Tirapazamine plus cisplatin in advanced or recurrent carcinoma of the uterine cervix: a Southwest Oncology Group study.

The objective of this study was to determine objective response and overall survival (OS) and progression-free survival (PFS) following cisplatin plus tirapazamine treatment in eligible consenting patients with metastatic or recurrent squamous or adenosquamous carcinoma of the cervix. Treatment consisted of intravenous tirapazamine, 260 mg/m(2), followed by cisplatin, 75 mg/m(2), every 21 days for six cycles. Of 56 registered cases, 52 were evaluable for toxicity. There were six grade 4 toxicities (anemia [three], dyspnea [one], neutropenia/granulocytopenia [one], and dehydration [one]). Fifty-three patients were evaluable for response, OS, and PFS. The 6-month OS rate was 56.6% (95% CI 43.3-69.9%). The objective response rate was 32.1% (4 complete [2 confirmed and 2 unconfirmed] and 13 partial [8 confirmed and 5 unconfirmed]). Higher response rates (16/34 [47.1%] vs 1/19 [5.3%], P= 0.0018) were observed in patients who had not previously received radiation-sensitizing chemotherapy, as were OS and PFS (13.9 vs 4.0 months, P < 0.0001; 5.3 vs 1.8 months, P= 0.01). The OS was considered too low to warrant further testing in this disease setting. Despite this, tirapazamine plus cisplatin was active in patients who had not received cisplatin previously. Prior use of radiosensitizing chemotherapy impacted response and survival significantly and should be considered in future clinical trials.

NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen.

Studies show that high Akt activity in breast carcinoma is associated with endocrine therapy resistance. Breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions, and are resistant to the growth inhibitory effects of tamoxifen. Understanding the targets of Akt signaling mediating tamoxifen resistance is of clinical significance. One possible target is nuclear factor kappa B (NF-kappa B), a transcription factor that plays a critical role in resistance to apoptosis and the induction of angiogenesis and invasion. In the present study, we found that Akt activity correlated with phosphorylation of I kappa B (the negative regulator of NF-kappa B), NF-kappa B DNA binding and tamoxifen resistance in vivo. Importantly, we found that co-treatment with the NF-kappa B inhibitor, parthenolide, or overexpression of I kappa B superrepressor restored tamoxifen sensitivity to our refractory Akt MCF-7 cells. These data suggest that activation of NF-kappa B via the PI3K/Akt signaling pathway may be a significant mechanism for development of endocrine therapy resistance in breast cancer, and that inhibition of NF-kappa B may be an effective treatment strategy to limit the progression of this disease.

Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326).

OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response.

Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial.

PURPOSE: This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non--small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization. PATIENTS AND METHODS: Two hundred two patients received VC (vinorelbine 25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months. RESULTS: Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and neutropenia (P =.008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P =.001, P =.007), and grade 3 peripheral neuropathy was higher on the PC arm (P <.001). More patients on the VC arm discontinued therapy because of toxicity (P =.001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs. CONCLUSION: PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.

A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077.

This Phase I study was performed to evaluate the tolerability and pharmacokinetic behavior of MKT-077, a water soluble rhodacyanine dye analogue, which partitions into tumor cell mitochondria where it is thought to act as a metabolic poison, leading to G1 arrest and apoptosis. Thirteen patients with advanced solid malignancies were treated with MKT-077 administered as a 30-min i.v. infusion weekly for 4 weeks every 6 weeks at doses ranging from 42 to 126 mg/m2/week. The principal toxicity was renal magnesium wasting, which was dose-limiting (grade 3) in one patient at each of the 84- and 126-mg/m2 dose levels. The other three patients at the 126-mg/m2 dose level developed grade 2 hypomagnesemia, which was cumulative in nature, improved with i.v. magnesium supplementation, and was controlled in two patients by the administration of prophylactic magnesium before and after treatment with MKT-077. Given the requirement for extensive monitoring of serum magnesium levels, dose escalation >126 mg/m2 was not considered feasible. Thus, the recommended dose for disease-oriented studies with this schedule of MKT-077 is 126 mg/m2/week. Pharmacokinetic studies revealed a prolonged terminal half-life (37 +/- 17 h) and a large volume of distribution (685 +/- 430 liters/m2). Clearance averaged 39 +/- 13 liters/h/m2. Peak MKT-077 plasma concentrations (1.2 +/-0.31 to 6.3 +/- 5.3 microg/ml) exceeded the IC50 concentrations required for human CX-1 colon, MCF-breast, CRL-1420 pancreas, EJ bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 microg/ml). These results indicate that at the recommended dose level of 126 mg/m2/week of MKT-077, the toxicity profile was consistent with the preferential accumulation of the agent within tumor cell mitochondria, and biologically relevant plasma concentrations were achieved.

Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies.

PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m(2)/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl(S/F)) averaging 1.8 hours and 115 mL/min/m(2), respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in Cl(S/F) was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration( )(median 16 v 9.5 microg/mL, P =. 0084) and area under the concentration-time curve (median 36 v 23 microg-h/mL, P =.0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m(2)/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.

Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies.

PURPOSE: To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined. PATIENTS AND METHODS: Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m(2)/d, whereas the paclitaxel dose was fixed at 135 mg/m(2). In stage II, paclitaxel was increased to a target dose of 175 mg/m(2), and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently. RESULTS: Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Other toxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted. CONCLUSION: Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2)/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.

Phase II trial of biochemotherapy with interferon alpha, dacarbazine, cisplatin and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial.

The therapeutic benefit of adding interferon alpha (IFNalpha) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1) subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.

A phase I and pharmacokinetic study of losoxantrone and paclitaxel in patients with advanced solid tumors.

A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials.

Phase II trial of oral beta-all trans-retinoic acid in hepatocellular carcinoma (SWOG 9157).

Twenty-nine chemotherapy-naive patients with primary hepatocellular carcinoma were treated with oral beta-all trans-retinoic acid (retinoic acid, TRA 50 mg/m2 t.i.d.) on a 3-week on/one week off schedule until progression or grade 3 or 4 toxicity. Eligibility requirements allowed abnormal liver function tests as long as the creatinine and bilirubin levels were normal. No responses were seen and the median survival was four months. Grade 3 side effects occurred in II patients and grade 4 in four and included a wide range of toxicities. The results indicate that oral TRA is ineffective against primary hepatocellular carcinoma and suggest that dose-modification of this retinoid may be required in patients with significant malignant hepatic involvement.

Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors.

PURPOSE: Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2. This phase I trial was designed to identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitabine when both drugs were given together on a once-every-two-week schedule in patients with solid tumors. PATIENTS AND METHODS: A total of 37 patients were treated at nine different dose levels ranging from paclitaxel 75-175 mg/m2 administered over three hours followed by gemcitabinc 1500-3500 mg/m2 administered over 30-60 minutes. Both drugs were administered on day 1 of a 14-day cycle. Dose escalation was performed in a stepwise manner in which the dose of one drug was escalated while the dose of the other drug was kept constant. RESULTS: Dose limiting toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m2 and gemcitabine 3500 mg/m2 in the form of grade 4 neutropenia lasting for > or = 5 days (one patient) and grade 3 elevation of alanine aminotransferase (AST/SGPT) (one patient). An analysis of delivered dose intensity (DI) over the first three cycles revealed that higher dosages of both drugs were delivered at dose level 7, paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2 dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m2 and gemcitabine 3500 mg/m2. Partial responses were confirmed in two patients with transitional cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary. CONCLUSIONS: Paclitaxel and gemcitabine is a promising drug combination that can be administered safely and repetitively on an every-other-week schedule. Using this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2.

Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: Cisplatin has played a major role in the treatment of non-small-cell lung cancer (NSCLC). This randomized trial was performed by the Southwest Oncology Group (SWOG) to determine whether the combination of vinorelbine and cisplatin has any advantage with regard to response rate, survival, and time to treatment failure over single-agent cisplatin in the treatment of patients with advanced NSCLC. METHODS: Between October 1993 and April 1995, 432 patients with advanced stage NSCLC were randomized to receive arm I (cisplatin 100 mg/m2 every 4 weeks) or arm II (cisplatin 100 mg/m2 every 4 weeks and vinorelbine 25 mg/m2 weekly). All patients were chemotherapy-naive, had performance status (PS) 0 or 1, and had adequate hematologic, renal, and hepatic function. RESULTS: Four hundred fifteen patients were eligible and assessable. On arm I (cisplatin), there was a 12% partial response rate. Arm II (cisplatin and vinorelbine) had a 26% response rate (2% complete responses and 24% partial responses, P = .0002). There was a statistically significant advantage with regard to progression-free survival (median, 2 v 4 months; P = .0001) and overall survival (median, 6 v 8 months; P = .0018) for the cisplatin and vinorelbine arm. One-year survival was 20% for cisplatin alone and 36% for the combination arm. There was more hematologic toxicity on arm II of the study (81% grades 3 and 4 granulocytopenia v 5% on arm I). Other toxicities, such as renal insufficiency, ototoxicity, and nausea and vomiting, and neuropathy were similar. CONCLUSION: The results of this study indicate that the combination of cisplatin and vinorelbine is a superior treatment when compared with single-agent cisplatin in the treatment of advanced NSCLC. Cisplatin and vinorelbine is the new standard for SWOG against which new therapies will be evaluated.

The treatment of metastatic renal cell carcinoma patients with recombinant human gamma interferon.

PURPOSE: Activity has been reported in phase II single-center, open-label studies after administration of low-dose recombinant interferon gamma-1b (rIFN-gamma) to patients with metastatic renal cell carcinoma, with an overall objective response proportion of around 15%. To confirm these data and define the complete response rate, we conducted a multicenter open-label trial in which 204 patients with metastatic renal cell carcinoma were treated with rIFN-gamma. PATIENTS AND METHODS: Two hundred and seven patients (134 males, 73 females, mean age 59) were enrolled, and 202 were evaluable. rIFN-gamma, 60: microgram/m2, was administered subcutaneously once every 7 days until disease progression. RESULTS: There were three (1.5%) complete responses and three (1.5%) partial responses, for an overall response proportion of 3% (95% CI: 1.2%, 6.7%). The median response duration was 13.3 months (range: 2 to 23 months). The median survival was 13.4 months (5.5 months to 29.2 months). Three (1%) deaths were observed during the course of study; they were considered to be related to progressive metastatic renal cell carcinoma. Toxicity was minimal, with 14% of patients experiencing grade 3/4 toxicity. The most frequent adverse events were chills (59%), fever (58%), asthenia (53%), nausea (29%), and headache (18%). Multivariate analysis revealed that younger age, higher performance status, higher hemoglobin, and lower LDH were predictive of survival. DISCUSSION: Recombinant interferon gamma 1b has only minimal efficacy in the treatment of metastatic renal cell carcinoma. Pretreatment variables associated with increased survival were male sex, higher Karnofsky performance status, higher hemoglobin, and low LDH.

A phase I and translational study of sequential administration of the topoisomerase I and II inhibitors topotecan and etoposide.

Because topoisomerase (topo) I- and topo II-targeting agents exert their principal effects on the two major classes of enzymes involved in regulating DNA topology in the cell, there has been considerable interest in evaluating combinations of these classes of agents. In preclinical studies of inhibitors of topo I and topo II in combination, drug scheduling and sequencing have been critical determinants of antitumor activity, with a greater magnitude of cytotoxicity generally occurring when treatment with the topo I inhibitor precedes treatment with the topo II-targeting agent. The underlying mechanism that has been proposed to explain this schedule dependency is compensatory up-regulation of topo II and, therefore, enhanced cytotoxicity of topo II inhibitors in cells treated initially with topo I inhibitors. The feasibility of sequentially administering the topo I inhibitor topotecan (TPT) followed by the topo II inhibitor etoposide to patients with advanced solid malignancies was evaluated in this Phase I and translational laboratory study. Fifty patients with solid neoplasms were treated with TPT doses ranging from 0.17 to 1.05 mg/m2/day as a 72-h continuous (i.v.) infusion on days 1-3 followed by etoposide, 75 or 100 mg/m2/day as a 2-h i.v. infusion daily on days 8-10. The combined rate of severe neutropenia and thrombocytopenia was unacceptably high above the TPT (mg/m2/day)/etoposide (mg/m2/day) dose levels of 0.68/100 and 0.68/75 in minimally and heavily pretreated patients, respectively, and these dose levels are recommended for further disease-directed evaluations of TPT/etoposide on this administration schedule. Successive biopsies of accessible tumors were obtained for quantitation of topo I and II levels prior to and immediately after treatment with TPT and prior to and immediately after treatment with etoposide in seven patients. The results of these limited studies in tumors did not fully support the proposed mechanistic rationale favoring the development of this particular sequential TPT/etoposide regimen, because only two of the six patients' tumors in whom topo I was successively measured had either modest or substantial decrements in topo I levels following treatment with TPT, and the principal effect of interest, up-regulation of topo II following treatment with TPT, was clearly documented in the tumors of only one of six subjects in whom successive measurements of topo I were performed. Even in view of the notable objective antitumor activity in three subjects, including a complete response in a patient with colorectal carcinoma and partial responses in one patient each with non-small cell lung and gastric carcinomas, the toxicity and ancillary laboratory results do not provide substantial evidence that sequential treatment with TPT and etoposide might be more advantageous than either TPT or etoposide administered as a single agent.

A phase I and pharmacokinetic study of tallimustine [PNU 152241 (FCE 24517)] in patients with advanced cancer.

Tallimustine [PNU 152241 (FCE 24517)] is a synthetic derivative of the DNA minor groove binder distamycin A, in which the NH2-terminal formyl group is substituted by benzoyl mustard. In this Phase I clinical trial, patients with advanced solid tumors received i.v. bolus injections of tallimustine daily for 3 consecutive days. Patients were treated at six dosage levels of 33.3 micrograms/m2/day to 250 micrograms/m2/day for 3 consecutive days, with courses of therapy repeated every 28 days. Detailed pharmacokinetic blood sampling was performed during the first 3 days of the first course of tallimustine. The plasma samples were analyzed by high-performance liquid chromatography with UV detection. Forty-eight eligible patients were treated at all six dosage levels. The dominant dose-related toxicity of tallimustine was neutropenia, becoming dose limiting at 250 micrograms/m2/day. At this dosage level, one patient experienced febrile neutropenia, and a second patient died on study of indeterminate cause. Thrombocytopenia was not observed, and only 10 patients developed anemia < 8.0 gm/dl. Sporadic elevation of liver enzymes or bilirubin was observed but was not dose related. Pharmacokinetic analysis gave reliable results for 33 patients. For most patients, analysis of the data best fit a three-exponential model. Dose-related increases in areas under the concentration-time curve and end-of-infusion concentrations were observed. There was no significant plasma accumulation of tallimustine over the 3 days of administration. The terminal half-life of tallimustine in individual patients ranged from 6.83 to 39.02 h following the last dose. In summary, the recommended Phase II dosage for tallimustine is 200 micrograms/m2/day for 3 consecutive days every 28 days. Neutropenia is the principal toxicity of this agent at this dosage and schedule.

A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea.

Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2, 000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (Cmax) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for Cmax, which was 19. 5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at steady-state was 19.71 L/m2, whereas Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration-36. 84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment.

Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: a Southwest Oncology Group study.

PURPOSE: The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS: Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.

13-cis-retinoic acid or all-trans-retinoic acid plus interferon-alpha in recurrent cervical cancer: a Southwest Oncology Group phase II randomized trial.

PURPOSE: Preclinical and clinical data support the study of retinoids and interferon-alpha (IFN-alpha) in advanced squamous cell carcinoma of the uterine cervix (SCC). This phase II randomized trial of the Southwest Oncology Group sought to estimate the response rate for IFN-alpha plus either 13-cis-retinoic acid (13cRA) or all-trans-retinoic acid (ATRA) in women with recurrent cervical SCC. PATIENTS AND METHODS: Eligibility for this trial required bidimensionally measurable locally recurrent or metastatic squamous or adenosquamous carcinoma of the uterine cervix; SWOG performance status of

Teniposide (VM-26) as a single drug treatment for patients with extensive small cell lung carcinoma: a Phase II study of the Southwest Oncology Group.

BACKGROUND: Teniposide (VM-26) was reported to have activity in small cell lung carcinoma (SCLC). The authors performed a Phase II study of teniposide as a treatment for patients with previously untreated extensive SCLC. METHODS: The study was open to patients with a histologic or cytologic diagnosis of extensive SCLC who had not received prior radiation or chemotherapy. Patients with hematologic values below normal were considered eligible if the impaired bone marrow function was directly attributable to disease involvement. Treatment consisted of teniposide 60 mg/m2 given intravenously (i.v.) on Days 1-5 every 3 weeks. RESULTS: This study opened on September 15, 1988, closed permanently on November 15, 1990, and accrued 45 patients identified at 19 academic, military, and Community Clinical Oncology Program institutions affiliated with the Southwest Oncology Group. Of the 45 registered patients, 41 were eligible. Twenty eight (68%) were males and 13 (32%) were females; the median age was 64 years (minimum, 46 years; maximum, 83 years). Twenty-four patients (59%) had a performance status (PS) on the Zubrod scale of 0-1 and 17 cases (41%) had a PS of 2. Of the 41 eligible patients, 10 had confirmed partial responses (24%) (95% confidence interval, 12-40%). The median survival was 7 months. The significant toxicities noted were Grade 4 leukopenia and/or granulocytopenia, experienced by 15 patients; 1 of these patients also had Grade 4 hyponatremia. One patient died of a respiratory infection. CONCLUSIONS: When administered according to the dosage and schedule selected for this study (60 mg/m2 i.v. on Days 1-5 every 3 weeks), teniposide as a single agent had modest activity in extensive small cell lung carcinoma. The toxicities observed in this study were acceptable.