bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective phenotypic screening for DPD deficiency in patients upon fluoropyrimidines administration: Impact on the reduction of drug-induced toxicities
Authors: Mercier C. , Ciccolini J. , Dupuis C. , Secq V. , Padovani L. , Pignon T. , Dahan L. , Duffaud F. , Seitz J. , Lacarelle B. , Favre R.
Published: March 2020

2541

Background: DPD deficiency is a pharmacogenetic syndrome associated with severe toxicities upon 5-FU/capecitabine intake. To detect patients at risk upon fluoropyrimidines administration we developed a simple, rapid and inexpensive phenotypic method for DPD status evaluation. Here, clinical relevance of DPD deficiency a priori determination was studied. Methods: This method was used prospectively in 50 head and neck cancers patients (60±7 years, 37M/13F). Screening for DPD deficiency was performed prior to the beginning of the platinum + 5-FU (± radiation therapy) administration. DPD status was evaluated by HPLC monitoring U/UH2 ratio levels in plasma as a surrogate marker. Only 5-FU doses were adjusted according to the level of detected impairment (mild deficiency: -20%, severe: - 50%, total: no 5-FU). Drug-induced toxicities and subsequent impact on treatment schedule were carefully monitored next for comparison with a retrospective subset of 50 patients (mean age: 58±9 years, 40M/10F), treated with standard dosage of the same chemotherapy or radio- chemotherapy schedule. Results: DPD determination permitted the detection of 11 patients with DPD impairment out of 50 (22%). These 11 patients had their 5-FU doses customized and, consequently, neither severe toxicity nor delays in the administration radiation therapy or chemotherapy were reported in this group. Conversely, 7 out of 50 (14%) patients administered with standard dosage of 5-FU displayed severe toxicities (>grade-3, WHO grading), with subsequent postponement of the following courses. One patient (2%) did not recover from his toxicities. Of these 8 patients, retrospective determination of DPD status suggested impaired function in 7 of them (87%), including the toxic- death one. Conclusions: Although non randomized, this study suggests that prospective use of DPD status has an immediate clinical benefit by, reducing the drug-induced toxicities incidence in patients treated with 5-FU, and allowing an optimal administration of several courses in a row. Our preliminary results advocate systematic DPD status screening in patients eligible for treatment with fluoropyrimidine drugs. Survival and response study still on going.

No significant financial relationships to disclose.
Recombinant erythropoietin (Epo)/darbepoetin (Darb) associated venous thromboembolism (VTE) in the oncology setting: Findings from the Research on Adverse Drug Events And Reports (RADAR) project
Authors: Gleason K. , Tigue C. , Yarnold P. , McKoy J. , Angelotta C. , Courtney D. , Edwards B. , Bohlius J. , Bennett C.
Published: March 2020

2552

Background: Cancer patients are at increased risk for VTE as compared to the general population, making VTE as a sADR difficult to detect in the oncology setting. In 2004, two phase III trials identified higher mortality rates among epo-treated cancer patients who were receiving chemotherapy in “off-label” settings- with these studies identifying higher VTE rates in the treatment arms. We reviewed data on epo/darb-associated VTE in the oncology setting. Methods: Data sources were meta-analyses and the FDA’s MedWatch database. Results: Since 1996, only 259 VTE reports (darb: n=30, epo: n=229) of VTE in the setting of chemotherapy and epo/darb were reported to MedWatch. Meta-analyses findings are tabulated below: Conclusions: In 2004, package inserts for Epo/Darb were revised, identifying increased risks of VTE with these agents in the oncology setting. Identification of this adverse drug reaction thirteen years after Epo received FDA approval for this indication (and had been prescribed to > 500,000 cancer patients) illustrates difficulties inherent with current pharmacovigilance efforts.

[Table: see text]

No significant financial relationships to disclose.
A phase I study evaluating a novel schedule of oral eniluracil (EU) combined with escalating doses of oral 5-fluorouracil (5- FU)
Authors: Infante J. R. , Jones S. F. , Lawton M. , Wing P. , Malik R. K. , Peters W. P. , Burris H. A.
Published: March 2020

2560

Background: 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by dihydropyrimidine dehydrogenase (DPD), and requires anabolic conversion for anti-tumor activity. It has poor oral bioavailability due to DPD in the GI tract and liver, and toxicities such as hand-foot skin reaction. In addition, high levels of DPD are associated with 5-FU resistance. EU is a mechanism-based irreversible inactivator of DPD. Early studies in combination with oral 5-FU demonstrated activity; however, 3 Phase 3 studies were negative, due to an unrecognized inhibition of 5-FU anabolic activation by EU (Fourie et al; 2006 ASCO Proceedings; a 2058). Lower doses of eniluracil given 12–20 hrs prior to 5- FU preserves the desired DPD inhibition, without inhibiting these anabolic enzymes. Methods: The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and DPD activity in peripheral blood mononuclear cells (PBMCs) following administration of a fixed dose of EU in combination with escalating doses of 5-FU. The combination of oral 5.0 mg EU 12 to 20 hours prior to oral 5-FU, is given qW for 3 weeks in 28 day cycles. Results: Twenty subjects have been enrolled, at 5-FU doses of 30, 40, 50, 60, and 70 mg. A total of 39 cycles have been administered, with 4 patients currently on study. The oral combination of EU and 5-FU has been well tolerated. All toxicities have been grade 1 or 2 with the exception of two grade 3 toxicities reported at the 50mg dose (anemia and neutropenia). The grade 3 neutropenia is the only observed DLT and resulted in a 1 week delay in initiation of cycle 2. No CR or PR noted, but 4 patients (2 previously treated with 5-FU) with 4 cycles of SD. 95–100% of DPD inhibition achieved at the time of 5-FU dosing and PK results demonstrate a dose proportional increase in 5-FU Cmax and AUC, and a half life of ∼3.5 hours. Conclusions: The oral combination of 5mg of EU given 12–20 hrs prior to 5-FU has been well tolerated and achieves full functional inhibition of DPD in all patients. The MTD is not yet defined and the next cohort is enrolling at the 80mg dose. EU in combination with 5-FU may provide a promising therapeutic option for patients with tumors known to be resistant to 5-FU due to high levels of DPD.

