Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer.

SP1049C is a novel anticancer agent containing doxorubicin and two nonionic pluronic block copolymers. In preclinical studies, SP1049C demonstrated increased efficacy compared to doxorubicin. The objectives of this first phase I study were to determine the toxicity profile, dose-limiting toxicity, maximum tolerated dose and pharmacokinetic profile of SP1049C, and to document any antitumour activity. The starting dose was 5 mg m(-2) (doxorubicin content) as an intravenous infusion once every 3 weeks for up to six cycles. A total of 26 patients received 78 courses at seven dose levels. The dose-limiting toxicity was myelosuppression and DLT was reached at 90 mg m(-2). The maximum tolerated dose was 70 mg m(-2) and is recommended for future trials. The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin. Evidence of antitumour activity was seen in some patients with advanced resistant solid tumours. Phase II trials with this agent are now warranted to further define its antitumour activity and safety profile.

A cancer research (UK) randomized phase II study of idoxifene in patients with locally advanced/metastatic breast cancer resistant to tamoxifen.

Idoxifene is a novel selective oestrogen receptor modulator (SERM) which had greater binding affinity for the oestrogen receptor (ER) and reduced agonist activity compared with tamoxifen in preclinical studies. In a randomized phase II trial in 56 postmenopausal patients with progressive locally advanced/metastatic breast cancer we assessed whether idoxifene showed evidence of activity compared with an increased 40 mg/day dose of tamoxifen in patients who had previously demonstrated resistance to the standard 20 mg/day dose of tamoxifen. Of 47 patients eligible for response (25 idoxifene, 22 tamoxifen), two partial responses and two disease stabilizations (SD) for >6 months were seen with idoxifene (overall clinical benefit rate 16%, 95% CI 4.5-36.1%). The median duration of clinical benefit was 9.8 months. In contrast, no objective responses were seen with the increased 40 mg/day dose of tamoxifen, although two patients had SD for 7 and 14 months (clinical benefit rate 9%, 95% CI 1.1-29.2%). Idoxifene was well tolerated and the reported possible drug-related toxicities were similar in frequency to those with tamoxifen (hot flushes 13% vs 15%, mild nausea 20% vs 15%). Endocrine and lipid analysis in both groups showed a similar significant fall in serum follicle-stimulating hormone and luteinizing hormone after 4 weeks, together with a significant rise in sex hormone binding globulin levels and 11% reduction in serum cholesterol levels. In conclusion, while idoxifene was associated with only modest evidence of clinical activity in patients with tamoxifen-resistant breast cancer, its toxicity profile and effects on endocrine/lipid parameters were similar to those of tamoxifen.

Infrared body temperature measurement of mice as an early predictor of death in experimental fungal infections.

Temperatures of mice were measured using an infrared high performance non-contact thermometer, after the device had been calibrated using implantable microchips containing temperature transponders. Mice were infected with three species of Candida (isolates) and the resultant disseminated infections monitored. Mouse temperatures could be reliably measured using the infrared device and this measurement caused little distress to the mice. We were further able to demonstrate that mice rarely recovered if their body temperature dropped below 33.3 degrees C (sensitivity 68%, specificity 97%). Adoption of a 33.3 degrees C endpoint in fungal sepsis experiments measured by infrared non-contact thermometer would significantly reduce the suffering in the terminal stages of this type of infection model.

Effect of temozolomide on central nervous system relapse in patients with advanced melanoma.

Temozolomide has shown efficacy in the treatment of metastatic melanoma similar to that of dacarbazine (DTIC), the standard chemotherapy, but with the added benefit of penetration into the central nervous system (CNS). Isolated CNS relapse is increasingly a problem for patients who respond to biochemotherapy. By replacing DTIC with temozolomide in treatment regimens, the incidence of CNS relapse might be reduced. This hypothesis is difficult to test in a prospective randomized controlled trial because of the large number of patients that would be required. We have examined this question in a retrospective case control study, observing the rates of CNS relapse in advanced metastatic melanoma patients responding to DTIC- or temozolomide-based chemotherapy in three institutions. Twenty-one DTIC and 20 temozolomide responders were identified, and have been followed up for a median of 19.0 months (range 6.0-74.3 months). CNS relapse occurred in nine DTIC- and two temozolomide-treated patients, a statistically significant difference in favour of the new agent (P = 0.03). These results support the investigation of temozolomide as a replacement for DTIC in systemic treatment regimens for melanoma.

