MTD and allow further dose refinement. While this design may underperform slightly compared with the complex continuous reassessment methods, this design is easier to implement and more intuitive to investigators and ethical and regulatory review boards. In addition, it maximizes enrollment continuity while ensuring appropriate patient safety.

[Table: see text]
Phase I study of vorinostat plus docetaxel in patients with solid tumor malignancies
Authors: Schneider B. J. , Bradley D. , Smith D. C. , Egorin M. , Kalemkerian G. , Dunn R. , Daignault S. , Hussain M.
Published: August 2020

2528

Background: Vorinostat is an inhibitor of histone deacetylase 6, which results in the acetylation of tubulin and the stabilization of microtubules. Since taxanes bind to stabilized microtubules, the administration of vorinostat followed by docetaxel, we hypothesized, should result in synergistic cytotoxicity. A phase I trial was conducted to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤ 30% of patients (pts). Methods: Eligible pts had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, a performance status of 0–2 and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle. Docetaxel was given intravenously over 1 hour on day 4. The time-to-event continuous reassessment method guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Blood was collected on days 1 and 4 of cycle 1 to measure drug levels by HPLC. Results: 12 pts were enrolled: median age 65 yrs (49–74); gender 9M:3F; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles was 2. 2 pts were treated at DL -1, 4 pts at DL 0, 5 pts at DL 1 and 1 pt at DL 2. 5 DLTs occurred in 5 pts: grade 4 neutropenic fever/sepsis (n = 2), anaphylactic reaction (n = 1), myocardial infarction (n = 1) and GI bleed (n = 1). Other toxicities included grade 4 neutropenia (n = 2), pulmonary embolus (n = 1) and GI bleed (n = 1). The estimated probability of DLT for DL -1 was .32 (90% posterior probability interval [PI], .11 to .53) for DL 0, .38 (90% PI, .16 to .58) and for DL 1, .43 (90% PI, .23 to .64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions: Combination vorinostat plus docetaxel was poorly tolerated with excessive DLTs requiring study termination. PK analysis will be presented. Supported in part by a grant from Merck & Co., Inc.

[Table: see text]
Design of a phase 0 microdosing trial for correlation of platinum-induced DNA damage to chemotherapy outcomes
Authors: Pan C. , Li T. , He M. , de Vere White R. , Gandara D. , Mack P. , Lara P. N. , Turteltaub K. , Henderson P.
Published: August 2020

2543

Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS), an ultrasensitive method for measuring radiocarbon, can detect [14C]carboplatin bound to the DNA of cancer cells from cell culture, mice bearing tumor xenografts and patients receiving subtoxic microdoses of compound. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Relevant parameters such as drug influx/efflux, intracellular drug inactivation, DNA damage and repair, were measured and correlated with response to chemotherapy. A Phase 0 microdosing trial has been designed to study patients with non-small cell lung or bladder transitional cell cancers who are planning to receive Pt-based chemotherapy. One microdose of [14C]carboplatin is administered to these patients 4 hours before biopsy. Pt-induced DNA damage and repair in tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Results: Preclinical studies showed that AMS can detect Pt-DNA damage when cancer cells and mice with tumor xenografts are exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage are directly proportional to the damage caused by a therapeutic drug dose (p<0.001); and these levels of DNA damage correlate with chemoresistance as measured by MTT assay. Measuring drug uptake/efflux and intracellular inactivation allows insights into resistance mechanisms. These data support the conclusion that the levels of DNA damage induced by microdosing can potentially predict chemoresistance in patients. Consequently, a Phase 0 microdosing trial is in progress. Conclusions: These results support a phase 0 microdosing trial employing AMS to identify chemoresistance and determine the underlying chemoresistant mechanisms for personalized therapy before patients receive cytotoxic chemotherapy.