No significant financial relationships to disclose.
Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors
Authors: Manda S. , Mauser C. , Bokar J. , Cooney M. , Brell J. , Krishnamurthi S. , Savvides P. , Ivy P. , Remick S. , Dowlati A.
Published: March 2020

2561

Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health.

No significant financial relationships to disclose.
Absorption, metabolism, and excretion of 14C gimatecan (LBQ707) after oral administration in patients with advanced cancer
Authors: Woo M. M. , Rodriguez L. , Gu H. , Crenshaw-Williams K. , Rocha F. , Freestone S. , Dickson J. , Jodrell D. , Mangold J. B.
Published: March 2020

2564

Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [14C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) Tmax for Gim was 1 h (0.5 to 3 h) and mean t1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development.

[Table: see text]
Phase I and pharmacological study of orally administered indibulin in advanced solid tumors
Authors: Oostendorp R. L. , Witteveen P. O. , Schwartz B. , Beijnen J. H. , Voest E. E. , Schellens J. H.
Published: March 2020

2565

Background: Indibulin (ZIO-301/D-24851) (N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid) a novel, oral, synthetic, anti-mitotic drug is widely active against human tumor cell lines and xenografts, including multidrug resistant and taxane refractory tumors. Indibulin destabilizes microtubule polymerization; its tubulin binding site is distinct from taxanes and vinca alkaloids. In preclinical studies indibulin lacks neurotoxicity typically associated with other tubulin binding drugs. Methods: Phase I study to evaluate safety, pharmacokinetics (PK), maximum tolerated dose (MTD) and dose limiting toxicity (DLT) in patients with advanced solid tumors. Initial dosing was in lactic acid drinking solution, which later was converted to a capsule formulation. Administration was po daily for 14 consecutive days at 21 day intervals at pre-determined dose increases between cohorts. Results: 31 patients (20 M, 11F) with advanced refractory cancers were treated; 14 received 20–80 mg/dose po in lactic acid solution and 17 po capsules 100–600 mg/dose. Median age was 60 y (29–72 y); median number of prior therapies was 4 (1–8); ECOG PS = 2. Median number of cycles was 2 (1–14). Patients continued on study until disease progression or significant toxicity. DLT for solution was nausea and emesis, ascribed to lactic acid. To date, no MTD or DLT observed with oral capsules at 600 mg daily; dose escalation continues using a twice daily schedule. No neurotoxicity has been observed. There was a disproportionate increase of the AUC with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. The terminal half-life at the 600 mg dose was 25.2 ± 2.4 h. Prolonged disease stabilization was seen in 2 adenoid cystic carcinoma patients for 3 and 14 months and in one prostate cancer patient for 5 months. The latter patient went off study after 5 months due to liver function disorder (ALT CTC grade 2 and AST grade 3). Conclusions: Indibulin was well tolerated at doses showing preliminary clinical activity. Target plasma concentrations above the IC50 have been achieved. Dose escalation twice daily continues. Prolonged disease stabilization was noted in adenoid cystic carcinoma and prostate cancer.

[Table: see text]
Time finding study of chronomodulated irinotecan (I), fluorouracil (F), leucovorin (L) and oxaliplatin (O) (chronoIFLO) against metastatic colorectal cancer: Results from randomized EORTC 05011 trial
Authors: Garufi C. , Focan C. , Tumolo S. , Coudert B. , Iacobelli S. , Tubiana N. , Marreaud S. , Lentz M. , Gorlia T. , Lévi F.
Published: March 2020

