Lawrence Leichman

Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: Preliminary report from an ongoing trial

A clinical trial for patients with measurable, disseminated colorectal cancer is being conducted to determine: (1) if intratumoral expression of thymidylate synthase (TS) affects response to protracted-infusion 5-fluorouracil (5FU); and (2) whether intratumoral expression of TS increases when clinical resistance is found after response to 5-FU. Polymerase chain reaction technology is employed to determine TS expression. Using beta-actin as an internal standard, TS expressions for 26 patients range from 0.5 x 10(-3) to 22.6 x 10(-3). Currently, 22 patients are evaluable for response and TS quantitation of their measurable tumour. 8 patients (36%) have had partial responses; 3 responding patients had been previously treated with 5-FU. A strong statistical association between TS expression and resistance to therapy has been found (P = 0.004). No patient with TS expression of 4.0 x 10(-3) or greater has responded. On average, patients previously treated with 5-FU have slightly higher levels of TS expression in their measurable tumours (P = 0.4). Whether responding patients will develop increased expressions of TS upon clinical progression of their cancer remains to be determined. Confirmation of these results in a larger cohort could lead to a scientific rationale for deciding upon specific therapy for patients with disseminated colorectal cancers.

Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors

Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations. Clin Cancer Res; 17(17); 5774–82. ©2011 AACR.

Intraperitoneal 5-fluoro-2′-deoxyuridine (FUDR) and (S)-leucovorin for disease predominantly confined to the peritoneal cavity: a pharmacokinetic and toxicity study

Intraperitoneal (IP) administration of fluorinated pyrimidines has been evaluated for ovarian and gastrointestinal malignancies in phase I, II, and III trials. The tolerance and pharmacokinetic profile of IP 5-fluoro-2′-deoxyuridine (FUDR) alone and with (R,S)-leucovorin ((R,S)-LV) have each been evaluated in previous phase I studies. FUDR doses of 3 g per day with and without (R,S)-LV doses up to 640 mg per day given IP are well tolerated. The current phase I study was designed to determine the pharmacokinetic profiles and clinical tolerance of escalating doses of the pure biologically activeS-isomer of leucovorin ((S)-LV) given IP with the same dosing schedule of FUDR. A group of 16 patients with disease confined to the abdominal cavity were treated in this study. Pharmacokinetic studies of blood and peritoneal fluid, toxicity profiles, and clinical response for the first three cycles are reported here. The toxicity profile did not significantly differ from the prior two studies. All nonhematologic toxicities, such as fatigue, nausea, vomiting, diarrhea, and abdominal discomfort were less than grade 4, and most were less than grade 3. Neutropenia and thrombocytopenia were uncommon and observed only in patients with compromised bone marrow reserve. The pharmacokinetic profiles were also congruent with the previous studies and indicate a three-log advantage for FUDR. The (S)-LV profiles in the peritoneal cavity paralleled those of FUDR. Antitumor effects or absence of progression until after cessation of therapy were documented in 11 patients. At a median follow-up of 18 months 44% of patients were alive. IP administration of 3-g of FUDR and up to 640 mg (S)-LV daily for three days was well tolerated. The tolerance and antitumor effects observed during IP FUDR and LV in these studies encourage further exploration of this regimen against ovarian and gastrointestinal malignancies. The actual role and optimal dose of LV as an enhancer of the antitumor actions of FUDR administered by this route remain unknown.

Multifocal inflammatory leukoencephalopathy associated with levamisole and 5-fluorouracil: case report.

Levamisole and 5-fluorouracil have now become the standard chemotherapeutic regimen for patients with Stage III colon carcinoma. A case of multifocal inflammatory leukoencephalopathy secondary to levamisole alone or combination of levamisole and 5-fluorouracil is reported. Magnetic resonance imaging with gadolinium demonstrated multifocal contrast-enhancing frontal, parietal, occipital, and periventricular white matter lesions. A stereotactic biopsy revealed reactive gliosis and macrophage infiltration, without evidence of metastatic tumor. Despite continuation of 5-fluorouracil, resolution of contrast-enhancing lesions on magnetic resonance imaging without further neurological sequelae occurred when levamisole was stopped. The patient died with evidence of systemic metastasis 6 months later. Autopsy examination of the brain revealed multifocal demyelinating lesions, with no evidence of metastatic tumor. Immunoperoxidase studies of demyelinated lesions demonstrated infiltrating macrophages strongly positive for Class II antigens, interleukin-6, and interleukin-1 alpha. Surrounding astrocytes were positive for granulocyte macrophage colony-stimulating factor. Small numbers of perivascular T cells were present. This patient represents the first autopsy documented case of levamisole associated multifocal inflammatory leukoencephalopathy.

Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2′-deoxyuridine

SummaryIntraperitoneal (i.p.) 5-fluoro-2′-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32–78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at >3,000 mg ×3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg×3 days and leukopenia and thrombocytopenia at 5,000 mg×3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2–4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2–4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage, (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 l 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers. In addition, it is suitable for further exploration as a part of regimens including systemic therapy or drugs that modulate the action of fluoropyrimidines.