[Table: see text]
Metabolism and transport pathways of the blood stable camptothecin AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin)
Authors: Milewska M. , Horn J. , Monks N. , Moscow J. A. , Arnold S. M. , Leggas M.
Published: August 2020

2553

Background: AR-67 is a 3rd generation camptothecin analog with superior stability of its active lactone form (>85%). This stability has been credited in part to the -R10 hydroxyl group (-OH); a group also present on the two clinically approved analogs, topotecan and irinotecan. As with SN-38, the active metabolite of irinotecan, the -OH of AR-67 may be a site for glucuronidation by a UDP glucuronosyltransferase. Moreover, many camptothecins are substrates for the efflux transporter BCRP (ABCG2) and the anionic carboxylate may be a substrate for the liver uptake transporter OATP1B1 (SLCO1B1). Pharmacogenetic studies have established that significant portions of the population have polymorphisms in these genes, which lead to altered pharmacokinetics and toxicity profiles of their substrates. This report describes in-vitro metabolism and transport studies with AR-67 as well as identification of metabolites in plasma and urine from patients enrolled in a phase I study. Methods: AR-67 and its metabolites were detected using chromatography methods with fluorescence or MS/MS detection. In vitro metabolism studies were done with UGT and CYP450 enzyme isoforms expressed in Sf9 cells. In vivo AR-67 metabolic products were identified in clinical plasma and urine specimens. Collection of clinical specimens has been described (control #09-AB-30336-ASCOAM). AR-67 uptake and efflux studies were performed in cells transfected with ABCG2 or SLCO1B1. Results: AR-67 glucuronidation was demonstrated to occur in vitro, primarily by UGT1A8. AR-67 was also found to be a substrate of CYP3A4 and CYP3A5. Only limited glucuronide and oxidation metabolite peaks were observed in patient samples at the highest concentrations. Diminished accumulation of AR-67 lactone was observed in BCRP expressing Saos-2 cells and significant uptake of AR-67 carboxylate was observed in OATP1B1 expressing cells. Conclusions: Unlike SN-38, AR-67 was not found to be a major substrate of UGT1A1, but was rapidly processed by UGT1A8, an isoform that is highly expressed in the GI tract. These data may explain the absence of diarrhea during this phase I study. The pharmacologic significance of ABCG2 and SLCO1B1 polymorphisms should be explored further in the context of population studies.

[Table: see text]
Phase I, pharmacokinetic, and pharmacodynamic study of carboplatin and topotecan administered in two different schedules
Authors: Boss D. S. , Siegel-Lakhai W. S. , Schoemaker-van Egmond N. E. , Pluim D. , Rosing H. , Ten Bokkel-Huinink W. W. , Beijnen J. H. , Schellens J. H.
Published: August 2020

2561

Background: Preclinical studies showed sequence dependent synergy of the combination of topoisomerase I inhibitors and platinum agents. This trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of carboplatin (carbo) and topotecan (topo) in patients (pts) with solid malignancies in two different schedules. Methods: In part 1, pts received carbo as a 60 min IV infusion on day 1 and topo as a 30 min IV infusion on days 1, 2 and 3 (C→T). The sequence of drug administration was reversed in part 2 of the study (T→C): topo on days 1, 2, and 3, followed by carbo on day 3. In both schedules, the PK was determined of each agent in plasma and the TopI catalytic activity and Pt-DNA adducts in white blood cells (WBC) and tumor tissue. Results: 41 pts were included in this trial. Dose-limiting toxicities (DLTs) during C→T included grade (G) 4 thrombocytopenia and febrile neutropenia. The MTD was reached at carbo target AUC 4 min.mg/mL and topo 0.5 mg/m2/day. DLTs during T→C included G4 neutropenia, thrombocytopenia and neutropenic fever, G3 nausea and G4 vomiting. Carbo target AUC 6 min.mg/mL and topo 0.9 mg/m2/day was the MTD in this schedule. No schedule dependent differences in PK were found (clearance (Cl) of unbound carbo: 0.6 vs 0.7 mL/min, p=0.14; Cl of total topo: 24.1 vs 29.6 L/h, p=0.08; Cl of topo lactone: 84.5 vs 83.7 L/h, p=0.96). WBC and tumor samples were collected from 30 and 27 pts, respectively. Pt-DNA levels were not schedule dependent in WBC (range C→T = 0.44–4.13, and T→C = 0.22–6.07 fmol*h/μg DNA) and in tumor tissue (range C→T = 0.20–0.96, and T→C = 0.62–1.8 fmol/μg DNA). Also, no schedule dependent effects were seen in TopI catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule. One pt with ovarian cancer had a complete response (T→C schedule), 2 pts with ovarian cancer (C→T schedule) and 3 pts treated in the T→C schedule (ovarian, SCLC and gastric cancer) had a partial response. Conclusions: T→C was better tolerated as both hematological and non-hematological toxicities were milder. Other than the investigated PD factors must explain the schedule dependent differences in toxicities.