2566

Background: We previously showed that a) irinotecan (I) could be combined with chronoFLO in MMC patients; b) least toxic times (LTT) for combined I and oxaliplatin respectively correspond to the middle of the rest-phase and the middle of acivity-phase in tumor-bearing mice; c) chrono I showed adequate activity in a randomized phase II trial; and d) MMC resistance can be partly overcome with chronoIFL. Methods: The objective was to identify the LTT for I characterized by a minimal dose reduction/delay among the first 3 courses (c). Assuming that the toxic effect of I had a 24-h periodicity patients were randomized in 6 groups with I peak delivery (180 mg/m2, 6-h sinusoidal infusion on day 1) at 1:00, 5:00, 9:00 am, 1:00, 5:00, or 9:00 pm. . All the groups received also chronoFLO on days 2–5, q 3 weeks (F 700 mg/m2/d & L 150 mg/m2/d; from 22:15 to 9:45 with peak delivery at 4:00 , O 20 mg/m2/d from 10:15 to 21:45, with peak delivery at 16:00). Based on a logistic regression model, a 15% reduction in toxic events in the first 3 c, 186 patients were considered necessary to estimate the LTT with a 95% CI (calculated by bootsrap) of less than 6 h. Results: 197 of 199 randomized MMC patients were considered for tolerability and safety with median age 61 years (30–81), sex (M 68% - F 32%) and PS (0/1/2 73/23/4%); therapy was 1st line in 77 patients and 2nd line in 23%. Thithy-one percent of severe protocol violations occurred, 16% of pump malfunctions (>10% dose delivery deviation). Median number of c was 6 (1–18). There were 3 toxic deaths. The observed LTT for I tolerability was 3:15 am (95 CI: 3:40–1:50 pm, NS). Grade 3–4 diarrhea ranged from 34 to 51.6% with LTT at 1:53 pm (4:29 -2:53 am, not significant, NS); neutropenia from 9 to 25% with LTT at 3:26 pm (10:50 - 4:55 am, NS). Age was a negative prognostic factor for diarrhea (p =0.01). Conclusion: This trial failed to show a statistically significant LTT for this combination in MCC patients. The safety profile of I combined with ChronoIFLO was acceptable, with diarrhea and neutropenia within previously reported range.

No significant financial relationships to disclose.
Prognostic factors for cancer patients with good performance status considered for inclusion in phase I clinical trials
Authors: Bonneterre M. , Penel N. , Vanseymortier M. , Dansin E. , Clisant S. , Vendel Y. , Degardin M. , Adenis A. , Beuscart R. , Bonneterre J.
Published: March 2020

2568

Background: For investigators, the selection of patients to be considered for phase I clinical trials is difficult, because of the lack of objective criteria for a rational decision-making process. From October 1997 to October 2002, we retrospectively assessed prognostic factors for cancer patients considered for Phase 1 trials. Methods: 148 consecutive patients who had been screened for inclusion in 6 different phase I trials were included in the present study. 70 out of them actually received the phase I treatment. Univariate (Log-Rank test) and multivariate analysis (Cox proportional hazard ratio model) were performed to determine the prognostic factors related to overall survival (OS) after screening. Results: The study comprised 63 men and 85 women, with a median age of 54 (range 23–79). The most frequent primary cancer sites were: breast (38 cases), head and neck (28 cases), lung (18 cases) and colorectal (17 cases). 91 out of them had a performance status PS = 0. The median OS of the 148 patients was 5.7 months (173 days, range 1–2,421). Univariate analysis identified PS = 1, Body Mass Index < 20, liver and visceral metastasis, serum albumin < 38 g/L, lymphocytes count < 0.7 x 109/L and granulocytes count > 7.5 x 109/L as poor prognostic factors. The Cox model identified serum albumin < 38 g/L (HR 2.51 [1.51–4.18], p=0.0001) and lymphocyte count < 0.7 x 109/L (HR 2.27 [1.13–4.62], p=0.024) as independent prognostic variables for OS. All patients presenting with both prognostic factors died within 90 days. Conclusion: We propose a simple model, easily obtained at the patient bedside, which can discriminate patients who have a life expectancy of over 3 months and thus could be enrolled in phase-I anti-cancer trials.

No significant financial relationships to disclose.
A phase I dose escalation study of selenomethionine (SLM) in combination with fixed dose irinotecan (Iri) in patients with solid tumors
Authors: Rustum Y. , Pendyala L. , Creaven P. , Ross M. , Brady W. , Badmaev V. , Prey J. , Fakih M. G.
Published: March 2020

2574

Background: SLM reduces Iri toxicity in xenograft models at associated selenium (Se) concentrations (Con) = 15μM. We conducted a phase I clinical trial of a fixed dose Iri with escalating doses of SLM in order to identify the highest safe dose of SLM that achieves and maintains Se Conc > 15μM. Methods: A standard 3–3 escalation was conducted. Iri was given at 125mg/m2/week x 4 weeks every 6 weeks. SLM was started 1 week prior to 1st dose of Iri. A loading BID dose of SLM was given for 1 week, followed by a daily maintenance dose. Selenium trough levels were obtained on days 8 and 29 of the study (days 1 and 22 irinotecan) and once every 6 week-cycle. Seven dose-levels of SLM were investigated (loading/maintenance, in mcg): 3,200/2,800, 3,200/3,200, 4,000/3,200, 4,000/4,000, 4,800/4,800, 5,600/5,600, and 7,200/7,200. Results: 31 patients enrolled on this study: age (median 57, range 21–80), Male/Female 21/10, ECOG 0/1 (15/16), 31 with prior chemotherapy, 12 with prior radiation, 22 colorectal and 9 mixed solids. Dose escalation was successful up to dose level 7 (7,200mcg SLM PO BID × 1 week followed by 7,200mcg SLM PO QD), which was declared the recommended dose. 2 Dose limiting toxicities occurred on study: one DLT of Grade (G) 3 febrile neutropenia, G3 sepsis, G3 dehydration occurred on dose-level 1; one DLT of G3 febrile neutropenia, dehydration occurred on dose-level 7. Both DLT occurred in a setting of partial small bowel obstruction related to peritoneal carcinomatosis. Non-DLT = G3 treatment-related toxicities included: 3 G3 neutropenia (< 1 week) at DL2, 3 & 7; 2 G3 diarrhea lasting < 48 hours on DL5 & 7. A lower incidence of G2+ toxicities was noted in patients with higher Se Conc (86% for Se < 15; 67% for Se 15–20; 57% for Se> 20 μM). Toxicities related to SLM were limited to garlic-like smell to breath, sweat, and urine in few patients. Responses included 7 confirmed stable diseases and 2 confirmed partial responses. A Se Con > 15 μM was achieved at all SLM dose levels of 4,800 mcg and above. Conclusions: Doses of SLM up to 7,200 mcg BID × 7 days followed by 7,200 mcg QD can be administered safely with standard doses of Iri. Formal phase II and III studies are needed to determine if SLM reduces Iri toxicity.

