The effect of calmodulin inhibitors with bleomycin on the treatment of patients with high grade gliomas.

Glioblastoma multiforme is a fatal malignancy of the central nervous system, demanding new methods of treatment. The combination of a calmodulin antagonist with bleomycin has shown synergistic activity in several preclinical models and has been evaluated in a Phase I clinical trial. Since phenothiazines reach high concentrations in the central nervous system, and bleomycin has been reported to have antitumoral activity as well, we studied this combination in a Phase II clinical trial. In addition, we purified calmodulin from normal brain and malignant gliomas to determine its biochemical and pharmacological characteristics. Seventeen patients were entered onto this study and all were evaluable. There were no partial or complete responses. There was one case of fatal pulmonary toxicity in a patient showing an objective tumor response. Otherwise, the treatment was well tolerated. Calmodulin purified from the normal brain and gliomas of patients undergoing resection was identical to each other and to calmodulin prepared from rat cerebrum and glioma. These characteristics included elution from a TSK phenyl high pressure liquid chromatography column, migration on 16% sodium dodecyl sulfate gels, amino acid composition, and inhibition by drugs. Therefore, the failure of this combination therapy was not due to a difference in human glioma calmodulin as compared to previously reported studies with calmodulin from murine sources.

The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer.

The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated, measurable, advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2, followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX, 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks, with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%, P = .026), time to progression (TTP; median, 9.9 months v 5.9 months, P = .009), and survival (median, 15.3 months v 11.4 months, P = .003). Significant differences between arms were not found in response rate, median TTP, or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases, as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon, but not rectal cancer, when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).

Phase I trial of combined therapy with bleomycin and the calmodulin antagonist, trifluoperazine.

Calmodulin antagonists, such as trifluoperazine, can enhance the cytotoxic effects of bleomycin both in tissue culture and in vivo. Therefore, we evaluated the effects of combination treatment with these drugs in a phase I clinical trial. Patients with objectively measurable or evaluable cancer refractory to conventional treatment who had an acceptable performance status (ECOG 0-2) and acceptable laboratory studies were eligible. All patients gave written informed consent. A cycle of therapy consisted of three weekly treatments with trifluoperazine (days 1-4) and 30 IU bleomycin (day 3). After three patients completed a cycle of therapy without experiencing dose-limiting toxicity, new patients were entered in the study and received a higher dose of trifluoperazine. The dose of bleomycin remained constant. Evaluable patients received at least 2 weeks of treatment and survived for 6 weeks; of 19 patients, 2 were unevaluable. The major toxicities were neurological and pulmonary and included one case of fatal pneumonia with interstitial pulmonary fibrosis. There was no hematologic toxicity. Two patients underwent partial responses (PRs) and two had complete responses (CRs). We conclude that trifluoperazine can safely be given with bleomycin and that further study of the potential efficacy of this treatment is indicated.

Trifluoperazine as a modulator of multidrug resistance in refractory breast cancer.

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-pg. P_pg expression was detected both in the patient who responded to vinblastine plus trifluoperazine 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 the 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.

High-dose cisplatin plus WR-2721 in a split course in metastatic malignant melanoma. A phase II study.

Nine patients with metastatic malignant melanoma were entered onto a phase II trial consisting of WR-2721, 740 mg/m2 i.v. over 15 min, followed 15 min after completion by cisplatin, 100 mg/m2 i.v. over 30 min in 250 cc of 3% saline, on days 1 and 8 every 4 weeks. Six patients received two full courses of chemotherapy and were considered evaluable for response. No patients obtained a response. Toxicity, assessed according to the National Cancer Institute Common Toxicity Criteria, was acceptable and usually transient. However, fatigue, which manifested as a decrease in performance status, was significant in six of eight patients in whom this side effect could be evaluated. This subjective toxicity was most likely due to the high-dose cisplatin therapy. The lack of response in six fully evaluable patients allowed us to conclude with greater than 95% confidence that the combination of high-dose cisplatin and WR-2721 in a split-course day 1 and 8 schedule has a true response rate of less than 40%. In view of the relatively high subjective toxicity observed in our study and the more encouraging results observed by other groups using a different dose schedule of WR-2721 plus cisplatin, we do not recommend the use of high-dose cisplatin plus WR-2721 as employed in this trial.

Phase II study of pulse 5-fluoro-2'-deoxyuridine and leucovorin in advanced colorectal cancer patients previously treated with chemotherapy.

Because of possibly better activity against colorectal cancer of 5-fluoro-2'-deoxyuridine [floxuridine (FUdR)] compared to 5-fluorouracil (5-FU), and because of improved therapeutic results of leucovorin (LV) modulation of 5-FU, we carried out a phase II study of systemic FUdR and LV in 5-FU-treated patients with metastatic colorectal cancer. Weekly regimens consisted of a 4-hour infusion of LV, 200 mg/m2, and at 2 hours, a 2-hour infusion of FUdR, 30 mg/kg, with weekly dose escalation, as tolerated, to a maximum of 60 mg/kg. Twenty-nine patients were treated; they had a median age of 66, most had good performance status, and all had measurable disease. All had received 5-FU, although three had received it as adjuvant therapy only. Two patients had partial responses (6.9% response rate, 95% confidence interval, 1.9-21.9%) lasting 29 and 19 weeks, and five had stable disease. Median time to progression was 8 weeks and median survival was 36.5 weeks. The median number of courses was 6.5; escalation of FUdR was carried out in 27 patients. Hematologic toxicity was minimal and gastrointestinal toxicity was most frequent, although mild. This regimen, although well tolerated, is minimally effective in previously 5-FU-treated patients with metastatic colorectal cancer.

Cisplatin, doxorubicin, mitomycin C, and 5-fluorouracil for the treatment of metastatic non-small cell lung cancer. Limited activity of an aggressive chemotherapy regimen.

We conducted a Phase II study to determine the efficacy of cisplatin, doxorubicin, mitomycin C, and 5-fluorouracil in patients with untreated non-small cell lung cancer. Patients were accrued through the Connecticut Oncology Association (COA), an organization composed of community and university oncologists. Thirteen COA oncologists enrolled 30 patients over 12 months and 26 were eligible for the final analysis. Patients received cisplatin 75 mg/m2, doxorubicin 30 mg/m2, mitomycin C 6.5 mg/m2, and 5-fluorouracil 750 mg/m2 on day 1. The treatment was repeated every 4 weeks, with mitomycin C given during the first 3 cycles and then every other cycle. There were 5 (19%) partial responses, lasting 1.3-7.3 months. The median time to progression was 10.3 months (0.3-12.5 months). Median survival was 7.5 months (0.3-34 months). The major toxicities were related to myelosuppression and there was one septic death. This study demonstrates the limited efficacy of an aggressive regimen using "active" agents in patients with advanced non-small cell lung cancer.

High-dose cisplatin with dacarbazine and tamoxifen in the treatment of metastatic melanoma.

In an attempt to increase the antitumor effect of cisplatin (50 mg/m2) and dacarbazine (350 mg/m2), each repeated on days 1 to 3 every 4 weeks in patients with metastatic melanoma, tamoxifen was added to the regimen. Before the first course of chemotherapy, the patients received a loading dose of tamoxifen (100 mg orally twice a day for 7 days), followed by a maintenance dose of 10 mg orally twice a day and continued throughout the treatment. Aspirin (325 mg orally every other day) was administered at the same time as the tamoxifen in an attempt to reduce the risk of thromboembolic events. The activity of high-dose cisplatin with dacarbazine and tamoxifen was disappointing. Of 23 evaluable patients, only three responded--an overall response rate of 13% (95% confidence limits, 0% to 27%). These responses consisted of one pathologic complete remission in a patient with nodal metastases, one clinical complete remission in a patient with a very large pelvic mass, and one partial response in another patient with nodal metastases. The duration of responses was 12+, 4, and 4 months, respectively. These data do not support a significant interaction between tamoxifen and cisplatin or dacarbazine. Assuming that tamoxifen is important in the cisplatin, dacarbazine, and carmustine combination, as suggested by others, the most relevant interaction may be between tamoxifen and carmustine.

A phase I pilot study of BCNU plus thymidine in patients with refractory cancer.

Thymidine (dThd) has been shown to increase the activity of BCNU in mice, possibly due to its ability to inhibit poly(ADP-ribose)polymerase (PADPRP), an enzyme thought to be active in DNA repair. The present phase I study characterized the pharmacokinetics and toxicity of dThd combined with BCNU. Sixty patients with refractory malignancies were infused with escalating doses of dThd from 7.5g/m2/day to 105.5 g/m2/day for 48 hr, along with 100 mg/m2/day of BCNU for 2 doses. Further dose escalation of dThd was limited by large fluid volumes required; therefore, the BCNU dose was escalated to a maximum of 160 mg/m2/day for 2 days. Plasma dThd concentrations were determined using high-performance liquid chromatography. At doses above 37.5 g/m2/day, steady-state concentrations of dThd approached or exceeded 1 mM, a concentration that nearly completely abolished BCNU-induced PADPRP activity in preclinical studies. Myelosuppression was consistent with BCNU dose but was not apparently increased by the coadministration of dThd. One patient had a partial response to therapy. Both the lack of effect of increasing dThd doses on BCNU-induced myelosuppression and the low response rate suggest that the schedule of drug administration was not optimal to inhibit PADPRP, or that PADPRP may not be essential in repairing BCNU-mediated DNA damage in humans.