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m(2)24 h(-1), dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml(-1)min(-1), Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml(-1)min(-1). Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted.

O6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma.

Resistance of tumour cells to methylating and monochloroethylating agents in vitro and in vivo has been linked to levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In a clinical trial of temozolomide in advanced malignant melanoma, the relationship between pretreatment MGMT levels in biopsies of cutaneous tumours and involved lymph nodes and clinical response to the drug has been studied. Among 50 evaluable patients, there were three complete responses (CR), four partial responses (PR), six with stable disease (SD) and 37 with progressive disease (PD), with an overall response rate of 14%. In 33 patients in whom MGMT level and clinical response could be evaluated, the tumour MGMT levels (fmol mg(-1) protein) were: CR, 158 +/- 119; PR, 607 +/- 481; NC, 171 +/- 101; PD, 185 +/- 42.3. Thus, measurements of pretreatment levels of MGMT in melanoma did not predict for response to temozolomide.

Phase I trial of temozolomide using an extended continuous oral schedule.

Temozolomide, a methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanoma, and mycosis fungoides and is presently administered as a 5-day oral schedule every 4 weeks. This Phase I study aimed to determine the maximum tolerated dose of temozolomide administered as a single oral daily dose for a continuous 6- or 7-week period, evaluate the plasma pharmacokinetics on this schedule, and compare total plasma exposure over 7 weeks with the conventional 5-day regimen. Twenty-four patients with varying tumor types (17 of 24 gliomas) received temozolomide. All had clinically evaluable, refractory disease; normal renal, hepatic, and bone marrow function; and WHO performance status < or = 2. Temozolomide was administered at 50 mg/m2/day, increasing by 25 mg/m2/day/cohort until at 100 mg/m2/day grade 4 myelotoxicity forced dose reductions to 85 mg/m2/day, then 75 mg/m2/day. At 75 mg/m2/day the regimen was extended to 7 weeks, allowing the future potential combination with irradiation for primary gliomas. Patient responses (standard Union International Contre Cancer criteria; for gliomas objective response) and toxicity were assessed. Temozolomide plasma pharmacokinetics were determined on day 1 and at the beginning of the final week of administration (n = 5). The most frequent toxicities were myelosuppression and grades 1 and 2 nausea and vomiting. Grade 4 leucopenia and thrombocytopenia occurred in one of four patients receiving 100 mg/m2/day temozolomide and in one of seven patients receiving 85 mg/m2/day. These hematological toxicities did not exceed grade 2 in 10 patients receiving 75 mg/m2/day temozolomide. One of 4 malignant melanoma patients and 7 of 17 glioma patients (41%) demonstrated tumor responses. The overall response rate for this prolonged schedule was 33% (objective response, 7 of 24 patients; partial response, 1 of 24 patients); also, 6 of 17 glioma patients maintained SD. Peak plasma temozolomide concentrations were obtained 30-90 min after oral administration. Elimination in plasma was best described by a monoexponential equation with an elimination half-life of 96 +/- 16 min. No plasma accumulation of temozolomide occurred. Toxicity was greatest in higher dose cohorts, with a resultant maximum tolerated dose of 85 mg/m2/day, whereas lower dose cohorts tolerated the schedule well. The area under the temozolomide plasma versus time curve was noncumulative between the first and last week of the schedule. Temozolomide administration of 75 mg/m2/day over a 7-week period permits a 2.1-fold greater drug exposure/4 weeks in comparison with the 5-day schedule of 200 mg/m2/day repeated every 28 days. The overall response rate was 33% (glioma patients, 41% and a further 25% SD). Temozolomide (75 mg/m2/day) for 7 weeks is the recommended starting dose for further assessment of this schedule.

Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma.

PURPOSE: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. METHODS: The treatment schedule was 150-200 mg/m2 per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. RESULTS: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. CONCLUSIONS: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas.

Etoposide phosphate infusion with therapeutic drug monitoring in combination with carboplatin dosed by area under the curve: a cancer research campaign phase I/II committee study.

The area under the plasma concentration-time curve (AUC) following an intravenous dose of etoposide varies considerably among patients, which in part contributes to the unpredictability of toxicity and response seen in individual patients. This study evaluated the utility of therapeutic drug monitoring of etoposide in reducing the interpatient variability of etoposide steady-state concentrations during prolonged infusion. The etoposide prodrug etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) was administered by infusion using an adaptive dosing strategy. It was given in combination with carboplatin, which was dosed on an AUC basis. Patients with histologically or cytologically proven small cell lung cancer were treated with etoposide phosphate by continuous 120-hour infusion and carboplatin at a dose calculated by the Calvert formula to give an AUC of 5 mg/ mL.min. Blood samples were taken on days 2 through 5 of each treatment cycle, and high-performance liquid chromatography was used to measure the plasma etoposide concentration. The resultant concentrations were compared with target concentrations of 1 or 2 micrograms/mL and these data were used to calculate the rate of infusion for the following 24 hours. In the first cohort, the target etoposide concentration was 1 microgram/mL, and this was achieved (mean +/- SD = 1.05 +/- 0.24 micrograms/mL) by infusing etoposide phosphate doses of 21 to 109 mg (15 to 68 mg/m2) per day. In the second cohort, the target concentration of 2.0 micrograms/mL was achieved (mean +/- SD = 2.05 +/- 0.31 micrograms/mL) with infused etoposide phosphate doses of 69 to 193 mg (41 to 114 mg/m2) per day. This technique reduced the variation in plasma levels and resulted in predictable hematologic toxicity. Cumulative hematologic toxicity necessitated an extension of the treatment cycle from 3 to 4 weeks, however. Of six evaluable patients, two had a complete response and one had a partial response. Therapeutic drug monitoring was shown to reduce the interpatient variation in the plasma etoposide concentration by half and shows promise for individualizing treatment with combination chemotherapy. Exploiting the known relationships between the pharmacokinetics and pharmacodynamics of these two drugs by using therapeutic drug monitoring may lead to better therapeutic safety and efficacy.

The Charing Cross Hospital experience with temozolomide in patients with gliomas.

Temozolomide, a new oral cytotoxic agent, was given to 75 patients with malignant gliomas. The schedule used was for the first course 150 mg/m2 per day for 5 days (i.e. total dose 750 mg/m2), escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2 per day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4-week intervals. There were 27 patients with primary disease treated with two courses of temozolomide prior to their radiotherapy and 8 (30%) fulfilled the criteria for an objective response. There were 48 patients whose disease recurred after their initial surgery and radiotherapy and 12 (25%) fulfilled the criteria for an objective response. This gave an overall objective response rate of 20 (27%) out of 75 patients. Temozolomide was generally well tolerated, with little subjective toxicity and predictable myelosuppression. However, the responses induced with this schedule were of short duration and had relatively little impact on overall survival. In conclusion, temozolomide given in this schedule has activity against high grade glioma. However, studies evaluating chemotherapy in primary brain tumours should include a quality-of-life/performance status evaluation in addition to CT or MRI scanning assessment.

Phase I trial of elactocin.

Elactocin is a novel anti-tumour antibiotic which has potent activity in vitro against a range of tumours. This phase I trial of elactocin identified the dose-limiting toxicity as profound anorexia and malaise. The schedules used included 1 h infusion 3 weekly, 24 h infusion 3 weekly, 1 h infusion daily x 5 (3 weekly), 1 h infusion weekly and finally continuous 5 day intravenous infusion. On all these schedules dose-limiting toxicity was the same and as no partial or complete responses were identified, we do not recommend that further trials of elactocin are performed.

Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics. PATIENTS AND METHODS: Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 2-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m2/d. PSC 833 was administered from day 2 as a 2-hour loading dose and as a 5-day continuous infusion. Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion). RESULTS: Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses > or = 6.6 mg/kg/d by continuous infusion. Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUC) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and an insignificant increase in alpha half-life (t 1/2 alpha) and significant increase of beta half-life (t 1/2 beta) of 19% and 77%, respectively. CONCLUSION: PSC 833 can be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days. PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833.

Phase II trials of rhizoxin in advanced ovarian, colorectal and renal cancer.

Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug was fairly well tolerated, but the response rate was disappointing: 0/18, colorectal cancer; 0/18, renal cancer; 1 partial response (PR)/17, ovarian cancer.

Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma.

Temozolomide, an imidazotetrazine derivative, was given to 18 patients with low-grade non-Hodgkin's lymphoma (NHL) at a dose of 750 mg m-2 orally, divided over five consecutive days, escalated to 1000 mg m-2 over 5 days (i.e. 200 mg m-2 day-1) if no significant myelosuppression was noted at day 22 of the 28 day cycle. Fifty-six treatment cycles were given to 18 patients. The drug was well tolerated. Only one partial tumour response was documented. The patients were heavily pretreated but had chemoresponsive disease, as shown by a response rate of 69% among 13 patients who went on to receive alternative cytotoxic regimens. We conclude that temozolomide given in this schedule is inactive in previously treated low-grade NHL.

Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma.

PURPOSE: Sixty patients with metastatic melanoma were treated in a phase II study with the imidazotetrazine derivative temozolamide to assess further the efficacy demonstrated in previous phase I studies. PATIENTS AND METHODS: Fifty-five of 56 eligible patients were assessable for toxicity and 49 for response. The patients received temozolomide 150 mg/m2/d over 5 successive days orally (total dose, 750 mg/m2) in the first course. Courses were repeated every 4 weeks and the dose was escalated to 200 mg/m2/d x 5 (total dose, 1 g/m2) after the first course if toxicity was acceptable. Patients were all chemotherapy-naive, except for two who had previously received interferon alfa and one who had received interleukin-2 (the latter patient had also received two phase I drugs some time previously). RESULTS: A complete response (CR) was documented in three patients (all with lung metastases) and a partial response (PR) in nine patients (21% CR plus PR rate). Seven of 56 patients were not assessable for response because of early death or deterioration. The overall response rate excluding these patients is 12 of 49 (24%). The median response duration was 6 months (range, 2.5 to 22+). Toxicity of the regimen, which was mainly hematopoietic, was low. The median survival duration for all patients was 5.5 months (range, 0.5 to 29.5). For responders, the median survival duration was 14.5 months (range, 3 to 28+), with four patients still alive. CONCLUSION: Temozolomide in the schedule used has as good activity in chemotherapy-naive metastatic melanoma as the other most active agents currently in use. Further studies of the drug on its own and in combination with other agents is recommended.

A Cancer Research Campaign (CRC) phase II trial of CB10-277 given by 24 hour infusion for malignant melanoma.

The decarbazine analogue CB10-277 has been investigated for anti-tumour activity in a phase II study on malignant melanoma. Treatment was administered as a slow infusion of 12,000 mg m-2 over 24 h and repeated every 3 weeks. A total of 28 patients were entered into the study, of whom 23 were eligible for review. A total of 64 courses was given. There was one objective partial response in 22 patients assessable for response. The major toxicities were leucopenia and thrombocytopenia. CB10-277 in this schedule therefore does not appear to have major activity in melanoma.

The long-term outcome of patients who relapse after chemotherapy for non-seminomatous germ cell tumours.

OBJECTIVE: To examine the long-term survival of a group of patients with non-seminomatous germ cell tumours, who relapse after chemotherapy and are retreated with a cisplatin and etoposide-based regimen. PATIENTS AND METHODS: At the Charing Cross Hospital between 1979 and 1988 38 patients in relapse were seen. The median interval after primary therapy was 8 months. They were treated with an intensive cisplatin and etoposide-based regimen with cycles repeated at 7-10 day intervals, and with surgery in 22 patients. RESULTS: Forty-seven per cent of patients entered a second complete remission and 88% of these remain disease free. The overall survival was 46% with a median follow-up of more than 4.3 years. Surgery was performed in 14 of 18 patients who entered a second complete remission. Adverse risk factors before initial chemotherapy and the time to relapse did not predict outcome but patients with unresectable radiological masses after relapse therapy had a poor outcome despite normalization of serum tumour markers. The tumours of 68% of patients initially treated with cisplatin-based regimens and 62% of patients who also received etoposide remained responsive to conventional doses of these drugs at relapse. CONCLUSIONS: This study demonstrates that there is a group of patients with relapsed teratoma who can be cured without the need for very high dose chemotherapy and autologous bone marrow rescue.

Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours.

Temozolomide, a new oral cytotoxic agent, has been given to 28 patients with primary brain tumours. Treatment was given at a dose of 150 mg/m2/day for 5 days (i.e. total dose 750 mg/m2) escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2/day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4 week intervals. A major improvement in computer tomography (CT) scan was noted in 5/10 patients with astrocytomas recurrent after radiotherapy, with a major clinical improvement but minor improvement on CT scan in one further patient. Reduction in the size of the CT lesion was also observed in 4/7 patients with newly diagnosed high grade astrocytomas given 2-3 courses of temozolomide prior to irradiation. 1 patient with recurrent medulloblastoma had a clinical response in bone metastases. Temozolomide was well tolerated with little subjective toxicity and usually predictable myelosuppression and is a promising new drug in the treatment of primary brain tumours.

Computer system for assisting with clinical interpretation of tumour marker data.

OBJECTIVE: To design and evaluate a computer advisory system for the treatment of gestational trophoblastic tumour. DESIGN: A comparison of clinicians' treatment decisions with those of the computer system. Two datasets were used: one to calibrate the system and one to independently evaluate it. SETTING: Department of medical oncology. PATIENTS: Computerised records of 290 patients with low risk gestational trophoblastic tumour for whom the advisory system could predict the adequacy of treatment. The calibration set comprised patients admitted during 1979-86(227) and the test set patients during 1986-89(63). MAIN OUTCOME MEASURES: The system's accuracy in predicting need to change treatment compared with clinicians' actions. The mean time faster that the system was in predicting the need to change treatment. RESULTS: On the calibration dataset the system was 94% (164/174) accurate in predicting patients whose treatment was adequate, recommending change when none occurred in only 10 (6%) patients. In patients whose treatment was changed the system recommended change earlier than clinicians in 39/53 cases (74%), with a mean time advantage of 14.9 (SE 2.02) days. On the test dataset the system had an accuracy of 91% (31/34) in predicting treatment adequacy and a false positive rate of 9% (3/34). The system recommended change earlier than clinicians in 22/29 cases (76%), with a mean time advantage of 12.5 (2.22) days. CONCLUSIONS: The computer advisory system could improve patient management by reducing the time spent receiving ineffective treatment. This has implications for both patient time and clinical costs.

Phase II trials of fosquidone, (GR63178A), in colorectal, renal and non-small cell lung cancer. CRC Phase II Clinical Trials Committee.

A total of 61 eligible patients with metastatic cancer have been treated in a series of Phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were colorectal (23), renal (21), and non small cell lung (17). No patient had received prior chemotherapy. The drug was given intravenously as a 20 min infusion at the dose of 120 mg-2 on days 1 to 5 every 3 weeks. Treatment was well tolerated; the only significant side effects being mild nausea and generalised musculo-skeletal pains. Response was assessed after two cycles of therapy. No patient achieved an objective partial response. A total of nine patients demonstrated stable disease for a median duration of 11 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.