No significant financial relationships to disclose.
Phase I study of TP300 in patients (pts) with advanced solid tumors
Authors: Anthoney D. A. , MacPherson I. , Twelves C. , Crawford D. , Siller C. , Nemat S. , Abe M. , Miwa M. , Evans J.
Published: August 2020

2563

Background: TP300 (CH4556300) is a synthetic camptothecin analogue and potent topoisomerase I inhibitor designed to have superior efficacy, tolerability and pharmacokinetic (PK) characteristics compared to current inhibitors. Intravenous (i/v) TP300 undergoes rapid chemical conversion to the active compound CH0793076, then enzymatic conversion to an active metabolite, CH0793011. The objectives of this study were to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and PK profiles of TP300; antitumor activity and pharmacodynamics (PD) were also evaluated. Methods: Eligible pts with refractory, advanced solid tumors who had adequate PS, hematologic, renal, and hepatic function were recruited into this open-label, modified- Fibonacci dose escalation (“3 + 3” pts/dose level, with expansion at the MTD) study. TP300 was given as a 1-hour i/v infusion 3-weekly; the starting dose was 1 mg/m2. The MTD was defined as the dose level below that where > 2 of 3–6 pts experienced DLT. PK profiles of TP300, CH0793076 and CH0793011 were analysed; DNA strand breaks in peripheral blood mononuclear cells (PBMCs) were measured with the comet assay as a PD marker. Results: 32 pts (m=20; f=12), median age 58 (range 31–72), received TP300 at doses of 1, 2, 4, 8, 12, then 10mg/m2. The MTD was 10mg/m2; DLTs seen at 12mg/m2 (2/4 pts) and 10mg/m2 (3/12 pts) included anaemia, thrombocytopenia and febrile neutropenia. Other grade 3/4 toxicities included lethargy, chills and lower back pain. Diarrhoea was uncommon. Seven pts, all previously treated with irinotecan, had disease stabilisation for 1.5–5 months. CH0793076 PK (AUC and Cmax) were linear from 1 to 10mg/m2. There was a strong PD relationship between CH0793076 AUC and fall in neutrophils, the threshold AUC for DLT neutropenia being 5 hr.umol/L. DNA strand breaks were detected consistently in PBMCs on completion of TP300 infusion . Conclusions: The Phase II starting dose will be 8mg/m2 because hematologic toxicity was seen in cycle 1 at the MTD. As the AUC of CH0793076 at MTD is substantially greater than that of SN38 in pts treated with irinotecan, and CH0793076 is almost equipotent to SN38 pre-clinically, a PK advantage for TP300 is confirmed. Further investigation is warranted.

[Table: see text]
Phase I clinical trial with VEGFR2-epitope peptide and gemcitabine for patients with advanced pancreatic cancer
Authors: Yamaue H. , Miyazawa M. , Ohsawa R. , Tani M. , Kawai M. , Hirono S. , Ina S. , Tsunoda T. , Nakamura Y.
Published: August 2020