High-dose cisplatin plus dacarbazine in the treatment of metastatic melanoma.

The combination of cisplatin plus dacarbazine (DTIC) is active in metastatic melanoma with response rates reported between 10% and 55%. To optimize this regimen, a Phase II study was conducted employing a dose intensity of cisplatin higher than previously reported. Twenty-two patients were treated. Eight patients received cisplatin 100 mg/m2 on days 1 and 8 combined with DTIC 300 mg/m2 on days 1, 2, 8 and 9 (regimen A). Because of excessive toxicity, the protocol was modified so that cisplatin was given at 50 mg/m2 per day and DTIC 350 mg/m2 per day on days 1 through 3 (regimen B). The overall response rate was 32% and consisted of four partial and three complete responses (CR). The median duration of response was 6 months. Two of the CR remain in sustained, unmaintained remission in excess of 1.5 years. All seven patients that responded were treated on regimen B. High-dose cisplatin plus DTIC on a 3-day schedule represents an effective, well-tolerated therapy for metastatic melanoma.

A phase II study of irinotecan (CPT-11) in patients with advanced squamous cell carcinoma of the cervix.

BACKGROUND: This study was conducted to determine the efficacy and safety of irinotecan (CPT-11) as second-line therapy in patients with advanced cervical carcinoma. METHODS: Sixteen patients with platinum-resistant squamous cell carcinoma were treated with CPT-11 as second-line therapy. CPT-11 was administered in repeated 6-week cycles comprised of the administration of CPT-11 once weekly for 4 weeks, followed by a 2-week rest. The starting dose of CPT-11 was 125 mg/M2 given intravenously over 90 minutes; subsequent doses were adjusted based on individual patient tolerance. RESULTS: The median age of the patients was 43 years (range, 27-69 years). Three patients had a baseline Eastern Cooperative Oncology Group performance score (PS) of 0, 8 had a PS of 1, and 5 had a PS of 2. All patients had received cisplatin-based chemotherapy and 13 of 16 patients (81.3%) had been treated with prior pelvic/abdominal radiation therapy. Fourteen patients were evaluable for response. There were no objective responses although subjective decreases in symptoms were observed in some patients. Grade 3 to 4 toxicities included diarrhea in three patients, nausea and emesis in one patient, leukopenia in six patients, and neutropenia in five patients. Eighteen of 25 cycles required dose reductions leading to a median dose intensity of only 59.4 mg/M2/week, which was 71% of the planned dose of 83.3 mg/M2/week. CONCLUSIONS: The amount of CPT-11 actually delivered to the patients under the conditions of this pilot study failed to result in an antitumor response. However, the marked subjective improvement of symptoms observed in this study and the significant activity reported by other investigators justify future studies of CPT-11 in patients with cervical carcinoma.

Cyclosporine treatment of refractory T-cell lymphomas.

BACKGROUND: Cyclosporine (cyclosporin A, CSA) prolongs the survival of transplanted organs by reducing the transcription of cytokines, especially interleukin-2, that are thought to mediate T-cell expansion and subsequent graft rejection. Recently, CSA has been suggested as a potentially effective agent in the treatment of T-cell neoplasms. As a result, a Phase II trial of CSA was done in patients with refractory T-cell lymphomas. METHODS: Patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who had disease progression after at least one previous therapy were eligible for participation. CSA was administered orally at a dose of 7.5 mg/kg twice daily, and the patients were followed for disease response and toxicity. RESULTS: A total of 16 patients were treated. Five patients had PTCL, and 11 had CTCL. Most patients were pretreated extensively with chemotherapy and/or radiation therapy. No responses occurred in patients with PTCL. Two of 11 patients with CTCL responded to therapy. Both patients who responded to CSA had recurrent disease that approached baseline levels within 1 week of discontinuing therapy. A second response occurred in both patients after reinstitution of therapy. Although most patients were removed from the study because of disease progression, renal toxicity was significant. CONCLUSIONS: Most patients with refractory T-cell lymphomas did not respond to CSA, suggesting that these malignancies are not interleukin-2 dependent or, alternatively, that CSA did not reach its intracellular target. In the two responding patients, the pattern of repeated rapid regression of disease after CSA administration and subsequent rapid recurrence after a temporary halt in therapy suggested that CSA was cytostatic rather than cytocidal or that the clinical remissions were mediated by the antiinflammatory effects of the drug.