John R. Murren

Phase I study of inhaled doxorubicin for patients with metastatic tumors to the lungs

Purpose: To evaluate the toxicity profile of inhalational doxorubicin in patients with malignant disease in the lung. Experimental Design: The OncoMyst Model CDD-2a inhalation device aerosolizes compounds to particles of 2 to 3 μm and prevents exhaled aerosol from escaping into the environment. Deposition efficiency of inhaled Technetium 99m was used to predict deposition of doxorubicin and calculate dose. Treatment was repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (forced expiratory volume in 1 s, forced vital capacity, and diffusing capacity for carbon monoxide, all >50% predicted; resting SaO2 >90%). Results: Fifty-three patients were enrolled at 13 dose levels ranging from 0.4 to 9.4 mg/m2. The most common histologic diagnoses were sarcoma (n = 19) and non–small cell lung cancer (n = 16). Dose-limiting toxicity (DLT) was observed at the 9.4 mg/m2 dose level when two of four patients experienced pulmonary DLT. Of 11 patients treated at the 7.5 mg/m2 dose level, only one showed DLT consisting of a decline in forced vital capacity of >20% from baseline. No significant systemic drug-related toxicity was observed. Several patients experienced declines in pulmonary function test variables, which were attributed to progressive disease. Observed activity included a partial response in a patient with metastatic soft tissue sarcoma previously treated with i.v. doxorubicin and ifosfamide. Conclusions: Inhaled doxorubicin is safe up to a dose of 7.5 mg/m2 every 3 weeks in patients with cancer who had normal to moderately impaired pulmonary function.

Treatment of Malignant Pleural Effusions with Tunneled Long-term Drainage Catheters

PURPOSE To assess the effectiveness of tunneled pleural catheters (TPCs) in the treatment of malignant pleural effusions (MPEs). MATERIALS AND METHODS Twenty-eight patients with symptomatic MPEs had 31 hemithoraces treated with TPCs placed under image guidance. Chemical sclerotherapy had failed in two patients and two had symptomatic locules. Drainage was accomplished by intermittent connection to vacuum bottles. Pleurodesis was considered achieved when three consecutive outputs were scant and imaging showed no residual fluid. RESULTS All catheters were successfully placed. Dyspnea improved in 94% (29 of 31 hemithoraces) at 48 hours and 91% (20 of 22 patients) at 30 days. Control of the MPE was achieved in 90% of hemithoraces (28/31), although five required ancillary procedures. Pleurodesis occurred in 42% (13 of 31) of hemithoraces, including both that underwent an earlier attempt at chemical sclerotherapy and one treated locule. Continued drainage without pleurodesis controlled the effusion in 48% (15 of 31). In only 7% was hospital time necessary for care related to the TPC. Early, transient catheter-related pain was common, but only three complications (in two patients) occurred. Neither of these altered patient care. CONCLUSIONS Regardless of whether pleurodesis is achieved, TPCs provide effective long-term outpatient palliation of MPEs.

Phase 1 Study of Aflibercept Administered Subcutaneously to Patients with Advanced Solid Tumors

Purpose: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent. Experimental Design: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease. Results: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 μg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t1/2 of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year. Conclusion: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation. Clin Cancer Res; 16(1); 358–366

Progress in the therapy of small cell lung cancer

Small cell lung cancer (SCLC) accounts for approximately 14% of all cases of lung cancer. Combination chemotherapy is the most effective treatment modality for SCLC and recently, several new active drugs have emerged. Combinations of platinum agents with CPT-11 or gemcitabine have been successfully compared in phase III trials against the cisplatin/etoposide standard. Modest improvements in the outcome of patients with SCLC have been noted over the last two decades. Thoracic irradiation given concurrently with chemotherapy improves survival compared with sequential chemotherapy and radiation, but this approach is associated with more toxicity. Moreover, the optimal doses and fractionation of thoracic irradiation remain to be determined. Three-dimensional treatment planning is under investigation. Prophylactic cranial irradiation (PCI) has established a role in the management of patients who have achieved a complete response to the initial therapy. Novel molecular targeted therapies are among the strategies currently being investigated in SCLC.