No significant financial relationships to disclose.
A phase I study of TPI287: A third generation taxane administered weekly in patients with advanced cancer
Authors: Hwang J. J. , Marshall J. L. , Ahmed T. , Chun H. , Basche M. , Cohn A. , Kurman M. , Tapolsky G. , Tapolsky G. , Allen E.
Published: March 2020

2575

Background: TPI 287 is an investigational taxane designed to not be a substrate for mdr-1 and to bind to mutant tubulin. In preclinical studies, TPI 287 demonstrated activity against multiple human tumor xenografts in nude mice, including xenografts that expressed mdr-1 and that were resistant to other taxanes. The safety and tolerability of TPI 287 when administered weekly for 3 weeks followed by a 1 week rest (4 week cycle) was examined in this Phase 1 dose escalation study in patients (pts) with advanced neoplasms. Materials and Methods: TPI 287 was administered over 1 hour weekly for 3 weeks followed by 1 week of no treatment. Treatment cohorts consisted of 3 pts and were expanded to 6 pts in the face of dose-limiting toxicity (DLT); pts could remain on study until the development of progressive disease or an intolerable adverse event. DLT was defined as Gr 4 heme toxicity lasting 7 days; febrile neutropenia, Gr 3 thrombocytopenia with bleeding, Gr 3 elevation of transaminases lasting 7 days or any other Gr 3/4 toxicity other than nausea or vomiting. Results: 25 pts (M:F 16:9, median age 60, range 24 - 86) were enrolled in 7 dose levels ranging from 7–185 mg/m2. Pts’ cancers included colorectal (6 pts); NSCLC (2); prostate (2); squamous cell carcinoma (2) and 1 pt each with cervical, breast, ovarian, gastric, pancreatic, bladder endometrial, NSCLC, SCLC, glioblastoma, melanoma, renal cell and hepatocellular carcinoma. All pts but 1 had received prior chemotherapy (median no. prior treatments: 3 (range, 1–7). Drug related adverse events included nausea, vomiting, diarrhea, fatigue, anorexia, rash, anemia and peripheral neuropathy. 1 pt., who was inadvertently treated with inadequate marrow reserve, experienced Gr 4 neutropenia and died of sepsis. DLT of Grade 3 peripheral neuropathy has been observed. PK data to date reveal that AUC is generally dose linear. At a dose of 127.5 mg/m2, clearance was 30.2 + 11.9 L/hr/m2 and t1/2 8.6 + 1.3 hrs. Results are similar with non-compartmental methods and 2-compartment modeling. Conclusions: TPI 287 can be safely administered in doses of up to 127.5 mg/m2 weekly x 3.

No significant financial relationships to disclose.
A phase I study of EC145 administered weeks 1 and 3 of a 4-week cycle in patients with refractory solid tumors
Authors: Sausville E. , LoRusso P. , Quinn M. , Forman K. , Leamon C. , Morganstern D. , Bever S. , Messmann R.
Published: March 2020

2577

Background: Folic acid is internalized via two main pathways; a reduced folate carrier (RFC) or a folate-specific receptor (FR). While FR is minimally distributed in normal tissues, it is over-expressed in many human tumors, including cancers of the ovary, lung and kidney. Experimental data indicate that EC145, a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), is a high-affinity ligand for the folate receptor (FR) but not for RFC. EC145 is also highly active against FR-positive KB tumors in vivo. This phase I trial assessed the safety and pharmacokinetics (PK) of escalating bolus doses of EC145. Methods: The phase I study treated eligible patients with EC145 as an intravenous bolus according to a ‘flat dose‘ escalation plan on days 1, 3, 5 (week 1) and 15, 17, 19 (week 3) of a 4-week cycle. Endpoints included determination of a safe and tolerable EC145 dose, development of a PK model, and identification of antitumor activity. Results: As of Dec 2006, 16 patients had received bolus EC145 (1.2, 2.5 or 4 mg; n = 3, 11 and 2, respectively). EC145 was generally well tolerated at bolus doses < 2.5 mg with one patient continuing on study for 6 cycles. Overall, the most common side effects were fatigue (n = 9), constipation (n = 7) and neuropathy (n = 6). DLT at 4 mg included reversible ileus and neuropathy. Formal PK analysis will be available at the time of presentation. One patient has had a minor response and another has exhibited disease stabilization > 5 months (both ovarian cancer patients). Upon declaration of the bolus MTD, the trial was amended to explore the utility of a 1-hour EC145 infusion to take full advantage of potential high affinity interaction between EC145 and the FR to effect drug targeting. As of Jan 2, 2007, three patients had been accrued to a dose level of 2.5 mg over 1 hr, and all tolerated the therapy without significant toxicity. Conclusions: EC145 may be administered safely as a 2.5 mg intravenous bolus dose on days 1, 3, 5 (week 1) and 15, 17, 19 (week 3) of a 28-day schedule.