2567

Background: The prognosis of pancreatic cancer patients is one of the most dismal of all cancers. Gemcitabine is a potent anticancer drug for pancreatic cancer, however, one should consider that the clinical benefit of anticancer drugs is limited and other potent therapeutic tool is eagerly awaited. Vascular endothelial growth factor (VEGF) is a glycoprotein which is predominantly related to the neoplastic angiogenesis. VEGF-receptor 2 (VEGFR2; Flk-1 and KDR) is an essential target for tumor angiogenesis. We first identify the epitope peptides of vascular endothelial growth factor receptor 2 (VEGFR2) and confirmed that stimulation using these peptides induces CTLs with potent cytotoxicity in HLA class I-restricted fashion. Methods: We proceeded to Phase I clinical trial using gemcitabine and one of these peptides. Patients were sequentially allocated to cohorts of 6 patients per group receiving 0.5, 1.0, 2.0mg of peptides/body. No intra-patient dose escalation was permitted. The eligibility criteria are: being aged between 20- and 80- year old, expecting the survival more than 3 months after the initiation of this treatment, adequate organ function including bone marrow function, and having HLA-A*2402 (A24) genotype. The enrolled patients received 4 cycles of VEGFR2 peptide sc. and 3 cycles of 1,000 mg/m2 gemcitabine weekly. Results: No patients had grade 3 and 4 toxicity, and dose escalation was succeeded without any DLT. CTL response was observed in 50%, 67%, and 67% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. The delayed type hypersensitivity of the peptide-injection site was recognized in 83%, 67%, and 100% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. Therefore, we concluded that MTD should be 2.0mg of peptide. Disease control rate (>SD) was 67% (12/18 patients), and one patient had PR. The median survival time was 8.72 months. Conclusions: These results are promising to proceed the pivotal clinical trial, and the randomized phase II/III trial will start in 2009.

No significant financial relationships to disclose.
Biomodulation of capecitabine by weekly paclitaxel and carboplatin in patients with advanced solid tumor malignancies: A dose-escalating phase I study
Authors: Lustberg M. B. , Nuovo J. , Thomas J. P. , Monk P. J. , Kim S. , Villalona-Calero M. , Bekaii-Saab T.
Published: August 2020

2569

Background: A principal determinant of the therapeutic index with capecitabine-based treatment is the grade of thymidine phosphorylase (TP) activity in malignant tissue. The beneficial interactions of paclitaxel and carboplatin in upregulation of TP promise to make capecitabine more tumor specific and to provide the expected synergy. On the basis of the time-dependency and transiency for this upregulation we performed a phase I study of capecitabine in combination with weekly paclitaxel and carboplatin (CTX). Methods: Patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8–21, every 4 weeks. There were 5 planned dose levels (DL 1–5). Paclitaxel was escalated from 60 mg/m2 to 80 mg/m2 (DL 4) then 100 mg/m2 (DL 5). Capecitabine from 500 mg/m2 bid to 750 mg/2 bid (DL 2) then 1000 mg/m2 bid (DL 3–5). Carboplatin dose was fixed at AUC 6. Paraffin-embedded tissue was evaluated for expression of TP, thymidylate synthase and dihydropyrimidine dehydrogenase by immunohistochemistry. Results: 32 patients from Ohio State University (OSU) were enrolled. 84% had prior therapy. The most common grade 3/4 toxicities were neutropenia (59%), leukopenia (56%), and fatigue (16%). DLTs included neutropenic fever (1), prolonged neutropenia or thrombocytopenia (2) and diarrhea (1). The MTD was at DL 2. There were 10 confirmed responses [4 CR (esophagus, stomach, unknown primary and ampullary); 6 PRs (Pancreas (3), unknown primary, anal and esophagus] and stabilization of disease > 3 months in 12 patients. In normal tissue, there was no difference in expression levels of both TS and TP. On the other hand, in cancer tissue, TP levels seem to correlate with response whereas TS did not. Conclusions: CTX demonstrates acceptable tolerability. The recommended doses for phase II studies are capecitabine 750 mg/m2 bid, paclitaxel 60 mg/m2/week and carboplatin AUC=6. The acceptable toxicity profile in this dose schedule, and the promising antitumor activity observed warrant further evaluation of this regimen. Two phase II trials are already underway at OSU using this regimen for patients with pancreatic cancer and adenocarcinomas of unknown primary, the latter already actively enrolling patients. Pretreatment tumoral TP levels may help predict patients that are more likely to respond to CTX. Correlation of IHC data with responses will be presented at the meeting.

