A phase II trial of mitomycin, ifosfamide and cisplatin in recurrent carcinoma of the cervix.

The purpose of this study was to evaluate the efficacy and the toxicity of mitomycin, ifosfamide, and cisplatin in patients with recurrent carcinoma of the cervix. Between July 1992 and March 1995, 20 patients with recurrent cervical cancer were enrolled in this study. No patients had received prior chemotherapy for metastatic disease, except some were exposed to cisplatin as a radiosensitizer at the time of their diagnosis. Mitomycin-C 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 were given intravenously every 3 weeks. All patients were assessible for response and toxicity, and none was lost to follow-up. All patients except one had squamous cell carcinoma. The overall response rate was 45% (2 complete remissions and 7 partial remissions). The mean response duration was 35 months, and the median survival from treatment for the whole group was 14 months. Fifteen percent of all cycles produced grade 3 or 4 myelosuppression, and the main nonhematologic toxicity was nausea and vomiting, which was reported in 11.5% of all cycles. One death occurred secondary to chemotherapy-induced septicemia. Three patients are still alive, two with a complete response and one with a partial response. In conclusion, mitomycin, ifosfamide, and cisplatin have a good activity in recurrent carcinoma of the cervix and are comparable to other combination chemotherapy.

Combined results of two phase II studies of Taxol (paclitaxel) in patients with relapsed or refractory lymphomas.

This study was performed to determine the clinical activity and safety of paclitaxel in the treatment of patients with refractory or relapsing aggressive Non-Hodgkin's lymphoma (NHL). Between May 3, 1994 and February 16, 1996, 39 patients with refractory or relapsing NHL consented to be enrolled in two, multicenter, open-labelled studies to evaluate the efficacy, safety, time to progression and overall survival of paclitaxel given at a dose of 175 mg/m2 by a 3-hour IV infusion every three weeks without G-CSF use. Data from the two studies is combined. One patient, although registered, did not receive treatment. Of the remaining 38 patients, 17 men and 21 women aged 26-82 years (median 60) were given 104 courses of paclitaxel [median 2 (range 1-6)]. Seventeen patients had stage IV, 7 stage III, 8 stage II, 5 stage 1 and 1 unknown stage of disease. Histologic grades included 1 low, 33 intermediate, and 4 high. Three patients had bone marrow involvement. Median time from diagnosis to study entry was 19 months (1-160). The median number of previous chemotherapy regimens was 2 (range 1-6). Three of the 35 (8.6%) patients evaluable for response had partial remission (PR) of their disease for 1-7 months (median 2) and 11/35 (31.4%) stable disease (SD) for 1 to 19 months (median 3). All three responders and 3 of the 11 SD patients had received paclitaxel after relapsing from a CR. At analysis, nine of the 38 patients were alive. Median duration of follow up at analysis was 6 months (3 days-29 months). The estimated survival rates for all patients at 1 and 2 years are 34% and 27%, respectively (Kaplan-Meier) from the start of paclitaxel treatment. The median survival time was 5.4 months (3 days to 28+ months). Febrile neutropenia occurred in two patients. Seven (18%) patients developed a neutrophil nadir of < 0.5 x 10(9)/L and 2 (5%) patients developed a platelet nadir of < 50 x 10(9)/L. Six patients received blood transfusions. Non-hematologic toxicity was generally mild to moderate with all patients experiencing some toxicity. Twenty-seven patients experienced grade III toxicity including: alopecia (n = 19), pain (n = 9), fatigue (n = 5), nausea/vomiting (n = 3), diarrhoea (n = 2), pulmonary/shortness of breath (n = 2), anorexia (n = 1) and fluctuating levels of consciousness and somnolence (n = 1). Two patients experienced grade IV toxicity (infection, peripheral neuropathy, pain). No patient discontinued paclitaxel for a severe hypersensitivity reaction. In summary, administered as a 3-hour infusion, paclitaxel 175 mg/m2 results in mild myelotoxicity but minimal antitumor activity in patients with refractory NHL.

Phase I-II study of 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and long-term oral etoposide (FLAME) in unresectable or metastatic gastric cancer.

The objective of this phase I-II study was to determine the efficacy and toxicity of combination chemotherapy with 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and oral etoposide (FLAME) in patients with measurable unresectable or metastatic gastric cancer. Starting doses on the phase I study were as follows: methotrexate 50 mg/m2 intravenous bolus day 1; leucovorin 20 mg/m2 intravenous bolus days 2 through 4, starting 24 hours after the methotrexate dose; 5-fluorouracil 325 mg/m2 intravenous bolus 15 minutes after leucovorin days 2 through 4; doxorubicin 25 mg/m2 intravenous bolus day 8; and oral etoposide 50 mg/day for 14 days, starting on day 8. A new cycle started on day 28. A total of 42 patients were treated--10 patients in the phase I study and 32 patients in the phase II study. Dose-limiting toxicity was encountered in the phase I study on the second escalation step, when doxorubicin was escalated to 30 mg/m2 and 5-fluorouracil was escalated to 350 mg/m2. In the phase II study 28 patients (109 courses) were evaluable for toxicity. Neutropenia grade 3 or more was dose limiting and was documented in 12 patients (43%) during 22 treatment courses (20%). Neutropenia was associated with febrile neutropenia requiring hospitalization in four patients during five courses of therapy. Grade 3 stomatitis and grade 3 diarrhea was infrequent, documented in two patients (two courses) and three patients (four courses), respectively. All other toxicity was grade 1 and grade 2. The combined objective response rate in 38 evaluable patients entered in both studies was 23.3% (six partial responses and one complete response). Stable disease was documented in 15 patients (39.5%). The median survival for the 42 patients entered in both trials was 6.9 months (95% confidence interval, 5.9-8.5 months). The objective response rate and median survival for the combined group is comparable with that reported for the etoposide, leucovorin, and 5-fluorouracil (ELF), and 5-fluorouracil and methotrexate (FMTX) regimens in a recently reported, multicenter, phase III study.

A phase I-II study of bi-weekly paclitaxel as first-line treatment in metastatic breast cancer.

BACKGROUND: Single-agent bi-weekly paclitaxel was studied as first-line metastatic treatment for breast cancer in a phase I-II trial. PATIENTS AND METHODS: Thirty-eight women with metastatic breast cancer were enrolled. Thirty-seven are evaluable for toxicity, 35 for response. RESULTS: The MTD was defined at 160 mg/m2 q two weeks with dose limiting toxicity in two patients consisting of hematological toxicity (1) and neurotoxicity (2). Twenty patients were treated at 150 mg/m2, the recommended dose. Response rates were two CRs and nine PRs (overall 61%) at the RD of 150 mg/m2 and three CRs and 11 PRs for an overall RR of 67% for the two top doses. CONCLUSIONS: The good drug tolerance, response rates, and convenience over weekly treatment suggest this may be a worthwhile regimen.

A phase I trial of high-dose paclitaxel, cyclophosphamide and mitoxantrone with autologous blood stem cell support for the treatment of metastatic breast cancer.

The aim of this phase I study was to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and efficacy of a new combination of cyclophosphamide (6 g/m2), mitoxantrone (70 mg/m2), with dose escalation of paclitaxel (TaxolR) at a starting dose of 250 mg/m2 given intravenously over 3 h in a transplantation setting. Patients with metastatic breast cancer and chemosensitive disease were eligible. The autologous blood stem cell re-infusion and subsequent recovery occurred in an out-patient setting. 50 patients were enrolled, but 10 withdrew. 40 completed the entire protocol. At 400 mg/m2 paclitaxel administered over 3 h, 3 of 6 patients experienced serious adverse events: approximately 20-40 min after completion of infusion, diaphoresis, bradycardia mild hypotension and diarrhoea occurred; 2 patients lost consciousness for a few minutes. An extended infusion schedule delivering 400 mg/m2 paclitaxel over 6 h rather than 3 h was initiated at this level without patients experiencing this DLT. At the next dose of 450 mg/m2 paclitaxel over 6 h, the same DLT was seen as at 400 mg/m2 paclitaxel over 3 h and, therefore, MTD was reached. Time to recovery for the absolute neutrophil count > or = 0.5 x 10(9)/l was 10-19 days (median 12 days); and for platelets > or = 20 x 10(9)/l was 18-20 days (median 11.5 days). 21 patients developed neutropenic fever that required intravenous antibiotics and re-admission; the transfusion frequency for packed red blood cell was 0-5 units (median 2 units) and for platelets, 1-5 encounters (median 2). 13 complete responses, 1 patient with no evidence of disease and 19 partial remissions were documented. The dose of 400 mg/m2 at an infusion rate of 6 h will be used for the ongoing phase II study to evaluate efficacy and toxicity further.

In vitro carboplatin-mesna interaction in aqueous solution, human plasma and urine.

The chemotherapeutic benefit of synergistic drug combinations and higher drug dosages has generated interest in the application of these regimens to cancer patients. A major obstacle in the application of these strategies to the treatment of cancer is the dose-limiting toxicities of drug combinations. Sodium 2-mercaptoethane-sulfonate (mesna), a chemoprotective drug, may reduce the nephrotoxicity of carboplatin [CBDCA, paraplatin, JM-8, cis-diammine (1,1-cyclobutane dicarboxylato) platinum II] when administered in combination chemotherapy. The purpose of this study was to evaluate, compare and contrast in vitro the interaction of mesna with carboplatin in aqueous solution, human plasma and urine. Carboplatin and mesna were incubated separately and together at clinically relevant concentrations in plasma and urine. The concentration of carboplatin was assayed by HPLC, and the decay of carboplatin alone and in combination with mesna was compared. The incubation of carboplatin with mesna in human plasma up to 8 days did not result in a statistically significant interaction: the half-life of carboplatin in plasma when it was combined with mesna was 1.62 +/- 0.08 (SE) days compared to 1.85+/- 0.04 (SE) days for carboplatin by itself. The incubation of drugs in fresh human urine up to 15 days gave a half-life of 3.43+/- 0.8 (SE) days for carboplatin alone and 2.78 +/- 0.7 (SE) days for carboplatin when it was combined with mesna. Our results show that carboplatin and mesna do not significantly interact in plasma. Although a statistically significant difference between the half-life of carboplatin and the half-life of the carboplatin/mesna combination is detected in urine, it is not likely to be clinically significant, as there is no significant interaction detected in the first 48 h). It is thus unlikely that mesna would substantially affect the pharmacokinetics of carboplatin when both are given together to patients as part of combination chemotherapy regimens.

Effectiveness of megestrol acetate in patients with advanced cancer: a randomized, double-blind, crossover study.

PURPOSE: To evaluate the effect of megestrol acetate at a lower dose than previously investigated on the symptoms of cachexia in patients with advanced cancer. METHODS: A total of 84 patients with advanced, solid tumours not responsive to hormone therapy were enrolled in this double-blind, crossover study. During phase 1, patients were randomly assigned to receive megestrol acetate (160 mg 3 times daily) for 10 days or placebo. During phase 2, after a 2-day washout period, patients received the alternate treatment for 10 days. Patients underwent daily assessments of activity, nausea, appetite and well-being by means of a visual analogue scale (VAS). In addition, nutritional status (weight, tricep skinfold measure, arm muscle circumference), energy intake, fatigue (Piper Fatigue Scale) and quality of life (Functional Living Index-Cancer [FLIC]) were assessed. RESULTS: Among the 53 evaluable patients megestrol acetate resulted in a significant improvement in appetite (p = 0.005), activity (p = 0.007) and well-being (p = 0.03). There was no significant change in the intensity of nausea, nutritional parameters, energy intake or FLIC scores. There was a significant improvement in 2 of the 3 factors measured by the Piper Fatigue Scale and in the overall fatigue score. Upon completion of the study, while still blind to the treatment condition, 30 patients indicated that they felt better overall after megestrol, 15 said they felt better after placebo, and 10 indicated no preference (p = 0.001). CONCLUSION: Treatment with megestrol acetate results in rapid and significant improvement of symptoms in terminally ill patients at lower doses than previously reported. The effects are not secondary to nutritional changes. The FLIC quality-of-life questionnaire was unable to detect these changes.

A multicentre phase II study of carboplatin and prolonged oral etoposide in the treatment of cancer of unknown primary site (CUPS).

Cisplatin-based combination chemotherapy is frequently used to treat patients with carcinoma of unknown primary site (CUPS). Response rates in the literature range from 12% to 26% and median survival from 5 to 7 months. The goal of this study was to evaluate the combination of carboplatin and prolonged oral etoposide in patients with CUPS, with the hope of minimizing toxicity but improving efficacy and convenience. Treatment consisted of carboplatin, 300 mg m(-2) on day 1, and oral etoposide 50 mg on days 1-20, every 4 weeks for up to nine cycles. A total of 33 patients were treated and all were evaluable for toxicity. Non-haematological toxicity was mild to moderate, with the exception of one case of grade 4 stomatitis. Grade 4 leucopenia was observed in eight (24%) patients and sepsis in four (12%), with two and possibly three treatment-related deaths. For the 26 patients evaluable for response, the response rate was 23% with responses lasting a median of 11 months (range 7-13 months), with one patient still responding at 12 months. An additional nine patients (35%) had stable disease. Median survival for all patients was 5.6 months (range 2 weeks to 33 months). The combination of carboplatin with prolonged oral etoposide has moderate activity similar to that of other platinum-based regimens and is a well tolerated, convenient, outpatient regimen. Dosing according to estimated creatinine clearance to achieve a carboplatin AUC of 6.0 mg ml(-1) min might have decreased the incidence of severe myelotoxicity without compromising the regimen's efficacy.

A phase I/II study of paclitaxel (TAXOL) and concurrent radiotherapy in advanced nonsmall cell lung cancer.

PURPOSE: The addition of chemotherapy to radical radiotherapy (XRT) has been shown to improve survival in locally advanced nonsmall cell lung cancer (9). Consequently, different chemotherapeutic regimens in combination with XRT are being evaluated in the treatment of this disease. Paclitaxel (TAXOL) may be a valuable drug in this situation as, in addition to a demonstrated activity in NSCLC, it has been shown to enhance the effect of radiation on cell lines in vitro. METHODS AND MATERIALS: Seventeen patients were enrolled onto a Phase I/II trial to determine the maximum tolerated dose of paclitaxel given by a 3-h infusion every 2 weeks throughout a 6-week course of XRT, 60 Gy in 30 daily fractions, in patients with Stage III NSCLC and then to describe the response rate of this combination in an expanded cohort of patients treated at the recommended phase II dose. Three patients were entered at each dose level (45, 90, 120, and 135 mg/m2), except for the 120 mg/m2 dose level, which was expanded to nine patients. RESULTS: The dose limiting toxicity was neutropenia--two of three patients treated at the 135 mg/m2 level experienced Grade 3 neutropenia on day 15, which precluded administration of scheduled chemotherapy. Esophagitis was mild to moderate, and although profound lymphopenia was observed at all dose levels, there was no evidence of associated opportunistic infections. Of the nine patients treated at the recommended Phase II dose of 120 mg/m2, there were one complete and six partial responses (response rate 78%). CONCLUSION: The combination of XRT, 60 Gy in 6 weeks and paclitaxel, 120 mg/m2 q 2 weeks, can be safely given to patients with NSCLC, and although it demonstrates activity in this situation, consideration should be given to the addition of other agents, such as platinum compounds.

Phase II study of a one hour paclitaxel infusion in combination with carboplatin for advanced non-small cell lung cancer.

PURPOSE: To determine the activity, toxicity, and optimal dose of paclitaxel when given by one hour infusion combined with carboplatin in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-seven previously untreated patients with stage IIIB or IV NSCLC were enrolled. Paclitaxel was administered by one hour infusion at a dose of 175 mg/m2 for the first cycle, and was escalated up to 255 mg/m2 over successive cycles if tolerated. In the absence of toxicity, the carboplatin dose was kept constant at an area under the concentration-time curve (AUC) of 6. Cycles were repeated at 3-week intervals until progression or intolerable toxicity occurred. RESULTS: Thirty-six patients were evaluable for toxicity and survival, and thirty-five for responses. The partial response rate was 10 of 35 (29%) and there were no complete responses. The median duration of response was 4.8 months (range 0.5-11.7 months). The median survival duration was 6.5 months, and 1 year survival was 31%. The mean paclitaxel dose was 188 mg/m2. Treatment was generally well tolerated. Four patients (11%) had febrile neutropenia. Five patients (14%) had grade 3 neuropathy, and 4 (11%) had grade 3 nausea and vomiting. Minor toxicities included alopecia, myalgias, arthralgias and stomatitis. CONCLUSIONS: Paclitaxel and carboplatin is a well-tolerated regimen that can safely be given by a one hour paclitaxel infusion. The modest response rate observed in this study may be due to either the low dose-intensity of paclitaxel or the short infusion duration. Further trials to optimize the relative doses of paclitaxel and carboplatin are needed.