No significant financial relationships to disclose.
Pharmacokinetics (PK) of split-dose flavopiridol (F) administered with CPT-11 (CPT) and cisplatin (Cis)
Authors: Carvajal R. D. , Tse A. , Wu N. , Gonen M. , Lefkowitz R. , Dials H. , Barbi A. , Mui J. , Schwartz G. K. , Shah M.
Published: March 2020

2578

Background: F, a cyclin-dependent kinase inhibitor, induces tumor lysis in CLL when administered as a 30 mg/m2 loading dose over 0.5h followed by a 30 mg/m2 maintenance dose over 4h (hybrid F; Byrd et al, Blood 2006). F given as a 1h bolus (bolus F) demonstrates promising clinical activity when combined with CPT in solid tumors (Shah et al, CCR 2005). Data suggest that F concentrations of 2–3 μM are required to enhance the effects of CPT in solid tumors (Motwani et al, CCR 2001), but controversy exists over the optimal F schedule for chemotherapy potentiation. Methods: We are conducting a phase I trial of CPT/Cis→F, with F administered on both a bolus F and hybrid F schedule. After identifying the maximum tolerated dose (MTD) of bolus F (CPT/Cis→F 50mg/m2), the hybrid F schedule was examined. The F loading dose was escalated from 20→30mg/m2 and the F maintenance dose escalated from 20→50mg/m2. Plasma samples were obtained from patients (pts) treated with bolus F at the MTD and with hybrid F at all dose levels. To better assess F PK interaction with CPT/Cis, F was given before CPT/Cis on cycle 2 only. Results: Complete PK data are available from 6 pts treated at the bolus F MTD (50 mg/m2) and on 20 pts treated with hybrid F (20→20 mg/m2, 25→25 mg/m2 and 30→30 mg/m2) for cycles 1 and 2. Both bolus F and hybrid F PK are consistent with data previously reported. Although cycle 1 AUCs are similar for bolus F 50 mg/m2 and hybrid F 30→30 mg/m2 (10.47±4.97 vs 10.75±15.14 μM/h, p=NS), the Cmax achieved with bolus F 50 mg/m2 is significantly greater than that achieved with hybrid F 30→30 mg/m2 (2.31±0.65 vs 1.21±0.35 μM, p<0.02). No significant PK differences occurred between cycles 1 and 2. Toxicity was not associated with F Cmax. With CPT/Cis→bolus F, the PR rate was 10/29 (35%) vs 3/33 (9%) with CPT/Cis→hybrid F. Conclusions: The Cmax achieved with bolus F is greater than that achieved with hybrid F, with no increase in toxicity. Additionally, the Cmax achieved with hybrid F does not exceed the 2 μM plasma concentration required for potentiation of chemotherapy-induced apoptosis. The greater number of responses achieved with bolus F suggests that bolus F may be more efficacious than hybrid F when used in combination with CPT for the treatment of solid tumors. (Supported by R01-CA67819)

No significant financial relationships to disclose.
Comparing immunogenicities of tumor-specific antigens administered as therapeutic vaccines in metastatic melanoma patients
Authors: Baurain J. , Stas M. , Neyns B. , Schuler G. , Velu T. , Thielemans K. , Van Baren N. , Dorval T. , Marchand M. , Coulie P.
Published: March 2020

3003

Background: Therapeutic vaccination of metastatic melanoma patients with detectable disease is followed by some tumor regression in only about 10% of the patients, with no clear difference observed between studies carried out with various tumor-specific antigens and vaccination modalities. For antigenic peptide MAGE-A3168–176, presented by HLA-A1 molecules and administered as peptide alone or recombinant ALVAC poxvirus, anti-vaccine T lymphocyte (CTL) responses have been observed in no progressor patient and in only half of the regressors, suggesting a poor immunogenicity of these vaccines. Methods and Results: We compiled anti-vaccine CTL responses measured in the blood of 202 metastatic melanoma patients vaccinated with various associations of 10 different tumor antigens administered as peptides, alone or with adjuvant, recombinant ALVAC poxvirus, or peptide-pulsed dendritic cells. Blood lymphocytes collected before and after vaccination were all analyzed with the same method involving in vitro restimulation in limiting dilution condition followed by labeling with tetramers for each antigen. A CTL response was deemed to have occurred if the CTL frequency increased by at least 10 times, and if the pre-vaccination frequency was lower than 2 x 10-6 of the CD8 cells. No responses were detected against peptides MAGE- A4230–239 (0/26) and MAGE-C2336–344 (0/22). Some were observed against MAGE-A3168–176 (11/81), MAGE-A1278–286 (2/22), MAGE-A3112–120 (2/55), and MAGE-A10254–262 (2/35). Responses were frequently found against NY-ESO-1157–165 (10/19), GnTVVLPDVFIRC (18/73), gp100209–217 (21/33), or Tyrosinase369–377 (11/59). For the latter four antigens, there was no correlation between the occurrence of CTL responses and that of tumor regressions. Neither did we find a correlation between the CTL responses and the expression of the antigen-encoding genes in pre- vaccination tumor samples. Conclusions: These results suggest that some of the antigenic peptides that are commonly used in melanoma vaccines are more immunogenic than others but do not induce more tumor regressions. Therefore, inducing strong CTL responses against these immunogenic peptides is probably not the most appropriate endpoint of future vaccine trials.

No significant financial relationships to disclose.
Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma
Authors: Wolchok J. D. , Gallardo H. , Perales M. , Rasalan T. , Wang J. , Chapman P. B. , Krown S. E. , Livingston P. O. , Heywood M. , Yuan J.
Published: March 2020

3005

Background: T-cell and antibody responses to self antigens on cancer are usually constrained by immunologic tolerance and ignorance. We found that DNA vaccines encoding xenogeneic differentiation antigens, such as tyrosinase (TYR), can mediate tumor protection and regression in implantable mouse models and dogs with spontaneously arising melanoma. Based on this, we conducted a trial of DNA vaccines encoding mouse and human TYR in patients with AJCC stage III/IV melanoma. Methods: HLA-A*0201+ melanoma patients were randomized to 2 different schedules: one group received 3 injections of mouse TYR DNA followed by 3 injections of human TYR DNA while the other group received 3 injections of human TYR DNA followed by 3 injections with the mouse gene. The study was conducted a three different dose levels: 100, 500 and 1,500 mcg DNA/injection, administered IM every 3 weeks. A total of 18 patients were treated, 6 at each dose level being randomized to one of the two schedules. Anti-TYR antibodies and CD8+ T cells recognizing the native human tyrosinase369-377 (YMDGTMSQV) peptide were measured at fixed time points. T-cell responses were monitored with MHC tetramer and intracytoplasmic IFN-γ staining assays using 10-day in vitro stimulation. Multiparametric flow cytometry was performed to further define the phenotype of responding cells. Results: Most toxicities were transient grade I injection site reactions. Seven patients had CD8+ T cell responses, defined as a >3 standard deviation increase in baseline reactivity to the TYR peptide in either the tetramer or intracellular IFN-γ assay. There was no relationship between dose level or assigned schedule and occurrence of T-cell response. Phenotypic characterization of responding T cells showed that most were consistent with an effector memory phenotype including the expression of granzyme B and surface expression of CD107a. No antibody responses were observed. At a median of 42 months of follow-up, median survival has not been reached and 6/18 patients have died from melanoma (1 in the group of patients who had a T cell response and 5 in the non-responders). Conclusions: Mouse and human TYR DNA vaccines were safe and induced CD8+ T cell responses in 7/18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells.

No significant financial relationships to disclose.
Human papillomavirus (HPV) 16/18 l1 AS04 virus-like particle (VLP) cervical cancer vaccine is immunogenic and well-tolerated 18 months after vaccination in women up to age 55 years
Authors: Schwarz T. F. , Dubin G.
Published: March 2020

3007

Background: Although prevalence of oncogenic HPV infection is highest in women younger than 25, incident infection is estimated to occur in 5% - 10% of women aged 25–55. New infections decrease with age, but the proportion that persists is higher. Therefore, women over 25 also may benefit from HPV vaccination. In a primary Phase III study (GSK 105879/014), an HPV-16/18 AS04 cervical cancer vaccine candidate was highly immunogenic and well tolerated in women up to age 55. This extension study evaluates the persistence of immune response and safety through 18 months after the first vaccine dose. Methods: Healthy women aged 15–55 years in Germany and Poland who had received 3 doses of HPV-16/18 L1 AS04 VLP vaccine at months 0, 1, and 6 in the primary study were invited to participate in a follow-up extension (15–25 years [n=169], 26–35 years [n=83], 36–45 years [n=89], and 46–55 years [n=176]). Immunogenicity and safety were assessed up to 18 months after vaccination. Results: At 18 months, 100% of subjects remained seropositive for both antigens in all age groups. For HPV-16, GMCs were 2,220.1 in women 15–25, 1,276.9 in women 26–35, 905.6 in women 36–45, and 809.0 in women 46–55. For HPV-18, GMCs were 828.2 in women 15–25, 441.8 in women 26–35, 289.7 in women 36–45, and 275.5 in women 46–55. In women over 25, GMCs tended to be higher in those initially seropositive. In the oldest age group, HPV-16 and HPV-18 GMCs remained at least 10-fold higher than natural infection levels reported in another study.The HPV-16/18 AS04 vaccine was well tolerated among all age groups. Conclusions: The HPV-16/18 AS04 vaccine candidate was highly immunogenic and well-tolerated. As with other vaccines, an age- dependent decrease in GMCs was observed, but GMCs remained substantially higher than natural infection levels previously reported in women 15–25. More importantly, GMCs at month 18 for women over 25 remained in the same range as GMCs observed in another study in women 15- 25 that were associated with sustained efficacy up to 4.5 years. Thus, in women up to age 55, an HPV-16/18 AS04 vaccine may protect against new infections with oncogenic HPV types that can cause cervical cancer.