Phase I/II Study of Inhaled Doxorubicin Combined with Platinum-Based Therapy for Advanced Non–Small Cell Lung Cancer

Purpose: We have shown the feasibility of administering inhaled doxorubicin to patients with cancer. This study evaluated inhaled doxorubicin combined with cisplatin and docetaxel in patients with non–small cell lung cancer. The principal objective was to determine safety and, secondarily, efficacy. Experimental Design: Patients who had chemo-naïve advanced non–small cell lung cancer were enrolled in the study. Adequate organ and pulmonary function was required: diffusing capacity for carbon monoxide/forced expiratory volume in 1 second/forced vital capacity ≥50%, resting/exercise O2 saturation ≥90%/85%. In phase I, doxorubicin was escalated: dose level 1 (6 mg/m2) and level 2 (7.5 mg/m2). Escalation was permitted if ≤2 of 6 patients experienced pulmonary dose-limiting toxicity (grade 2 Radiation Therapy Oncology Group lung morbidity; resting O2 saturation of <85%; decrease in diffusing capacity for carbon monoxide, forced vital capacity, or forced expiratory volume in 1 second of ≥20% from baseline or ≤30% of predicted; or grade 3 Common Terminology Criteria for Adverse Events version 3.0 pulmonary toxicity). Doses of cisplatin and docetaxel were 75 mg/m2. Treatments and pulmonary function tests were repeated every 21 days, with up to eight cycles for responding patients. Results: Twenty-eight patients were treated at level 1 and eight patients at level 2. Doxorubicin was escalated to 7.5 mg/m2, however, after two patients developed pulmonary dose-limiting toxicity; the remainder were treated at 6.0 mg/m2. Twenty-four evaluable patients received at least two courses or had progressive disease following the first course at the phase II dose. Toxicity was associated with i.v. chemotherapy although one patient had delayed pulmonary toxicity responding to corticosteroids and oxygen. Seven (29%) evaluable patients responded (six partial responses and one complete response) and 13 (54%) patients had stable disease for up to eight cycles. Conclusion: Although this combination was safe, the primary objective was not met and will not be pursued further. Clin Cancer Res; 16(8); 2466–73. ©2010 AACR.

Phase I and pharmacokinetic study of VEGF Trap administered subcutaneously (sc) to patients (pts) with advanced solid malignancies

3009 Background: Vascular Endothelial Growth Factor (VEGF) Trap is a potent angiogenesis inhibitor that binds VEGF-A 100- to 1000- fold more tightly than monoclonal antibodies (Kd <1pM) and inactivates all circulating and tissue VEGF-A isoforms plus placental growth factor. VEGF Trap is comprised of portions of the human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to human IgG1 Fc. METHODS In this phase I trial, successive cohorts of pts with relapsed or refractory solid tumors received a single sc dose of VEGF Trap, followed 4 weeks later by 6 weekly doses. Pts without disease progression subsequently entered a long-term extension study. Study endpoints included safety, pharmacokinetics, and immunogenicity. Anti-tumor activity was assessed by CT scan. RESULTS A total of 30 pts have been treated across 6 dose levels to date: 0.025, 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg. Drug-related grade 3 AEs have included hypertension (HTN; n=4), proteinuria (n=1), and afebrile neutropenia (n=1). Other than HTN, No dose-related pattern of adverse events (AEs) has emerged. However, the maximum tolerated dose has not yet been reached, and no pts have died due to an AE. No pts have developed anti-VEGF Trap antibodies, including 14 pts treated for ≥ 4 mos. Free plasma VEGF Trap levels associated with anti-tumor activity in animal models were approached at, but not below, the 0.8 mg/kg dose level. Objective partial or complete responses have not yet been achieved, but 14 of 24 evaluable pts, including 5 of 6 pts treated with 0.8 mg/kg, maintained stable disease (SD) for at least 10 weeks and entered the extension study. CONCLUSIONS VEGF Trap has a favorable safety and tolerability profile and does not appear to elicit an antibody response. Consistent with previous findings with an anti-VEGF antibody, VEGF Trap may be associated with dose-dependent hypertension. Five of 6 evaluable pts treated with 0.8 mg/kg, compared with 9 of 18 evaluable pts who received lower doses, maintained SD at the end of the 10-week study. Evaluation of higher dose levels is ongoing. [Table: see text].

Terfenadine (Seldane®) : a new drug for restoring sensitivity to multidrug resistant cancer cells

In our efforts to identify clinically effective drugs for reversing multidrug resistance (MDR) mediated by P-glycoprotein, we tested terfenadine for anti-MDR activity because it appeared to sensitize a patient to doxorubicin and because it met structural requirements defined for this activity. Terfenadine sensitized MCF-7/ADR human breast cancer cells and L1210/VMDRC.06 murine leukemia cells to doxorubicin. At concentrations < or = 10 microM, terfenadine decreased the IC50 to doxorubicin by up to 25-fold against MCF-7/ADR cells and completely restored sensitivity to L1210/VMDRC.06 cells. The drug had no effect on the sensitive, parental cell lines and enhanced activity of other drugs affected by the MDR phenotype. Terfenadine was as potent as trans-flupenthixol, one of the most active modulators of MDR. The mechanism of action of terfenadine appeared to be due to inhibition of the function of P-glycoprotein since it augmented the accumulation of doxorubicin and inhibited the efflux of rhodamine 123 from MDR lines but had no effect on drug accumulation or efflux in sensitive cells. Terfenadine displaced azidopine from P-glycoprotein, but at concentrations higher than expected based on its overall potency. Since terfenadine is clinically available, has numerous structural derivatives available for study, and has a relatively low toxicity profile, this drug and drugs of its class should be evaluated for future clinical trials.

Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein

BACKGROUND Localization of parathyroid glands is critical in the treatment of recurrent or persistent hyperparathyroidism. Technetium sestamibi imaging may improve localization; however, the mechanism of visualization of parathyroid tissue remains unclear. On the basis of the chemical structure of sestamibi it has been suggested that p-glycoprotein is involved in the transport of sestamibi across cell membranes. This study was designed to examine sestamibi uptake and retention and p-glycoprotein expression in normal and abnormal parathyroid tissue. METHODS Thirty-two consecutive patients underwent 2-methoxy-isobutyl-isonitrile imaging immediately before parathyroid exploration. Tissue was obtained from normal and abnormal parathyroids and from the thyroid gland. Touch preparations gave rapid confirmation of tissue origin. Specimens were trimmed and weighed, and gamma-emission was counted. Percentage injected dose per gram of tissue was calculated. Immunohistochemistry was obtained with a battery of monoclonal antibodies to identify p-glycoprotein in parathyroid tissue submitted for permanent histologic examination. Slides were graded by a pathologist familiar with immunohistochemistry. RESULTS Abnormal parathyroid tissue had a higher mean retention of injected dose per gram than did normal thyroid and parathyroid tissue. Immunohistochemistry revealed that abnormal parathyroid tissue expresses less p-glycoprotein. CONCLUSIONS These results suggest that size is not the single determinant of parathyroid visualization and that p-glycoprotein expression may be involved in the mechanism of parathyroid imaging.

Dose escalation and pharmacokinetic study of irinotecan in combination with paclitaxel in patients with advanced cancer

Purpose: Based on preclinical data demonstrating synergy between camptothecin analogues and taxanes, we determined the maximum tolerated dose (MTD) of irinotecan that could be given in combination with a fixed dose of paclitaxel of 75 mg/m2, when both drugs were delivered on a weekly schedule. The pharmacokinetics of this combination were explored to determine whether the sequence of administration affected the elimination of irinotecan. Methods: For the first cycle patients with advanced cancer were treated with irinotecan given as a 90-min infusion followed immediately by paclitaxel given at a dose of 75 mg/m2 over 1 h. The sequence of drug administration was reversed in subsequent cycles for most patients. Chemotherapy was given weekly for 4 weeks, followed by a 2-week rest. In selected patients, plasma concentrations of irinotecan were determined by high-performance liquid chromatography during the first 24 h of cycle 1 and after the first dose of cycle 2 to determine whether the order of drug administration affected the elimination of irinotecan, or the toxicologic effects of the chemotherapy. Results: A total of 53 cycles were delivered to 21 patients. Reversible neutropenia was dose-limiting. Suppression of the other blood cell elements was modest. There was one partial response in a man with a previously treated cholangiocarcinoma that lasted 26 weeks. Prolonged stabilization of disease (6 months or more) was observed in five of the patients (24%). At the recommended dose of irinotecan (50 mg/m2), transfusions of red cells and platelets were not required. The sequence of drug administration produced no significant differences in the pharmacokinetic parameters of irinotecan or SN-38, which were similar to the values reported when irinotecan is administered alone. The most prominent nonhematologic toxicities were mild diarrhea and fatigue. Conclusions: The recommended dose of irinotecan on this schedule is 50 mg/m2. The sequence of drug administration affects neither the elimination of irinotecan nor the chemotherapy-related toxicity. This combination is well tolerated and causes minimal clinical side effects.

Trifluoperazine as a modulator of multidrug resistance in refractory breast cancer

Abstract Overexpression of P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of human cancers, including carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor, trifluoperazine, could sensitize patients with refractory breast cancer to vinblastine chemotherapy. Adult patients with histologically confirmed, refractory, advanced breast cancer were treated with vinblastine at a dose of 1.7 mg/m2 per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently treated with vinblastine plus trifluoperazine at a dose of 8 mg twice daily during the five days of chemotherapy. In patients from whom tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled, 30 were evaluable, 2 of whom (7%) achieved a partial response to vinblastine alone. Among the 16 patients treated with vinblastine plus trifluoperazine there was one response (6%) which lasted 16 weeks. Tumor samples were available from 16 patients, and 14 (87%) were immunoreactive for P-gp. P-gp expression was detected both in the patient who responded to vinblastine plus trifloperazine and in one of the two patients who responded to vinblastine alone. Continuous-infusion vinblastine demonstrated limited activity in this study. Furthermore, trifluoperazine did not effectively reverse established resistance to vinblastine. This failure may be related the presence of multiple mechanisms of drug resistance in this heavily pretreated population, or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop.