Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma.

BACKGROUND: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin. METHODS: Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months. RESULTS: 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501. CONCLUSIONS: While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.

Selection of GM2, fucosyl GM1, globo H and polysialic acid as targets on small cell lung cancers for antibody mediated immunotherapy.

Glycolipids GM2, GD2, GD3, fucosyl GM1, sialyl Lewis a (sLe(a)) and globo H, and polysialic acid on embryonal NCAM, are cell-surface antigens expressed on small cell lung cancer (SCLC) biopsy specimens. They are all candidates for inclusion in a polyvalent, antibody-inducing vaccine or for adoptive therapy with monoclonal antibodies (mAbs) against SCLC. To identify the minimum optimal combination of target antigens on SCLC and to confirm that antibodies against this combination might be able to mediate complement activation and lysis in the majority of cases, we tested ten SCLC cell lines with fluorescence activated cell sorter (FACS) and complement dependent cytotoxicity (CDC) assays using mAbs against these seven target antigens individually or pooled in different combinations. We find that (1) none of these mAbs demonstrated strong FACS reactivity with more than 6 of the 10 cell lines, (2) no mAb had strong CDC reactivity with more than 4 of the cell lines, (3) when the mAbs were pooled, nine cell lines were strongly positive by FACS and nine cell lines were strongly positive by CDC, and (4) mAbs against GM2, FucGM1, globo H and polysialic acid was the minimum optimal combination for inducing FACS reactivity. The addition of mAbs against sLe(a), GD2 and GD3 had no additional impact by FACS and only minimal additional impact in CDC assays. H345, the only cell line that had less than 30% CDC with the four mAb pool was strongly positive by FACS. To understand the lack of correlation between FACS and CDC in the case of H345, the ten cell lines were screened for expression of complement resistance factors CD55 and CD59. Three cell lines were strongly positive for CD55 and eight were strongly positive for CD59. Overall, no correlation was seen between expression of either of these factors on the ten cell lines and sensitivity to CDC. In the case of H345 however, complement resistance of H345 is demonstrated to be mediated primarily by CD59, and in the presence of mAb against CD59, the four mAb MEM-43 pool induced strong (94%) CDC. CD59 inhibits membrane attack complex formation but not activation of earlier complement components. Consequently, all ten cell lines are good targets for complement activation by the four antibody pool and for elimination by effector mechanisms including complement mediated inflammation and opsonization. These findings support our plan to develop a tetravalent vaccine against SCLC targeting GM2, fucosyl GM1, globo H and polysialic acid.

Phase I and pharmacokinetic study of 10-propargyl-10-deazaaminopterin, a new antifolate.

The 10-deazaaminopterins are a new class of rationally designed antifolates demonstrating greater antitumor effects than methotrexate in murine tumor models and human tumor xenografts. Their design was aimed at improving membrane transport and polyglutamylation in tumor cells, resulting in increased intracellular accumulation and enhanced cytotoxicity. Compared with other 4-aminofolate analogues, 10-propargyl-10-deazaaminopterin (PDX) is the most efficient permeant for the RFC-1-mediated internalization and substrate for folylpolyglutamate synthetase. PDX demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate or edatrexate. We undertook a Phase I study with PDX to identify the potential toxicities and define an optimal dose and schedule. Thirty-three patients were enrolled, all of whom had non-small cell lung cancer (NSCLC) and were treated previously with a median of two prior chemotherapy regimens. Initially, PDX was administered weekly for 3 weeks in a 4-week cycle. Mucositis requiring dose reduction and/or delay in the first cycle occurred in four of six patients treated at the initial dose level (30 mg/m2), making this the maximal tolerated dose for PDX given on this schedule. The treatment schedule was then modified to every 2 weeks. Twenty-seven patients were treated twice weekly with a total of 102 four-week cycles (median, 2 cycles/patient). Mucositis was the dose-limiting toxicity, with grade 3 and 4 mucositis occurring in the first two patients treated at the 170 mg/m2 dose level. Other toxicities were mild and reversible. No neutropenia was observed. The recommended Phase II dose is 150 mg/m2 biweekly. At that dose level, the mean area under the curve was 20.6 micromol x h, and the mean terminal half-life was 8 h. Two patients with stage IV NSCLC had major objective responses, and five patients had stable disease for 7 (two patients), 9 (one patient), 10 (one patient), and 13 months (one patient). PDX is a new antifolate with manageable toxicity and evidence of antitumor activity in NSCLC. A Phase II trial in NSCLC and a Phase I trial with paclitaxel are under way. These studies will also quantitate the expression of genes controlling internalization (RFC-1) and polyglutamylation of PDX in tumor cells as correlates of response.

