Piens, Jill

AbstractIntroductionNasal symptoms are frequently reported by patients undergoing chemotherapy.MethodsEligible patients planning to receive paclitaxel, docetaxel, nab‐paclitaxel, bevacizumab without a concomitant taxane, or “other” (non‐taxane, non‐bevacizumab) chemotherapy regimens were invited to participate in this prospective study. Patients reported nasal symptoms prior to each dose of chemotherapy.ResultsThe percentage of patients (95% CI) who reported nasal symptoms was the same for patients who received bevacizumab or nab‐paclitaxel, 82.6% (61.2%, 95.1%). There were no significant differences among the proportions of patients experiencing nasal symptoms within the paclitaxel, nab‐paclitaxel, and bevacizumab cohorts. Patients in the nab‐paclitaxel cohort were more likely to experience symptoms than those in the non‐taxane non‐bevacizumab cohort or docetaxel cohort (p = 0.001, p = 0.001). Patients in the bevacizumab cohort were more likely to experience nasal symptoms than those in the non‐taxane non‐bevacizumab cohort (p = 0.03).ConclusionNasal vestibulitis symptoms are common in patients receiving chemotherapy, especially those receiving paclitaxel, docetaxel, and bevacizumab. Further investigations into treatments of this symptom complex are warranted.

e24086 Background: Nasal vestibulitis has been infrequently described as a side effect of cancer-directed therapy; however, a preliminary study reported that 71% of patients undergoing taxane chemotherapy experienced nasal vestibulitis symptoms. This natural history trial describes the incidence, characteristics, and severity of nasal vestibulitis symptoms among patients undergoing paclitaxel, docetaxel, and non-taxane chemotherapy. Methods: Eligible participants who reported baseline (prior to starting chemotherapy) nasal symptoms ≤ 2 on a 10-point scale were enrolled in this trial upon initiation of a new treatment regimen, involving paclitaxel or docetaxel, or non-taxane chemotherapy. Participants completed nasal symptom logs each time they received a dose of therapy until either the regimen was stopped or four months had passed. The proportion of patients reporting new nasal symptoms was estimated within each cohort with the 95% exact confidence interval (CI). A cumulative incidence model was utilized to quantify the incidence of treatment-emergent nasal symptoms within each cohort, while controlling for age, sex, smoking history, and history of asthma or allergies. Results: Thirty-five participants received paclitaxel, 21 received docetaxel, and 25 received other types of chemotherapy. 86.4% of participants were female, mean age was 60.2 ± 11.2 years; 93.8% of participants completed 2 or more surveys. A higher percentage of participants in the paclitaxel cohort experienced new nasal vestibulitis symptoms than participants in the other two cohorts. The percentage (95% CI) of participants with nasal symptoms, for patients receiving paclitaxel, docetaxel, and non-taxane chemotherapy were 74.3% (56.7%, 87.5%), 47.6% (25.7%, 70.2%), and 44.0% (24.4%, 65.1%), respectively. Epistaxis was reported by 60% of participants in the paclitaxel cohort. Paclitaxel-receiving participants also reported nasal dryness (48.6%), scabbing (40.0%), and pain (20.0%). Nearly half of participants reported moderate symptoms (4-7 out of a 10-point scale), with 8.6% reporting symptoms as severe (8-10 on a 10-point scale). Conclusions: Nasal vestibulitis is a common side effect of chemotherapy, especially paclitaxel chemotherapy.

3044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumor cell growth, angiogenesis, and metastasis, including EGFR (erbB1), erbB2, VEGFR2/KDR, and EphB4. Methods: Patients (pts) with ASM were enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with PK sampling, followed by 5 continuous daily doses starting on day 4 with additional PK sampling. Pts then continued to receive XL647 for 5 consecutive days, followed by a break, with cycles repeating every 14 days. Tumor imaging was conducted at baseline, after the first 3 or 4 cycles, and then after every 4 cycles. Pts were allowed to stay on-study in the absence of unacceptable toxicity until evidence of disease progression. Results: A total of 37 pts have been treated across 9 dose levels to date: 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12, 4.68, and 7.0 mg/kg. One pt at 3.12 mg/kg had a dose limiting toxicity (DLT) of asymptomatic QTc prolongation on electrocardiogram, resulting in expansion of that cohort. The first two pts who received 7.0 mg/kg experienced DLTs of grade 3 diarrhea, requiring dose reduction. Both pts from the 7.0 mg/kg cohort tolerated 4.68 mg/kg well. Expansion of the 4.68 mg/kg cohort to 6 pts occurred without further DLTs and this is considered the maximum tolerated dose (MTD). One serious adverse event, grade 4 pulmonary embolism, was considered possibly related to study treatment in a pt dosed at 0.28 mg/kg. PK analysis indicates that XL647 shows approximately dose-proportional exposure, a mean time to maximal concentration (tmax) of 6–9 hours and an elimination half-life of 50–70 hours. To date, 1 pt (non-small cell lung cancer [NSCLC]) from cohort 1 had a partial response and 7 others (NSCLC [2], chordoma [2], adenoid cystic carcinoma, adrenocortical carcinoma, colorectal) have had prolonged stable disease (>3 months). Conclusions: XL647 has been well tolerated. An MTD of 4.68 mg/kg oral dosing for 5 consecutive days every 14 days has been established. Exploration of additional dosing schedules is ongoing, including continuous daily dosing. [Table: see text]

Abstract Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC). Experimental Design: Therapy was given every 3 weeks. Stage I: cisplatin was fixed at 30 mg/m2 with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin. Results: Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (>3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m2 cisplatin and 100 mg/m2/24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1. Conclusions: Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.

Purpose This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase) -1 and MEK2 , in patients with advanced malignancy. Patients and Methods CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients. Results Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients. Conclusion CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.