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Phase I study of oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients (pts) with advanced solid tumors
Authors: Koolen S. , Witteveen P. O. , Garcia-Ribas I. , Callies S. , Andre V. , Kronemeijer R. H. , Nol A. , Beijnen J. H. , Voest E. E. , Schellens J. H.
Published: August 2020

2576

Background: LY2334737 (LY) is an orally available valproic acid prodrug of gemcitabine that was developed to overcome the extensive first-pass metabolism of gemcitabine to 2',2'-difluorodeoxyuridine (dFdU). The objectives of this study were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of LY as monotherapy and in combination with erlotinib. Methods: Eligible pts had ECOG PS < 2 and adequate hematologic, renal and hepatic function. In Arm A, LY was given daily for 14 days in a 3-week cycle. Pts assigned to Arm B also received erlotinib daily 100 mg continuously. Dose escalation was based on observed toxicity and the modified continual reassessment method (mCRM). The dose was maximally increased by 100% depending on the toxicity observed in the previous cohort. PK of LY, gemcitabine, dFdU and intracellular metabolites were determined. Results: 33 pts (21 m, 12 f, median age 60 yrs (range 24–81)) were treated at 5 different dose-levels (range 5–50 mg/day). Pts received a median of 3 cycles (range 2–17). Three out of 7 pt treated with 50 mg experienced 5 dose limiting toxicities (DLT). DLTs observed at 40 and 50 mg include fatigue (4 pt), thrombocytopenia (1 pt), GGT elevation (1 pt), AST/ALT elevation (1 pt), fever (1 pt), and pulmonary embolism (1 pt). One death was possibly related to LY intake. This pt, treated with 40 mg LY, developed on day 15 dyspnea, hypovolemic shock, and suddenly died. No grade 3 or 4 toxicities were reported at dose-levels < 40 mg. The most common adverse events were fatigue, vomiting, nausea, pyrexia, anorexia, and diarrhea. Two pts with mesothelioma were stable for > 9 months. One pt with refractory prostate cancer presented a PSA CR as assessed by investigator. The PK show dose-proportional increase in exposure of both LY and gemcitabine. Both LY and gemcitabine are rapidly cleared, thus no accumulation occurs. The metabolite dFdU accumulates due to its long half life. Conclusions: LY displays linear PK. The dose level of 50-mg is non-tolerable and 40-mg is being confirmed as the MTD as single agent and in combination with 100 mg erlotinib. Antitumor activity warrants further development. Pt accrual is ongoing.

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A phase I study of capecitabine, oxaliplatin (CapOx), and lapatinib (L) in metastatic or advanced solid tumors
Authors: Dennie T. , Alberti D. , Oliver K. , LoConte N. , Mulkerin D. , Wilding G. , Holen K. , Fleming R. , Bowen C. , O'Neill V.
Published: August 2020