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Phase II trial of patients (pts) with extensive stage small cell lung cancer (ES-SCLC) immunized with p53-transduced dendritic cells (p53-DC): Immune sensitization to chemotherapy (CT)
Authors: Chiappori A. , Sereno M. , Gabrilovich D. , Mirza N. , Dunn M. , Janssen W. , Smilee R. , Menander K. , Chada S. , Antonia S.
Published: March 2020

3012

Background: Although ES-SCLC is initially, very responsive to CT, responses are not durable and relapse is characterized by chemoresistance. High incidence of p53 gene mutations, which prolong the protein’s half life, result in its frequent overexpression and enhanced detection in SCLC cells. This in turn allows for their recognition by p53-specific cytotoxic T cells. Here, we evaluated the clinical and immune response of a vaccine (vac) using p53-DC. Methods: Eligibility: Untreated, ES-SCLC pts. Age = 18 years. Performance status (PS) 0–2. Treated and controlled brain metastases. Adequate renal, hepatic and bone marrow function. Toxicity (T), survival (MST) and clinical and p53- specific immune responses were determined by CTCAE v2.0, Kaplan-Meier, RECIST and ELISPOT and tetramer staining respectively. Pts first received CT to best clinical response. Eight weeks later, those with minor progression (PD) or better, underwent leukapheresis. DC, generated from peripheral blood precursors, were infected with an adenoviral construct containing p53 (Advexin; Ad-p53) to produce the p53-DC vac. Each vaccination consisted of subcutaneous injections in 4 different nodal basins every 2 weeks x3 (2–5×106 p53-DC/dose). Results: Thirty-six pts received at least one vac; median age=58.8, (range=39–79), M/F=13/23, PS 0/1=16/20. All pts were evaluable for T and MST. Total vac=127 (median=3, range=2–6). Overall, vac was well tolerated (no > grade 2 toxicities detected). p53-specific immune response was positive in 11/21 (52.4%) pts; pending in 15 pts. After 3 vac doses, 10 (27.7%) pts. had stable disease (SD) and 26 (72.2%) had PD. Pts with SD were re-vaccinated (x3). Upon PD, all pts were offered further CT. Clinical response to post-vac CT was evaluated in 22 pts. Ten pts (45%) responded to post-vac CT (second line=7, third line=3) and 6 pts had SD. MST=473 days (95% CI: 380,534). Conclusions: ES-SCLC pts were treated safely with p53-DC vaccine and demonstrated significant immune response. The p53-DC vaccine appears to sensitize ES-SCLC to subsequent CT resulting in improved survival.

[Table: see text]
Interferon-alpha-2b induced signal transduction and gene regulation in patient immune cells is not enhanced by a dose increase from 5 MU/m2 to 10 MU/m2
Authors: Zimmerer J. M. , Lehman A. , Ruppert A. , Olencki T. , Kendra K. , Walker M. J. , Carson W. E.
Published: March 2020

3026

Background: High dose interferon-alpha-2b (IFN-a) is employed as an adjuvant in melanoma patients who have had surgery for high-risk lesions. It mediates its anti-tumor effects via activation of the transcription factor STAT1 (signal transducer and activator of transcription) within host immune cells. We hypothesized that intermediate doses of IFN-a would be just as effective as higher doses in stimulating the activation of STAT1 and gene transcription in immune cells. Methods: Samples for analysis were obtained from patients with metastatic melanoma who were enrolled in a clinical trial of bevacizumab in combination with escalating doses of IFN-a (5 MU/m^2 and then 10 MU/m^2). Peripheral blood mononuclear cells (PBMCs) were procured before and 1 hour after the administration of IFN-a and analyzed for the presence of phosphorylated STAT1 (P-STAT1) and P-STAT2 by intracellular flow cytometric analysis and the induction of interferon stimulated gene (ISG) transcripts by Real Time PCR. Results: P-STAT1 in response to 5 MU/m^2 IFN-a was higher than that for the 10 MU/m^2 dose (p = 0.0617). The 5 MU/m^2 dose also led to a greater activation of STAT2 (p = 0.0388). The induction of interferon stimulated genes (ISGs; IFIT1, IFIT2, OAS3) within PBMCs was not enhanced following the increase in IFN-a dose to 10 MU/m^2 at 2 weeks although inhibitors of IFN-a-signaling (SOCS1 and SOCS3) were activated to a greater degree. In addition, microarray analysis was performed on 4 patients and revealed that only one of 36 interferon regulated genes was expressed to a greater extent following treatment with 10 MU/m^2 IFN-a as compared to 5 MU/m^2. Conclusions: These results suggest that 5 MU/m^2 of IFN-a are as effective as higher doses with respect to the induction of STAT signal transduction and ISGs within immune effector cells.