Phase I trial of docetaxel and vinorelbine in patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: With preclinical evidence of synergy, this dose-finding trial examining the combination of docetaxel and vinorelbine given with prophylactic filgrastim for the treatment of patients with nonsmall cell lung carcinoma was undertaken. METHODS: Twenty-seven patients with advanced nonsmall cell lung carcinoma received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks at 1 of 7 different dose levels. Vinorelbine was escalated from 15 mg/m(2) (Level I) to 45 mg/m(2) (Level VII) and docetaxel was increased from 50 mg/m(2) (Level I) to 60 mg/m(2) (Level VII). Prophylactic corticosteroids and filgrastim were employed prospectively. RESULTS: After completion of dose Level VII, accrual was terminated because Phase II dose intensity of both agents had been reached and further escalation was believed to be unsafe. At dose Level VII, one episode of first-cycle febrile neutropenia and a death after three treatment cycles due to Haemophilus influenzae sepsis (Grade 5 toxicity according to the Common Toxicity Criteria of the National Cancer Institute) without neutropenia were noted. In all, 209 treatment cycles were administered and febrile neutropenia was observed in only 4 of these treatments (1.9%). Bacteremia occurred in three patients (four episodes) in the absence of neutropenia. Symptomatic onycholysis was observed in three patients. Clinically significant peripheral neuropathy and fluid retention were rare. Confirmed partial responses were noted in 10 patients for a response rate of 37% (95% confidence interval, 20-57%). CONCLUSIONS: Docetaxel at a dose of 60 mg/m(2) and vinorelbine at a dose of 45 mg/m(2), both given every 2 weeks, can be combined safely to achieve Phase II dose intensity of both agents. An ongoing Phase II trial will define the activity of this treatment combination.

Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer.

PURPOSE: Docetaxel and vinorelbine are active agents in advanced non-small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m(2)) and vinorelbine (45 mg/m(2)) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed. PATIENTS AND METHODS: Thirty-five chemotherapy naïve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used. RESULTS: We delivered median doses of 450 mg/m(2) of vinorelbine and 600 mg/m(2) of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy. CONCLUSION: Docetaxel 60 mg/m(2) and vinorelbine 45 mg/m(2), both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.

Phase II trials of vinorelbine and docetaxel in the treatment of advanced non-small cell lung cancer.

Both vinorelbine and docetaxel are effective as single agents in non-small cell lung cancer, with response rates of 25% to 30%. Several in vitro and in vivo models demonstrate schedule-dependent synergy between these agents. In phase II clinical trials of the combination, response rates and median survivals ranged from 27% to 49% and 5 to 9 months, respectively. Common toxicities included neutropenia, febrile neutropenia, and mucositis. With prolonged therapy, severe onycholysis and eye irritation also have been noted. In conclusion, docetaxel and vinorelbine are active together and offer one alternative to cisplatin-based therapy for patients with adequate performance status.

Strategies to eradicate minimal residual disease in small cell lung cancer: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

In the last 25 years, treatment for small cell lung cancer (SCLC) has improved with advances in chemotherapy and radiotherapy. Standard chemotherapy regimens can yield 80% to 90% response rates and some cures when combined with thoracic irradiation in limited-stage patients. Nonetheless, small cell lung cancer has a high relapse rate due to drug resistance; this has resulted in poor survival for most patients. Attacking this problem requires a unique approach to eliminate resistant disease remaining after induction therapy. This review will focus on three potential strategies: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

Na+, K(+)-adenosine triphosphatase regulation in hypertrophied vascular smooth muscle cells.