Concurrent use of multiple chemotherapy resistance modulators with etoposide in patients with resistant malignancies.

Since chemotherapy resistance is probably multifactorial, we studied the toxicity and efficacy of adding to etoposide in sequence 5 resistance modulators in the treatment of resistant solid tumors. In cohort 1, metronidazole and ketoconazole were given with i.v. etoposide 100 mg/m(2)/day x 5 days. Because of excessive toxicity, cohort 2 received just metronidazole with etoposide, and metronidazole doses were reduced. Subsequent patient cohorts had the following drugs added to etoposide plus metronidazole: ketoconazole (cohort 3), dipyridamole (cohort 4), tamoxifen [cohort 5 (with etoposide 75 mg/m(2)/day) and 6 (with etoposide 60 mg/m(2)/day)], and cyclosporin (cohort 7). Hence, cohort 7 received daily x 5 i.v. etoposide 60 mg/m(2)/day plus 5 resistance modulators. Forty patients were treated, of whom 38 were evaluable for toxicity. Metronidazole resulted in augmentation of both central neurotoxicity and peripheral neuropathy. Sequential addition of each of dipyridamole, tamoxifen, and cyclosporin appeared to increase hematological toxicity. Some patients also experienced reversible hepatic and renal toxicity. Partial responses were seen in adrenocortical and small cell lung cancers, and minor responses with symptomatic improvement were seen in adrenocortical, small cell lung, non-small cell lung and colorectal carcinomas. Further evaluation of this approach may be warranted in patients with minimal prior chemotherapy exposure.

Paclitaxel plus hydroxyurea as second line therapy for non-small cell lung cancer.

We tested paclitaxel (Taxol) and low dose hydroxyurea as second line therapy in 30 patients with non-small cell lung cancer since both drugs are active against non-small cell lung cancer in other settings, and since hydroxyurea may reverse chemotherapy resistance by disrupting double minute chromosomes. Hydroxyurea 500 mg was given orally each Monday, Wednesday, Friday starting 1 week before paclitaxel, and continuing until removal from study. Paclitaxel 135 mg/m2 was given i.v. over > or = 1 h every 3 weeks with dexamethasone, diphenhydramine, and ranitidine. Patients could have paclitaxel doses escalated to 175 mg/m2 in course 2 and to 200 mg/m2 in course 3, where tolerated. Sixteen males and 14 females were treated. All patients had previously received a single cisplatin-based chemotherapy regimen and 23 had previously received radiotherapy. Twelve patients had adenocarcinomas, six had squamous cell carcinomas, and 12 had large cell carcinomas. Eight patients had Stage IIIb cancers and 22 had Stage IV. Paclitaxel doses were 135 mg/m2 in 56 courses, 175 mg/m2 in 24, and 200 mg/m2 in 15. Treatment was well tolerated. Median granulocyte nadirs were 2.5 (x 10(9)/l) for paclitaxel 135 mg/m2, 1.8 for 175 mg/m2, and 1.3 for 200 mg/m2. No patient developed febrile neutropenia, and none required a dose reduction. Two patients had reversible anaphylaxis. Other toxicities were quite tolerable. They included fatigue, myalgias, dizziness, paresthesias, diarrhea, alopecia, mucositis, flushing, headache, swollen red hands, and anxiety. One patient had a partial remission and 15 had stable disease (including six with minor responses). Median survival was 20 (95% CI, 12-34) weeks, with 19% of patients remaining alive at 1 year from initiation of treatment. This is a well-tolerated regimen with modest activity as second line chemotherapy for patients with non-small cell lung cancer previously treated with cisplatin regimens. Higher doses would be feasible and other strategies are now being explored.

In vitro cytotoxicity and differential cellular sensitivity of derivatives of diamino acids. I. N1-methyl, N1-allyl, N1-(2-chloroethyl) and N1-propargyl ureas.

The in vitro cytotoxicity and differential cellular sensitivity of a series of new N1-methyl, N1-allyl, N1-2-chloroethyl and N1-propargyl urea derivatives of diamino acids were determined in the National Cancer Institute's primary antitumor drug screen. The compounds tested showed an in vitro anticancer activity similar to commercialized nitrosoureas such as CCNU, BCNU, MeCCNU, chlorozotocin, streptozotocin and PCNU. The alkylating moiety of the ureas seems to play a role in the general selectivity of our compounds. The N1-methyl and N1-2-chloroethyl urea derivatives are more selective for central nervous system cell lines and the N1-allyl urea derivatives are more selective for lung cancer cell lines. The N1-propargyl ureas did not show any particular selectivity in the 60 human cell lines tested.

In vitro cytotoxicity and differential cellular sensitivity of derivatives of diamino acids. II. N1-methyl, N1-allyl, N1-(2-chloroethyl) and N1-propargyl nitrosoureas.

The in vitro cytotoxicity and differential cellular sensitivity of a series of new N1-methyl, N1-allyl, N1-2-chloroethyl and N1-propargyl nitrosourea derivatives of diamino acids were determined in the National Cancer Institute's primary antitumor drug screen. The compounds tested showed an in vitro anticancer activity similar to commercialized nitrosoureas such as CCNU, BCNU, MeCCNU, chlorozotocin, streptozotocin and PCNU. The alkylating moiety of the nitrosoureas seems to play a role in the general selectivity of our compounds. The N1-methyl and N1-2-chloroethyl nitrosourea derivatives are more selective for central nervous system cell lines, the N1-allyl nitrosourea derivatives are more selective for lung cancer cell lines and the N1-propargyl nitrosoureas are more selective for leukemia cell lines.

Synthesis and anti-HIV activity of new urea and nitrosourea derivatives of diamino acids.

A series of N1-methyl,N1-allyl,N1-(2-chloroethyl) and N1-propargyl urea and nitrosourea derivatives of diamino acids (L-ornithine and L-lysine) was synthesized and was shown to have weak activity in counteracting the cytopathic effects of the HIV-1 on a T4 lymphocyte cell line (CEM-IW). However, selected compounds may possess some immunomodulatory activity.

Synthesis and preliminary in vitro cytotoxicity evaluation of 1,3-bis-(2-propynyl)-1-nitrosourea (BPNU) and derivatives.

The in vitro cytotoxicity and differential cellular sensitivity of a series of new N1-(propargyl) nitrosourea derivatives, including 1,3-bis-(2-propynyl)-1-nitrosourea (BPNU), a carmustine (BCNU) analog, were determined in the National Cancer Institute's primary antitumor drug screen. BPNU has a level of cytotoxic activity comparable to BCNU, CCNU and Methyl-CCNU. Unexpectedly, the bi-substitution of BPNU at the amino N3 position produced an inactive compound. Compared to BCNU, BPNU has a marked specificity towards leukemic cells and could potentially be useful as an anti-leukemic agent. In this series, the N1-(propargyl) group seems to induce cell line specificity.

In vitro cytotoxicity and differential cellular sensitivity of new N-methyl and N-propargyl urea and nitrosourea derivatives of diamino acids against sixty human NCI tumor cell lines.

The in vitro cytotoxicity and differential cellular sensitivity of a series of new N-methyl and N-propargyl urea and nitrosourea derivatives of diamino acids were determined in the National Cancer Institute's primary antitumor drug screen. These compounds have a level of cytotoxic activity comparable to BCNU, CCNU and Methyl-CCNU. In this series of diamino acid derivatives, the N-nitroso group does not seems to be essential to the in vitro activity of these compounds. The N-Propargyl derivatives have shown significantly more differential cellular sensitivity than the N-Methyl derivatives. Hence, the N-Propargyl group seems to induce more cell line specificity in our compounds. Based on their in vitro cytotoxic activity and mostly their pattern of differential cellular sensitivity, two compounds described in this work have been selected by the NCI for further development. These compounds are currently being screened in animal models.