No significant financial relationships to disclose.
The response of IFNAR2 to high-dose IFNα2b during a neoadjuvant clinical trial
Authors: Wang W. , Edington H. , Rao U. , Jukic D. , Land S. , Kirkwood J. M.
Published: March 2020

3027

Background: The appropriate subgroup of melanoma patients to select for high-dose IFNa2b (HDI) adjuvant therapy has been undefined since approval of this modality in 1996. A biomarker appropriate for clinical practice and relevant to the biological effects of this agent would be of great importance. IFNAR2 is required for type I IFN-dependent signaling. Therefore, the response of IFNAR2 during HDI was evaluated during a prospective neoadjuvant clinical trial of HDI. Methods: Following diagnostic biopsy and before definitive surgery, HDI was administered as a neoadjuvant therapy for patients with stage IIIB melanoma, in the context of an IRB-approved protocol UPCI 00- 008, separately reported. Immunohistochemical analysis of IFNAR2 was performed on fixed paired biopsies of 8 patients. Paired-sample permutation tests and two-sample permutation tests were used to evaluate the findings of this study. Mean values of the percentage of IFNAR2 positive cells are presented with standard errors (SE). Results: HDI down-regulates IFNAR2 in both responders and non- responders, from 86.875 ± 5.82 (pre-treatment) to 34.375 ± 9.919 (post-treatment), p = 0.0145. However, the decrease in IFNAR2 differs between responders (25.0 ± 12.583) and non-responders (69.0 ± 3.588), p = 0.021. Conclusions: HDI down-regulates IFNAR2 expression, and may provide a biomarker relevant to HDI benefit, given differences between patients with and without response to neoadjuvant therapy. A larger clinical trial is needed to evaluate these pilot data.

No significant financial relationships to disclose.
Humanized anti-CEACAM6 PEGylated scFv: A promising novel therapy for pancreatic cancer
Authors: Mahadevan D. , Garewal H. , Riley C. , Zhu Y. , Engelhardt K. , Cooke L. , Nagle R. , Saldanha J. , Von Hoff D.
Published: March 2020

3042

Background: Novel Therapies for pancreatic cancer (PC) based on biological insight are urgently needed. CEACAM6, a member of the carcinoembryonic antigen (CEA) family, is a cell surface oncogene on PC cells. It is a glycoprotein composed of 3 Ig-like domains (Mr ∼35.2kD) and is linked to the plasma membrane via a glycophospholipid linked anchor. It is over-expressed on ≥95% PC patients’ found irrespective of stage of disease and represents a target for antibody therapy. Methods: Murine anti-CEACAM6 monoclonal antibody (Mab) 13–1 was humanized by a structure-based approach and single chain variable fragments (scFv) designed consisting of a Gly/Ser-linker which includes a cysteine residue for PEGylation. Murine scFv and 4 humanized scFv fragments (Version.1, 2, 7, 8) were bacterially expressed, purified, PEGylated and evaluated for activity alone or in combination with gemcitabine in human PC cell lines and mouse xenograft tumors. Cell viability, apoptosis and in-cell Westerns were done for efficacy and binding. Mouse xenograft tumors were treated with scFv or PEGylated scFv or combination with gemcitabine. Tumors (treated Vs untreated) were analyzed by immunohistochemistry for Ki-67, CD31, CEACAM6 and Caspase 3 Results: Mab 13–1, murine and 4 humanized scFvs’ were cytotoxic to CEACAM6 expressing PC cells (BxPC-3, HPAF-2) and not to PC cells that lack CEACAM6 (CaPan-2) with increased PARP-cleavage that was dose dependent (IC50=10μg/mL). Western blotting of culture media and serum from xenograft mice showed that CEACAM6 is not shed. In-cell Western confirmed humanized V.7 to be the best binder (KD=1–10μg/mL) confirming protein-protein interaction studies performed in silico with homology models of murine and humanized scFvs’ and CEACAM6. The murine scFv alone or the humanized scFV (V.8) in combination with gemcitabine delayed tumor growth by >50%. This tumor reduction correlated well with the immunohistochemical markers of response. Conclusions: We have demonstrated that CEACAM6 is a clinically relevant target in PC and that a PEGylated humanized scFv is a novel effective therapy alone and/or in combination with gemcitabine. Humanized scFv V.7 is undergoing mouse xenograft evaluation and expect will be the most effective agent to take forward into clinical development.

No significant financial relationships to disclose.
Combined neoadjuvant weekly paclitaxel and trastuzumab for HER2-overexpressing breast cancer
Authors: Horiguchi J. , Koibuchi Y. , Rokutanda N. , Nagaoka R. , Kikuchi M. , Sato A. , Ishikawa Y. , Odawara H. , Iino Y. , Takeyoshi I.
Published: March 2020

3045

Background: The purpose of this study is to determine the clinical efficacy of neoadjuvant paclitaxel and trastuzumab in women with advanced breast cancer, with or without metastatic disease. Methods: Patients with HER2-positive breast cancer (clinical stage IIB-IV) were included in this study. The patients received trastuzumab 4mg/kg loading dose intravenously then 2mg/kg weekly and concurrently paclitaxel 80mg/m2 (Day 1, 8, 15) weekly for 4 cycles followed by surgery. Results: Preliminary results from 15 patients are reported. Of these, six patients (40%) had a clinical complete response and nine patients (60%) a clinical partial response. Fourteen of 15 patients received surgery; eight breast-conserving surgery and six modified radical mastectomy. Six patients (43%) had pathological complete response. With a median follow-up of 19 months (range, 5–32 months), these 15 patients are alive. Patients with clinical stage IIB-III breast cancer are alive without any distant metastasis. Conclusion: Combined neoadjuvant weekly paclitaxel and trastuzumab had high clinical and pathological response rates for HER2 overexpressing breast cancer.

No significant financial relationships to disclose.