Vascular smooth muscle cell hypertrophy is a normal compensatory state that may play a pathogenic role in hypertension. Angiotensin II stimulates a hypertrophic response in cultured vascular smooth muscle cells. As part of the growth response, angiotensin II rapidly activates the Na(+)-H+ exchanger, increasing Na+ influx. Because Na+, K(+)-ATPase is the major cellular mechanism for regulating intracellular Na+, we studied the effects of angiotensin II-induced hypertrophy on Na+, K(+)-ATPase expression and activity. Angiotensin II caused rapid increases in both steady-state Na+, K(+)-ATPase activity (ouabain-sensitive 86Rb uptake) and intracellular [Na+]. Angiotensin II also caused a sustained increase in Na+, K(+)-ATPase at 24 hours with a 73% increase in maximal 86Rb uptake per milligram protein and a fourfold increase in Na+, K(+)-ATPase alpha-1 messenger RNA levels. Thus, angiotensin II hypertrophy was associated with rapid increases in Na+, K(+)-ATPase activity due to increased Na+ entry and sustained increases due to a specific increase in Na+, K(+)-ATPase expression. These data demonstrate dynamic regulation of Na+, K(+)-ATPase at the functional and molecular level and suggest that similar compensatory mechanisms should be present in vivo. Alterations in such compensatory pathways may be fundamental to the pathogenesis of hypertension.

The relationship of ovarian steroids, headache activity and menstrual distress: a pilot study with female migraineurs.

Fourteen female volunteers who met diagnostic criteria for migraine headache monitored their headache activity and menstrual distress symptoms for one menstrual cycle. Serum estradiol and progesterone levels, and menstrual distress measures were collected at four points of the menstrual cycle: menstrual, ovulatory, luteal and premenstrual. Results indicated that one patient (7.1%) had menstrual migraine, 10 patients (71.4%) had menstrually-related headache and 3 (21.4%) had migraine headache unrelated to their menstrual cycle: subsequent analyses were conducted with the first two groups. Headache activity for the sample was highest during the premenstrual phase. Headache activity during the luteal and premenstrual phases was related to luteal phase progesterone levels. Menstrual distress was highest during the menstrual and premenstrual phases of the cycle, and these symptoms were related to higher estradiol levels, higher estradiol/progesterone ratios, and increased headache activity. These results indicated that for women with menstrual migraine or menstrually-related migraine, luteal progesterone and estradiol and the estradiol/progesterone ratio may be significantly related to menstrual distress during the premenstrual phase of the cycle. The estradiol/progesterone ratio was not more related to headache or menstrual distress than either of these ovarian hormones alone. Suggestions for future research in this area are offered.

Exercise habits and exercise relapse in persons with non-insulin-dependent diabetes mellitus.

Exercise is widely recognized as a crucial component in the management of non-insulin-dependent diabetes mellitus (NIDDM), but little is known about actual exercise practices in this group. This study investigated exercise habits in 60 persons with NIDDM and 60 nondiabetic significant others. Despite the importance of exercise, most of the persons with NIDDM in our study were not exercising regularly, and the percent of persons exercising regularly was no greater in the diabetic group than in the group of significant others. Although those with NIDDM reported more frequent discussion about exercise with health care professionals, only 25% reported receiving specific guidelines for exercise. Diabetic respondents reported a greater number of relapse or dropout episodes than did the nondiabetic significant others, and relapse was associated with increased guilt. Persons with NIDDM appear to receive recommendations to exercise without instruction on exercise maintenance strategies, resulting in more failed attempts to exercise, and increased guilt. Interventions shown to be effective for increasing exercise maintenance need to be incorporated into the diabetic regimen.