2579

Background: CapOx is a standard treatment for patients (pts) with metastatic colorectal cancer (mCRC) and has been shown to be equivalent to FOLFOX in a phase III study. L is a tyrosine kinase inhibitor with targeting of the EGF and Her-2 receptors. Preclinical data suggest there may be synergy between L and Cap as well as L and Ox. This phase I study was designed to determine the maximum tolerated dose (MTD) of CapOx and L. Methods: Pts eligible for treatment included those with advanced or metastatic cancers, ECOG PS 2 or less, adequate renal and liver function, and ≤ 3 prior chemotherapy regimens. Treatment over a 21-day cycle was as follows: Ox, single IV infusion on Day 1; Cap, twice-daily oral administration on Days 1 through 14; L, continuous once-daily oral administration. Pts were treated with escalating doses of L (starting at 1000 mg daily) and Cap (starting at 1500 mg/m2/day), while Ox was kept at 130 mg/m2. The primary endpoint was determination of MTD. Results: Ten pts (9/10 female, median age 62 yrs.) were enrolled. One pt had breast cancer and the remainder had non- colorectal GI malignancies (esophagus, hepatobiliary, and pancreas). One pt at dose level 0 experienced dose-limiting toxicity (DLT) (dehydration, elevated bilirubin, hypokalemia). Two pts at dose level 1 (L 1000, Ox 130, Cap 2000) had DLTs of hypokalemia and diarrhea. At an intermediate dose level of L 1000, Cap 1700, Ox 130, two pts experienced DLTs (grade 2 fatigue/anorexia, grade 3 fatigue and dizziness). The MTD was determined to be L 1000 mg daily, Cap 1500 mg/m2/day, Ox 130 mg/m2. There were no treatment-related grade 4 toxicities. The most common grade 3 toxicity was diarrhea (4 pts). There were no grade 3 neuropathies, hematologic toxicities, or rash, and only one case of grade 3 fatigue. One pt with pancreatic cancer had a confirmed partial response (PR) to treatment, and 3 others had stable disease for > 90 days. Conclusions: The regimen of CapOx and L has efficacy in the treatment of solid tumors with established responsiveness to fluoropyrimidines or Ox. The MTD was L 1000 mg daily, Ox 130 mg/m2, and Cap 1500 mg/m2/day. This regimen will be investigated further in a Phase II study involving pts with mCRC.

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A phase I trial of TRU-016, an anti-CD37 small modular immunopharmaceutical (SMIP) in relapsed and refractory CLL
Authors: Andritsos L. , Furman R. , Flinn I. W. , Foreno-Torres A. , Flynn J. M. , Stromatt S. C. , Byrd J. C.
Published: August 2020

3017

Background: CD37 is a tetraspan family member expressed predominantly on normal and transformed B-cells across a wide range of maturational stages. TRU-016 is a novel humanized anti-CD37 SMIP. Pre-clinical studies have demonstrated CD37 SMIP mediates significantly greater direct and NK-cell mediated killing of CLL cells as compared to other therapeutic antibodies used in CLL. A phase I study with TRU-016 was initiated based upon these data. Methods: Patients with relapsed/refractory CLL or SLL who had adequate organ function, platelets > 30,000/mm3 were eligible. Six doses and two different schedules (cohorts 1–8) have/or will be studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses (cohort 1–6). The second schedule (cohort 7–8) will test 3.0 or 10.0 mg/kg on days 1, 3, and 5 the first week followed by 3 weekly doses. Dose escalation and de-escalation is based on CTC AE toxicity grades. Results: To date, 10 patients have been enrolled (cohort 1–5) and completed treatment; 1 patient (cohort 1–3: 0.03, 0.1, and 0.3 mg/kg); 3 patients at 1.0 mg/kg, and 4 patients at 3.0 mg/kg. Eight of the 10 have high risk genomic features [del(17p13.1), n=5 and del(11q22.3), n=3]. No dose limiting toxicities or serious adverse events have occurred. Mild (grade 1–2) infusion toxicity has been observed in 3 patients. Beginning with the 0.3 mg/kg dose, all eight patients demonstrated evidence of biological activity including patients with del(17p13.1). Two patients had partial clearing of leukemia cutis, and the other six had 27–94% reduction in peripheral lymphocyte count. One pt. had an increase in Hgb of 40% and a reduction in lymph nodes of 36%. Two patients had a significant increase in platelet count. Enrollment to cohort 6 is complete and further up-to-date data will be presented. Conclusions: To date, TRU-016 is a well tolerated treatment with minimal infusional toxicity and no observed dose limiting toxicity. Encouraging reduction in tumor lymphocyte blood counts, lymph node/spleen size and improvement in normal hematopoeitic function in patients with high risk genomic CLL have already been observed at low, non-saturating doses of CD37. Future single agent and combination studies of Tru16 in CLL are warranted.

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Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab
Authors: Berman D. M. , Wolchok J. , Weber J. , Hamid O. , O'Day S. , Chasalow S. D.
Published: August 2020

3020

Background: Ipilimumab, an anti-CTLA-4 monoclonal antibody, induces durable survival benefits in advanced melanoma pts. Peripheral ALC from routine safety labs were collected from 533 pts with unresectable stage III/IV malignant melanoma treated with ipilimumab 0.3, 3, or 10 mg/kg (recommended dose) in 4 Phase II studies. Methods: Ipilimumab was given every 3 weeks (Q3W) x 4; eligible pts could then continue to receive ipilimumab Q12W starting at Week 24. ALC was analyzed first in studies CA184007, 008, and 022 combined (ipilimumab 0.3, 3, or 10 mg/kg), and then prospectively analyzed for confirmation in study CA184004 (ipilimumab 3 or 10 mg/kg). Using the modified World Health Organization criteria, Response-evaluable pts (n = 444) were classified by clinical activity (complete or partial response, or stable disease ≥ 24 wks) or without clinical activity. Results: Across studies 007, 008, and 022, pts with clinical activity had a greater mean rate of ALC change (slope) than did pts without clinical activity (P = 0.0013); no pt with a negative ALC slope over the induction period had clinical activity (P = 0.0013) (Table). These associations were confirmed in 004; pts with benefit had a greater mean slope (P = 0.00042), and only 1 pt with a (slightly) negative ALC slope had clinical activity (Table). Over all pts (n = 533), the rate of ALC change was significantly associated with dose (007, 008, 022: P < 0.0001; 004: P = 0.0015). Conclusions: A higher rate of ALC change was associated with clinical activity in a pooled analysis of studies 007, 008, and 022 (n = 379). This was confirmed in study 004 (n = 65). A negative ALC slope was associated with a lack of clinical activity. In both analyses, the rate of change in ALC was dose-dependent, favoring 10 mg/kg.

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Effect of clinical status and previous treatment of melanoma patients on expansion of TIL for adoptive T-cell therapy
Authors: Peddareddigari V. R. , Miller P. W. , Nebiyou B. B. , Overwijk W. W. , Ross M. I. , Lee J. E. , Gershenwald J. E. , Prieto V. G. , Hwu P. , Radvanyi L.
Published: August 2020

3021

Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) is a promising therapy for the treatment of metastatic melanoma. Trials at the NCI have shown a 50% response rate. However, outside of the NCI, ACT has been quite limited and little is known about how patient characteristics and prior treatment affect large-scale TIL expansion needed for treatment. Methods: As part of a phase II melanoma ACT clinical trial at M. D. Anderson Cancer Center, we evaluated how clinical characteristics such as age, gender, biopsy site, melanoma type, primary tumor location, and prior treatment of patients (N=134) affected TIL expansion rates. 159 isolated metastatic melanomas (19 patients having >1 tumor harvest) were analyzed for the ability to expand a minimum of 40 million TIL, considered a minimum number for the subsequent rapid expansion protocol (REP) needed for TIL infusion. Effects of these parameters on TIL anti-tumor reactivity and TIL/tumor fragment were also analyzed. Statistical analysis was done by either Fisher's Exact test, Wilcoxon Rank Sum test, or Kruskal-Wallis Test. Results: 54.7% of the samples evaluated generated ≥ 40 million TIL, and 70% of 70 samples tested had anti-tumor reactive TIL. There was a significant relationship between age categories (p=0.0216) and gender (p=0.0164) on TIL expansion success. Younger patients did the best and females did better than males (odds 2.19, p=0.044). The site of the primary melanoma affected success of TIL expansion (p=0.0059), while no effect of tumor biopsy site and histological type was found. Prior chemotherapy (or biochemotherapy) greatly reduced TIL growth (odds 0.32, p=0.010) when compared to no prior therapy. Multivariate linear regression analyses showed that prior chemotherapy decreased TIL/tumor fragment yield by 6.19 million (p=0.0004) while immunotherapy increased it by 3.51 million (p=0.16) compared to no prior therapy. Total TIL yield or TIL/tumor fragment did not correlate with patient overall survival. Conclusions: Parameters such as age, sex, primary melanoma site, and prior therapy significantly affect TIL expansion and should be considered in selecting patients for melanoma ACT.

No significant financial relationships to disclose.