Biological Modification of protracted infusion of 5-fluorouracil with weekly leucovorin

SummaryA clinical trial was designed to find the maximally tolerated dose of weekly leucovorin (LV) that could be combined with 4 weeks of protracted infusion (PI) of 5-fluorouracil (5FU) at a fixed soe of 200 mg/m2. A total of 36 patients with disseminated gastrointestinal malignancies were treated; 9 either progressed or died before receiving 4 weeks of treatment leaving 27 patients evaluable for toxicity and response. 5FU was given as a protracted infusion using an ambulatory infusion pump and indwelling venous access. LV doses included 20, 25, 50, and 75 mg/m2 given as an i. v. push at the time of weekly pump fill with 5FU. In all, 72% of the patients tolerated LV at 20 mg/m2 for 4 continous weeks, whereas the higher doses required treatment rests prior to 4 weeks. The dose-limiting toxicity at all doses was stomatitis. No significant myelosuppression was seen; diarrhea was infrequent. Overall, 40% of the patients with measurable cancer had partial responses. In view of evidence of biologic and therapeutic effects of these weekly doses of 20 mg/m2 LV with 200 mg/m2 5FU per day given as a protracted infusion over 4 weeks, phase II trials and multimodality studies for patients with gastrointestinal malignancies are being initiated at our institution using this dose and schedule.

Multifocal Inflammatory Leukoencephalopathy Associated with Levamisole and 5-Fluorouracil

Levamisole and 5-fluorouracil have now become the standard chemotherapeutic regimen for patients with Stage III colon carcinoma. A case of multifocal inflammatory leukoencephalopathy secondary to levamisole alone or combination of levamisole and 5-fluorouracil is reported. Magnetic resonance imaging with gadolinium demonstrated multifocal contrast-enhancing frontal, parietal, occipital, and periventricular white matter lesions. A stereotactic biopsy revealed reactive gliosis and macrophage infiltration, without evidence of metastatic tumor. Despite continuation of 5-fluorouracil, resolution of contrast-enhancing lesions on magnetic resonance imaging without further neurological sequelae occurred when levamisole was stopped. The patient died with evidence of systemic metastasis 6 months later. Autopsy examination of the brain revealed multifocal demyelinating lesions, with no evidence of metastatic tumor. Immunoperoxidase studies of demyelinated lesions demonstrated infiltrating macrophages strongly positive for Class II antigens, interleukin-6, and interleukin-1 alpha. Surrounding astrocytes were positive for granulocyte macrophage colony-stimulating factor. Small numbers of perivascular T cells were present. This patient represents the first autopsy documented case of levamisole associated multifocal inflammatory leukoencephalopathy.

High incidence of coagulopathy in phase II studies of recombinant tumor necrosis factor in advanced pancreatic and gastric cancers

This multi-center trial was carried out to assess the therapeutic potential of recombinant tumor necrosis factor (rTNF) as the first form of systemic therapy for advanced carcinomas of gastric and pancreatic origin. To be eligible patients were required to have no overt sign of coagulopathy and hepatic function studies with enzymes less than two times beyond the normal range. Twenty nine patients with gastric cancer and 26 with pancreatic cancer were entered from various institutions in the Southwest Oncology Group with 27 and 22, respectively, meeting eligibility criteria. Drug treatment consisted of rTNF (Genentech) given at a dose of 150 micrograms intravenously for five consecutive days every 3 weeks; 50% dose reduction was made for acute intolerance such as hypotension or severe fever and chills. Although eight patients with gastric cancer and five patients with pancreatic cancer received four or more courses of treatment, no objective antitumor responses were recorded. As in other trials common toxicities of rTNF included nausea and vomiting, chills and fever, hypotension, headache, myalgias, fatigue and malaise. However, in this trial, other toxicities became prominent: four episodes of symptomatic disseminated intravascular clotting occurred among patients with pancreatic cancer. Eleven with this disease and five with gastric cancer manifested laboratory findings of abnormal amounts of fibrin split products, and/or hypofibrinogenemia, and/or thrombocytopenia after treatment began. Other laboratory abnormalities that were commonly encountered included hyperglycemia, hypertriglyceridemia, anemia, neutropenia and an elevation in liver enzymes. We conclude that rTNF does not demonstrate antitumor efficacy against adenocarcinomas of the stomach and the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and pharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study

PurposePrevious studies established the safety of continuous gefitinib 250 or 500xa0mg daily. It was postulated that a higher dose may have increased efficacy by inhibiting signaling in both the mitogen-activated protein kinase and AKT pathways. This study investigated the tolerability, pharmacokinetics, and antitumor activity of high-dose gefitinib in patients with refractory solid malignancies.MethodsSequential cohorts received oral gefitinib once or twice-weekly, with dose escalation from 1,500 to 3,500xa0mg.ResultsTwenty-three patients received gefitinib at seven dose levels (1,500, 2,000, 2,500, 3,000, and 3,500xa0mg once-weekly; 1,500 and 2,000xa0mg twice-weekly). Gefitinib was well tolerated, with no dose-limiting toxicities. The maximum tolerated dose was not reached. The most common gefitinib-related adverse events were nausea and diarrhea, vomiting, and rash. Pharmacokinetic data demonstrated no consistent increase in exposure to gefitinib with increasing dose across cohorts. Consequently, the study was stopped early and gefitinib 2,000xa0mg twice-weekly was the highest dose administered. One of eight patients with non-small-cell lung cancer achieved a partial response.ConclusionsExposure to gefitinib did not increase consistently with increasing dose beyond gefitinib 1,500xa0mg once-weekly or twice-weekly. These data do not support further evaluation of gefitinib at high-dose schedules.

Cancer of the Esophagus: The Wayne State University experience

SummaryThe rationale for the preoperative therapy for cancer of the esophagus is described. The first trial with infusion FUra mitomycin-c and radiation performed at Wayne State University (WSU) is described. The dramatic responses were duplicated when cisplatin was substituted for mitomycin. Moreover, survival was improved over the mitomycin-c trial. These neoadjuvant trials led to a third WSU clinical trial in which the neoadjuvant therapy became the definitive therapy.